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Ghorab BEA, Liu T, Ying M, Wang P, Qin M, Xing J, Wang H, Xu F. Advances in the Drug Development and Quality Evaluation Principles of Oncolytic Herpes Simplex Virus. Viruses 2025; 17:581. [PMID: 40285023 PMCID: PMC12031214 DOI: 10.3390/v17040581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/07/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Oncolytic herpes simplex virus (oHSV) represents a promising therapeutic approach to treating cancers by virtue of its selective replication in and lysis of tumor cells, with stimulation of host antitumor immunity. At present, four OV drugs have been approved for the treatment of cancers worldwide, two of which are oHSV drugs that have received extensive attention, known as T-VEC and Delytact. This review discusses the history, mechanism of action, clinical development, quality control, and evaluation principles of oHSV products, including viral species and genetic modifications that have improved these products' therapeutic potential, limitations, and future directions. Integration of oHSVs with immunotherapeutic agents and conventional therapies has a promising future in the field of treatment of malignant tumors. Although much progress has been achieved, there is still much work to be done regarding the optimization of treatment protocols and the quality control of oncolytic virus drugs. The approval of various oncolytic virus therapies underlines their clinical relevance, safety, and efficacy, thereby paving the way for further research aimed at overcoming the existing limitations and enhancing patient responses.
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Affiliation(s)
- Basma Eid Abdullah Ghorab
- Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (B.E.A.G.); (T.L.); (J.X.)
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Guangdong Provincial Key Laboratory of Viral Biotechnology and Application, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tongtan Liu
- Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (B.E.A.G.); (T.L.); (J.X.)
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Guangdong Provincial Key Laboratory of Viral Biotechnology and Application, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Min Ying
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
- Department of Anesthesiology, Second Affiliated Hospital, Third Military Medical University, Chongqing 400037, China
| | - Ping Wang
- Shenzhen Institute for Drug Control, Shenzhen 518057, China; (P.W.); (M.Q.)
| | - Meirong Qin
- Shenzhen Institute for Drug Control, Shenzhen 518057, China; (P.W.); (M.Q.)
| | - Jiayong Xing
- Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (B.E.A.G.); (T.L.); (J.X.)
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Guangdong Provincial Key Laboratory of Viral Biotechnology and Application, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huadong Wang
- Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (B.E.A.G.); (T.L.); (J.X.)
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Guangdong Provincial Key Laboratory of Viral Biotechnology and Application, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fuqiang Xu
- Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (B.E.A.G.); (T.L.); (J.X.)
- NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Guangdong Provincial Key Laboratory of Viral Biotechnology and Application, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
- Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
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Zhu Y, Zhang X, Jin J, Wang X, Liu Y, Gao J, Hang D, Fang L, Zhang H, Liu H. Engineered oncolytic virus coated with anti-PD-1 and alendronate for ameliorating intratumoral T cell hypofunction. Exp Hematol Oncol 2025; 14:16. [PMID: 39955603 PMCID: PMC11829442 DOI: 10.1186/s40164-025-00611-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 02/07/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Glioblastoma is a highly aggressive and devastating primary brain tumor that is resistant to conventional therapies. Oncolytic viruses represent a promising therapeutic approach for glioblastoma by selectively lysing tumor cells and eliciting an anti-tumor immune response. However, the clinical efficacy of oncolytic viruses is often hindered by challenges such as short persistence, host antiviral immune responses, and T cell dysfunction. METHODS We have developed a novel therapeutic strategy by "dressing" oncolytic viruses with anti-PD-1 antibodies and alendronate (PD-1/Al@OV) to prevent premature clearance of the oncolytic viruses and enhance T cell function, thereby improving immunotherapy outcomes against glioma. RESULTS We found that in the high reactive oxygen species environment of the tumor, PD-1/Al@OV disassembled to release oncolytic viruses, anti-PD-1, and alendronate. The released anti-PD-1 blocked the PD-1/PD-L1 pathway, activating T cells; the alendronate eliminated tumor-associated macrophages, increasing the concentration of oncolytic viruses; and the oncolytic viruses directly lysed cancer cells, enhancing intratumoral T cell infiltration. CONCLUSION This approach effectively improved the immunosuppressive microenvironment of glioblastoma and achieved a robust anti-tumor effect. Consequently, this study presents a novel strategy for immune combination therapy and the improvement of the glioblastoma immune microenvironment, thereby offering new prospects for the clinical application of oncolytic viruses.
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Affiliation(s)
- Yufu Zhu
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China.
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, No.99 Huaihai West Road, Xuzhou, 221002, China.
| | - Xuefeng Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China
| | - Jiaqi Jin
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, No.99 Huaihai West Road, Xuzhou, 221002, China
| | - Xiaoqian Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China
| | - Yang Liu
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155, Nanjing Bei Street, Shenyang, 110001, China
| | - Jian Gao
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China
| | - Diancheng Hang
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China
| | - Lin Fang
- Cancer Institute, Xuzhou Medical University, No. 209, Tongshan Road, Xuzhou, 221004, China.
| | - Hengzhu Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China.
- Department of Neurosurgery, The Yangzhou Clinical Medical College of Xuzhou Medical University, Yangzhou University, No. 98, Nantong West Road, Yangzhou, 225009, China.
| | - Hongmei Liu
- Institute of Nervous System Diseases, Xuzhou Medical University, No.84 Huaihai West Road, Xuzhou, 221002, China.
- Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088, Xueyuan Avenue, Shenzhen, 518055, China.
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3
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Zambom-Ferraresi F, Zambom-Ferraresi F, Izco M, Martínez-Velilla N, Extramiana L, Fernández-Irigoyen J, Santamaría E, Llamas-Urbano A, Hanaee Y, Martinez-Moreno JM, Barbarroja N, Pérez-Sánchez C. Monitoring Cerebrospinal Fluid Inflammatory Mediators by Olink Target 48 Cytokine Panel. Methods Mol Biol 2025; 2914:51-64. [PMID: 40167910 DOI: 10.1007/978-1-0716-4462-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The diagnosis and monitoring of neurological disorders are challenging due to their complexity and the difficulty of obtaining samples of damaged tissue while the patient is alive. Cerebrospinal fluid (CSF) is an excellent biofluid for conducting diagnostic and monitoring studies because it is in direct contact with the brain, allowing for the analysis of secreted proteins and peptides associated with various neurological disorders.The Proximity Extension Assay, which combines antibodies with oligonucleotides to detect proteins via qPCR, is revolutionizing the field of biomarker identification. The Olink Target 48 Cytokine Panel is an optimal tool for evaluating the inflammatory profile of CSF samples, requiring only one microliter. The workflow involves incubation with antibody-linked oligonucleotides, extension, amplification through a PCR assay, and detection using microfluidic qPCR, enabling precise and accurate quantification of cytokine levels in pg/mL. This approach offers valuable insights into inflammatory processes within the CSF, serving as a robust tool for studying and understanding inflammation in neurological contexts.
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Affiliation(s)
- Fabricio Zambom-Ferraresi
- Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Navarrabiomed, Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
- CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Fabiola Zambom-Ferraresi
- Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Navarrabiomed, Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Maite Izco
- Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Navarrabiomed, Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Nicolás Martínez-Velilla
- Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Navarrabiomed, Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
- CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Leire Extramiana
- Clinical Neuroproteomics Laboratory, Proteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Joaquín Fernández-Irigoyen
- Clinical Neuroproteomics Laboratory, Proteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Enrique Santamaría
- Clinical Neuroproteomics Laboratory, Proteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | | | - Yasin Hanaee
- Cobiomic Bioscience. EBT University of Cordoba/IMIBIC, Cordoba, Spain
| | | | - Nuria Barbarroja
- Cobiomic Bioscience. EBT University of Cordoba/IMIBIC, Cordoba, Spain
- Rheumatology Unit/Reina Sofia Hospital/University of Cordoba/IMIBIC, Cordoba, Spain
| | - Carlos Pérez-Sánchez
- Cobiomic Bioscience. EBT University of Cordoba/IMIBIC, Cordoba, Spain.
- Rheumatology Unit/Reina Sofia Hospital/University of Cordoba/IMIBIC, Cordoba, Spain.
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Feldman L. Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments. Front Immunol 2024; 15:1384249. [PMID: 38994360 PMCID: PMC11238147 DOI: 10.3389/fimmu.2024.1384249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/10/2024] [Indexed: 07/13/2024] Open
Abstract
Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues for GBM treatment. However, challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness hinder their effectiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.
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Affiliation(s)
- Lisa Feldman
- Division of Neurosurgery, City of Hope National Medical Center, Duarte, CA, United States
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5
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Kappel AD, Jha R, Guggilapu S, Smith WJ, Feroze AH, Dmytriw AA, Vicenty-Padilla J, Alcedo Guardia RE, Gessler FA, Patel NJ, Du R, See AP, Peruzzi PP, Aziz-Sultan MA, Bernstock JD. Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era. Cancers (Basel) 2024; 16:1594. [PMID: 38672676 PMCID: PMC11049132 DOI: 10.3390/cancers16081594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.
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Affiliation(s)
- Ari D. Kappel
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Rohan Jha
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
| | - Saibaba Guggilapu
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
| | - William J. Smith
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Abdullah H. Feroze
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Adam A. Dmytriw
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Juan Vicenty-Padilla
- Neurosurgery Section, School of Medicine University of Puerto Rico, Medical Sciences Campus, San Juan P.O. Box 365067, Puerto Rico (R.E.A.G.)
| | - Rodolfo E. Alcedo Guardia
- Neurosurgery Section, School of Medicine University of Puerto Rico, Medical Sciences Campus, San Juan P.O. Box 365067, Puerto Rico (R.E.A.G.)
| | - Florian A. Gessler
- Department of Neurosurgery, Rostock University Hospital, 18057 Rostock, Germany
| | - Nirav J. Patel
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Rose Du
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Alfred P. See
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Pier Paolo Peruzzi
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Mohammad A. Aziz-Sultan
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Joshua D. Bernstock
- Harvard Medical School, Boston, MA 02115, USA; (A.D.K.); (S.G.); (R.D.); (A.P.S.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
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Calderón-Peláez MA, Maradei Anaya SJ, Bedoya-Rodríguez IJ, González-Ipuz KG, Vera-Palacios D, Buitrago IV, Castellanos JE, Velandia-Romero ML. Zika Virus: A Neurotropic Warrior against High-Grade Gliomas-Unveiling Its Potential for Oncolytic Virotherapy. Viruses 2024; 16:561. [PMID: 38675903 PMCID: PMC11055012 DOI: 10.3390/v16040561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 04/28/2024] Open
Abstract
Gliomas account for approximately 75-80% of all malignant primary tumors in the central nervous system (CNS), with glioblastoma multiforme (GBM) considered the deadliest. Despite aggressive treatment involving a combination of chemotherapy, radiotherapy, and surgical intervention, patients with GBM have limited survival rates of 2 to 5 years, accompanied by a significant decline in their quality of life. In recent years, novel management strategies have emerged, such as immunotherapy, which includes the development of vaccines or T cells with chimeric antigen receptors, and oncolytic virotherapy (OVT), wherein wild type (WT) or genetically modified viruses are utilized to selectively lyse tumor cells. In vitro and in vivo studies have shown that the Zika virus (ZIKV) can infect glioma cells and induce a robust oncolytic activity. Consequently, interest in exploring this virus as a potential oncolytic virus (OV) for high-grade gliomas has surged. Given that ZIKV actively circulates in Colombia, evaluating its neurotropic and oncolytic capabilities holds considerable national and international importance, as it may emerge as an alternative for treating highly complex gliomas. Therefore, this literature review outlines the generalities of GBM, the factors determining ZIKV's specific tropism for nervous tissue, and its oncolytic capacity. Additionally, we briefly present the progress in preclinical studies supporting the use of ZIKV as an OVT for gliomas.
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Affiliation(s)
- María-Angélica Calderón-Peláez
- Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia; (M.-A.C.-P.); (S.J.M.A.); (J.E.C.)
| | - Silvia Juliana Maradei Anaya
- Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia; (M.-A.C.-P.); (S.J.M.A.); (J.E.C.)
| | | | - Karol Gabriela González-Ipuz
- Semillero ViroLogic 2020–2022, Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia
| | - Daniela Vera-Palacios
- Semillero ViroLogic 2020–2022, Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia
| | - Isabella Victoria Buitrago
- Semillero ViroLogic 2020–2022, Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia
| | - Jaime E. Castellanos
- Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia; (M.-A.C.-P.); (S.J.M.A.); (J.E.C.)
| | - Myriam L. Velandia-Romero
- Virology Group, Vice-Chancellor of Research, Universidad El Bosque, Bogotá 110121, Colombia; (M.-A.C.-P.); (S.J.M.A.); (J.E.C.)
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7
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Kienzler JC, Becher B. Immunity in malignant brain tumors: Tumor entities, role of immunotherapy, and specific contribution of myeloid cells to the brain tumor microenvironment. Eur J Immunol 2024; 54:e2250257. [PMID: 37940552 DOI: 10.1002/eji.202250257] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 10/30/2023] [Accepted: 11/07/2023] [Indexed: 11/10/2023]
Abstract
Malignant brain tumors lack effective treatment, that can improve their poor overall survival achieved with standard of care. Advancement in different cancer treatments has shifted the focus in brain tumor research and clinical trials toward immunotherapy-based approaches. The investigation of the immune cell landscape revealed a dominance of myeloid cells in the tumor microenvironment. Their exact roles and functions are the subject of ongoing research. Current evidence suggests a complex interplay of tumor cells and myeloid cells with competing functions toward support vs. control of tumor growth. Here, we provide a brief overview of the three most abundant brain tumor entities: meningioma, glioma, and brain metastases. We also describe the field of ongoing immunotherapy trials and their results, including immune checkpoint inhibitors, vaccination studies, oncolytic viral therapy, and CAR-T cells. Finally, we summarize the phenotypes of microglia, monocyte-derived macrophages, border-associated macrophages, neutrophils, and potential novel therapy targets.
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Affiliation(s)
- Jenny C Kienzler
- Institute of Experimental Immunology, Inflammation Research Lab, University of Zurich, Zurich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, Inflammation Research Lab, University of Zurich, Zurich, Switzerland
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8
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Ngo HD, Formanski JP, Grunwald V, Schwalbe B, Schreiber M. Generation of Viral Particles with Brain Cell-Specific Tropism by Pseudotyping HIV-1 with the Zika Virus E Protein. Methods Protoc 2023; 7:3. [PMID: 38251196 PMCID: PMC10801502 DOI: 10.3390/mps7010003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/19/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024] Open
Abstract
Flaviviruses are a family of RNA viruses that includes many known pathogens, such as Zika virus (ZIKV), West Nile virus (WNV), dengue virus (DENV), and yellow fever virus (YFV). A pseudotype is an artificial virus particle created in vitro by incorporating the flavivirus envelope proteins into the structure of, for example, a retrovirus such as human immunodeficiency virus type-1 (HIV-1). They can be a useful tool in virology for understanding the biology of flaviviruses, evaluating immune responses, developing antiviral strategies but can also be used as vectors for gene transfer experiments. This protocol describes the generation of a ZIKV/HIV-1 pseudotype developed as a new tool for infecting cells derived from a highly malignant brain tumor: glioblastoma multiforme grade 4.
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Affiliation(s)
- Hai Dang Ngo
- Department of Virology, LG Schreiber, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - Jan Patrick Formanski
- Department of Virology, LG Schreiber, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - Vivien Grunwald
- Department of Virology, LG Schreiber, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - Birco Schwalbe
- Department of Neurosurgery, Asklepios Kliniken Hamburg GmbH, Asklepios Klinik Nord, Standort Heidberg, 22417 Hamburg, Germany
| | - Michael Schreiber
- Department of Virology, LG Schreiber, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
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Andrews CE, Zilberberg J, Perez-Olle R, Exley MA, Andrews DW. Targeted immunotherapy for glioblastoma involving whole tumor-derived autologous cells in the upfront setting after craniotomy. J Neurooncol 2023; 165:389-398. [PMID: 38017340 PMCID: PMC10942892 DOI: 10.1007/s11060-023-04491-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/25/2023] [Indexed: 11/30/2023]
Abstract
PURPOSE To date, immunotherapeutic approaches in glioblastoma (GBM) have had limited clinical efficacy as compared to other solid tumors. Here we explore autologous cell treatments that have the potential to circumvent treatment resistance to immunotherapy for GBM. METHODS We performed literature review and assessed clinical outcomes in phase 1 safety trials as well as phase 2 and 3 autologously-derived vaccines for the treatment of newly-diagnosed GBM. In one recent review of over 3,000 neuro-oncology phase 2 and phase 3 clinical trials, most trials were nonblinded (92%), single group (65%), nonrandomized (51%) and almost half were GBM trials. Only 10% involved a biologic and only 2.2% involved a double-blind randomized trial design. RESULTS With this comparative literature review we conclude that our autologous cell product is uniquely antigen-inclusive and antigen-agnostic with a promising safety profile as well as unexpected clinical efficacy in our published phase 1b trial. We have since designed a rigorous double-blinded add-on placebo-controlled trial involving our implantable biologic drug device. We conclude that IGV-001 provides a novel immunotherapy platform for historically intransigent ndGBM in this ongoing phase 2b trial (NCT04485949).
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Affiliation(s)
- Carrie E Andrews
- Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | | | | | | | - David W Andrews
- Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
- Imvax, Inc., Philadelphia, PA, 19602, USA.
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10
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Dong S, Liu X, Bi Y, Wang Y, Antony A, Lee D, Huntoon K, Jeong S, Ma Y, Li X, Deng W, Schrank BR, Grippin AJ, Ha J, Kang M, Chang M, Zhao Y, Sun R, Sun X, Yang J, Chen J, Tang SK, Lee LJ, Lee AS, Teng L, Wang S, Teng L, Kim BYS, Yang Z, Jiang W. Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer. Nat Commun 2023; 14:6610. [PMID: 37857647 PMCID: PMC10587228 DOI: 10.1038/s41467-023-42365-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 10/09/2023] [Indexed: 10/21/2023] Open
Abstract
The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.
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Affiliation(s)
- Shiyan Dong
- School of Life Science, Jilin University, Changchun, 130012, China
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xuan Liu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Chemical Engineering, Institute for Micromanufacturing, Louisiana Tech University, Ruston, LA, 71272, USA
| | - Ye Bi
- Practice Training Center, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Yifan Wang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Abin Antony
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - DaeYong Lee
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kristin Huntoon
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Seongdong Jeong
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yifan Ma
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Xuefeng Li
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Weiye Deng
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Benjamin R Schrank
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Adam J Grippin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - JongHoon Ha
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Minjeong Kang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mengyu Chang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yarong Zhao
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Rongze Sun
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Xiangshi Sun
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Jie Yang
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Jiayi Chen
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Sarah K Tang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - L James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
- Spot Biosystems Ltd., Palo Alto, CA, 94305, USA
| | - Andrew S Lee
- Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518055, China
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China
| | - Lirong Teng
- School of Life Science, Jilin University, Changchun, 130012, China
| | - Shengnian Wang
- Chemical Engineering, Institute for Micromanufacturing, Louisiana Tech University, Ruston, LA, 71272, USA.
| | - Lesheng Teng
- School of Life Science, Jilin University, Changchun, 130012, China.
| | - Betty Y S Kim
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Zhaogang Yang
- School of Life Science, Jilin University, Changchun, 130012, China.
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Wen Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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11
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Karandikar PV, Suh L, Gerstl JVE, Blitz SE, Qu QR, Won SY, Gessler FA, Arnaout O, Smith TR, Peruzzi PP, Yang W, Friedman GK, Bernstock JD. Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma. Front Cell Dev Biol 2023; 11:1271575. [PMID: 37860820 PMCID: PMC10582965 DOI: 10.3389/fcell.2023.1271575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.
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Affiliation(s)
- Paramesh V. Karandikar
- T. H. Chan School of Medicine, University of Massachusetts, Worcester, MA, United States
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Lyle Suh
- T. H. Chan School of Medicine, University of Massachusetts, Worcester, MA, United States
| | - Jakob V. E. Gerstl
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Sarah E. Blitz
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Qing Rui Qu
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Sae-Yeon Won
- Department of Neurosurgery, University of Rostock, Rostock, Germany
| | | | - Omar Arnaout
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Timothy R. Smith
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Pier Paolo Peruzzi
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Wei Yang
- Department of Anesthesiology, Multidisciplinary Brain Protection Program, Duke University Medical Center, Durham, NC, United States
| | - Gregory K. Friedman
- Department of Neuro-Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States
| | - Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
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12
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Zhang H, Du Y, Qi L, Xiao S, Braun FK, Kogiso M, Huang Y, Huang F, Abdallah A, Suarez M, Karthick S, Ahmed NM, Salsman VS, Baxter PA, Su JM, Brat DJ, Hellenbeck PL, Teo WY, Patel AJ, Li XN. Targeting GBM with an Oncolytic Picornavirus SVV-001 alone and in combination with fractionated Radiation in a Novel Panel of Orthotopic PDX models. J Transl Med 2023; 21:444. [PMID: 37415222 PMCID: PMC10324131 DOI: 10.1186/s12967-023-04237-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/30/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. MATERIALS AND METHODS 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. RESULTS PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. CONCLUSION A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.
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Affiliation(s)
- Huiyuan Zhang
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yuchen Du
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
- Department of Pharmacology, School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Lin Qi
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Sophie Xiao
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Frank K Braun
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Mari Kogiso
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yulun Huang
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Neurosurgery, Dushou Lake Hospital, Soochow University Medical School, Suzhou, Jiangsu, China
| | - Frank Huang
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Aalaa Abdallah
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Milagros Suarez
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Sekar Karthick
- Pediatric Brain Tumor Research Office, Cancer and Stem Cell Biology Program, SingHealth Duke-NUS Academic Medical Center, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Duke-NUS Medical School, 169610, Singapore, Singapore
| | | | | | - Patricia A Baxter
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jack M Su
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | | | - Wan-Yee Teo
- Texas Children's Cancer Center, Houston, TX, USA
- Pediatric Brain Tumor Research Office, Cancer and Stem Cell Biology Program, SingHealth Duke-NUS Academic Medical Center, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Duke-NUS Medical School, 169610, Singapore, Singapore
| | - Akash J Patel
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.
- Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
| | - Xiao-Nan Li
- Texas Children's Cancer Center, Houston, TX, USA.
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA.
- Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
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13
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Gross EG, Hamo MA, Estevez-Ordonez D, Laskay NMB, Atchley TJ, Johnston JM, Markert JM. Oncolytic virotherapies for pediatric tumors. Expert Opin Biol Ther 2023; 23:987-1003. [PMID: 37749907 PMCID: PMC11309584 DOI: 10.1080/14712598.2023.2245326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 08/03/2023] [Indexed: 09/27/2023]
Abstract
INTRODUCTION Many pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients. AREAS COVERED We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies. EXPERT OPINION Substantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.
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Affiliation(s)
- Evan G Gross
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohammad A Hamo
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Nicholas MB Laskay
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Travis J Atchley
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- Division of Pediatric Neurosurgery, Children’s of Alabama, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
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14
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Li S, Guo Y, Hu H, Gao N, Yan X, Zhou Q, Liu H. TANK shapes an immunosuppressive microenvironment and predicts prognosis and therapeutic response in glioma. Front Immunol 2023; 14:1138203. [PMID: 37215097 PMCID: PMC10196049 DOI: 10.3389/fimmu.2023.1138203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
Background Glioma, the most prevalent malignant intracranial tumor, poses a significant threat to patients due to its high morbidity and mortality rates, but its prognostic indicators remain inaccurate. Although TRAF-associated NF-kB activator (TANK) interacts and cross-regulates with cytokines and microenvironmental immune cells, it is unclear whether TANK plays a role in the immunologically heterogeneous gliomas. Methods TANK mRNA expression patterns in public databases were analyzed, and qPCR and IHC were performed in an in-house cohort to confirm the clinical significance of TANK. Then, we systematically evaluated the relationship between TANK expression and immune characteristics in the glioma microenvironment. Additionally, we evaluated the ability of TANK to predict treatment response in glioma. TANK-associated risk scores were developed by LASSO-Cox regression and machine learning, and their prognostic ability was tested. Results TANK was specifically overexpressed in glioma and enriched in the malignant phenotype, and its overexpression was related to poor prognosis. The presence of a tumor microenvironment that is immunosuppressive was evident by the negative correlations between TANK expression and immunomodulators, steps in the cancer immunity cycle, and immune checkpoints. Notably, treatment for cancer may be more effective when immunotherapy is combined with anti-TANK therapy. Prognosis could be accurately predicted by the TANK-related risk score. Conclusions High expression of TANK is associated with the malignant phenotype of glioma, as it shapes an immunosuppressive tumor microenvironment. Additionally, TANK can be used as a predictive biomarker for responses to various treatments and prognosis.
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Affiliation(s)
- Shasha Li
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China
| | - Youwei Guo
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Huijuan Hu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Na Gao
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xuejun Yan
- Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Quanwei Zhou
- The National Key Clinical Specialty, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hui Liu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
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15
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Rocha Pinheiro SL, Lemos FFB, Marques HS, Silva Luz M, de Oliveira Silva LG, Faria Souza Mendes dos Santos C, da Costa Evangelista K, Calmon MS, Sande Loureiro M, Freire de Melo F. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol 2023; 14:138-159. [PMID: 37124134 PMCID: PMC10134201 DOI: 10.5306/wjco.v14.i4.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023] Open
Abstract
Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.
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Affiliation(s)
- Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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16
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Kao YT, Wang HI, Shie CT, Lin CF, Lai MM, Yu CY. Zika virus cleaves GSDMD to disseminate prognosticable and controllable oncolysis in a human glioblastoma cell model. Mol Ther Oncolytics 2023; 28:104-117. [PMID: 36699618 PMCID: PMC9845690 DOI: 10.1016/j.omto.2022.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/31/2022] [Indexed: 01/03/2023] Open
Abstract
Glioblastoma (GBM) is the most common aggressive malignant brain cancer and is chemo- and radioresistant, with poor therapeutic outcomes. The "double-edged sword" of virus-induced cell death could be a potential solution if the oncolytic virus specifically kills cancer cells but spares normal ones. Zika virus (ZIKV) has been defined as a prospective oncolytic virus by selectively targeting GBM cells, but unclear understanding of how ZIKV kills GBM and the consequences hinders its application. Here, we found that the cellular gasdermin D (GSDMD) is required for the efficient death of a human GBM cell line caused by ZIKV infection. The ZIKV protease specifically cleaves human GSDMD to activate caspase-independent pyroptosis, harming both viral protease-harboring and naive neighboring cells. Analyzing human GSDMD variants showed that most people were susceptible to ZIKV-induced cytotoxicity, except for those with variants that resisted ZIKV cleavage or were defective in oligomerizing the N terminus GSDMD cleavage product. Consistently, ZIKV-induced secretion of the pro-inflammatory cytokine interleukin-1β and cytolytic activity were both stopped by a small-molecule inhibitor targeting GSDMD oligomerization. Thus, potential ZIKV oncolytic therapy for GBM would depend on the patient's GSDMD genetic background and could be abolished by GSDMD inhibitors if required.
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Affiliation(s)
- Yu-Ting Kao
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
| | - Hsin-I Wang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
| | - Chi-Ting Shie
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
| | - Chiou-Feng Lin
- Department of Microbiology and Immunology, Taipei Medical University, Taipei 110, Taiwan
| | - Michael M.C. Lai
- Research Center for Emerging Viruses, China Medical University Hospital, Taichung 404, Taiwan,Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan
| | - Chia-Yi Yu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan,Department of Microbiology and Immunology, National Cheng Kung University, Tainan 701, Taiwan,Corresponding author: Chia-Yi Yu, PhD, National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan.
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17
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Qi Z, Zhao J, Li Y, Zhang B, Hu S, Chen Y, Ma J, Shu Y, Wang Y, Cheng P. Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity. Front Immunol 2023; 14:982180. [PMID: 37114043 PMCID: PMC10126305 DOI: 10.3389/fimmu.2023.982180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 03/27/2023] [Indexed: 04/29/2023] Open
Abstract
Glioblastomas (GBMs) are highly aggressive brain tumors that have developed resistance to currently available conventional therapies, including surgery, radiation, and systemic chemotherapy. In this study, we investigated the safety of a live attenuated Japanese encephalitis vaccine strain (JEV-LAV) virus as an oncolytic virus for intracerebral injection in mice. We infected different GBM cell lines with JEV-LAV to investigate whether it had growth inhibitory effects on GBM cell lines in vitro. We used two models for evaluating the effect of JEV-LAV on GBM growth in mice. We investigated the antitumor immune mechanism of JEV-LAV through flow cytometry and immunohistochemistry. We explored the possibility of combining JEV-LAV with PD-L1 blocking therapy. This work suggested that JEV-LAV had oncolytic activity against GBM tumor cells in vitro and inhibited their growth in vivo. Mechanistically, JEV-LAV increased CD8+ T cell infiltration into tumor tissues and remodeled the immunosuppressive GBM microenvironment that is non-conducive to immunotherapy. Consequently, the results of combining JEV-LAV with immune checkpoint inhibitors indicated that JEV-LAV therapy improved the response of aPD-L1 blockade therapy against GBM. The safety of intracerebrally injected JEV-LAV in animals further supported the clinical use of JEV-LAV for GBM treatment.
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Affiliation(s)
- Zhongbing Qi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Zhao
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yuhua Li
- Department of Arboviruses Vaccine, National Institute for Food and Drug Control, Beijing, China
| | - Bin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Shichuan Hu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yanwei Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhu Ma
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yongheng Shu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yunmeng Wang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Ping Cheng,
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18
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Zhang W, Song G. A comprehensive analysis-based study of triphenyl phosphate-environmental explanation of glioma progression. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 248:114346. [PMID: 36455348 DOI: 10.1016/j.ecoenv.2022.114346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/17/2022] [Accepted: 11/24/2022] [Indexed: 06/17/2023]
Abstract
As BFRs have gradually been banned recently, organophosphorus flame retardants (OPFRs) have been manufactured and used in their place. Although OPFRs are considered the better alternatives to BFRs, many studies have discovered that OPFRs may be associated with various cancers, including prostate cancer, bladder cancer, hepatocellular carcinoma, and colorectal cancer. However, few studies have examined the relationship between OPFRs and gliomas. This study investigated the relationship between triphenyl phosphate (TPP) and glioma using bioinformatics analysis approaches. The comparative toxicogenomics database (CTD) and The Cancer Genome Atlas (TCGA) databases were accessed for TPP-related genes and gene expression data from glioma patients. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses show that TPP might be closely related to many pathways. Further, the analysis of protein-protein interactions revealed strong intrinsic relationships between TPP-related genes. In addition, the TPP-based prognostic prediction model demonstrated promising results in predicting the prognosis of patients with gliomas. Several TPP-related genes were closely related to glioma patients' overall survival rates. The proliferation and migration abilities of glioma cells were further demonstrated to be significantly enhanced by TPP. In a bioinformatics analysis, we also discovered that melatonin is highly correlated with the presence of TPP and gliomas. According to the cell proliferation and migration assays, exposure to melatonin and TPP inhibited the ability of glioma cells to invade compared with the TPP group.
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Affiliation(s)
- Wanyun Zhang
- Guihang Guiyang Hospital, Guiyang 550000, Guizhou Province, China
| | - Guoping Song
- The Fourth People's Hospital of Guiyang, Guiyang 550000, Guizhou Province, China.
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19
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Investigational Microbiological Therapy for Glioma. Cancers (Basel) 2022; 14:cancers14235977. [PMID: 36497459 PMCID: PMC9736089 DOI: 10.3390/cancers14235977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/27/2022] [Accepted: 11/29/2022] [Indexed: 12/07/2022] Open
Abstract
Glioma is the most common primary malignancy of the central nervous system (CNS), and 50% of patients present with glioblastoma (GBM), which is the most aggressive type. Currently, the most popular therapies are progressive chemotherapy and treatment with temozolomide (TMZ), but the median survival of glioma patients is still low as a result of the emergence of drug resistance, so we urgently need to find new therapies. A growing number of studies have shown that the diversity, bioactivity, and manipulability of microorganisms make microbial therapy a promising approach for cancer treatment. However, the many studies on the research progress of microorganisms and their derivatives in the development and treatment of glioma are scattered, and nobody has yet provided a comprehensive summary of them. Therefore, in this paper, we review the research progress of microorganisms and their derivatives in the development and treatment of glioma and conclude that it is possible to treat glioma by exogenous microbial therapies and targeting the gut-brain axis. In this article, we discuss the prospects and pressing issues relating to these therapies with the aim of providing new ideas for the treatment of glioma.
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20
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Handoko H, Wahyudi ST, Setyawan AA, Kartono A. A dynamical model of combination therapy applied to glioma. J Biol Phys 2022; 48:439-459. [PMID: 36367670 PMCID: PMC9727046 DOI: 10.1007/s10867-022-09618-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/28/2022] [Indexed: 11/13/2022] Open
Abstract
Glioma is a human brain tumor that is very difficult to treat at an advanced stage. Studies of glioma biomarkers have shown that some markers are released into the bloodstream, so data from these markers indicate a decrease in the concentration of blood glucose and serum glucose in patients with glioma; these suggest an association between glucose and glioma. This decrease mechanism in glucose concentration can be described by the coupled ordinary differential equations of the early-stage glioma growth and interactions between glioma cells, immune cells, and glucose concentration. In this paper, we propose developing a new mathematical model to explain how glioma cells evolve and survive combination therapy between chemotherapy and oncolytic virotherapy, as an alternative to glioma treatment. In this study, three therapies were applied for analysis, that is, (1) chemotherapy, (2) virotherapy, and (3) a combination of chemotherapy and virotherapy. Virotherapy uses specialist viruses that only attack tumor cells. Based on the simulation results of the therapy carried out, we conclude that combination therapy can reduce the glioma cells significantly compared to the other two therapies. The simulation results of this combination therapy can be an alternative to glioma therapy.
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Affiliation(s)
- Handoko Handoko
- Department of Physics, Faculty of Mathematical and Natural Science, IPB University (Bogor Agricultural University), Jalan Meranti, Building Wing S, 2nd Floor, Dramaga IPB Campus, 16680, Bogor, Indonesia.
| | - Setyanto Tri Wahyudi
- Department of Physics, Faculty of Mathematical and Natural Science, IPB University (Bogor Agricultural University), Jalan Meranti, Building Wing S, 2nd Floor, Dramaga IPB Campus, 16680, Bogor, Indonesia
| | - Ardian Arif Setyawan
- Department of Physics, Faculty of Mathematical and Natural Science, IPB University (Bogor Agricultural University), Jalan Meranti, Building Wing S, 2nd Floor, Dramaga IPB Campus, 16680, Bogor, Indonesia
| | - Agus Kartono
- Department of Physics, Faculty of Mathematical and Natural Science, IPB University (Bogor Agricultural University), Jalan Meranti, Building Wing S, 2nd Floor, Dramaga IPB Campus, 16680, Bogor, Indonesia.
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21
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Cheng K, Zhang H, Guo Q, Zhai P, Zhou Y, Yang W, Wang Y, Lu Y, Shen Z, Wu H. Emerging trends and research foci of oncolytic virotherapy for central nervous system tumors: A bibliometric study. Front Immunol 2022; 13:975695. [PMID: 36148235 PMCID: PMC9486718 DOI: 10.3389/fimmu.2022.975695] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/16/2022] [Indexed: 12/19/2022] Open
Abstract
BackgroundCentral nervous system tumor (CNST) is one of the most complicated and lethal forms of human tumors with very limited treatment options. In recent years, growing evidence indicates that oncolytic virotherapy (OVT) has emerged as a promising therapeutic strategy for CNSTs. And a considerable amount of literature on OVT-CNSTs has been published. However, there are still no studies summarizing the global research trends and hotspots of this field through a bibliometric approach. To fulfill this knowledge gap, bibliometric analysis was conducted based on all publications relating to OVT-CNSTs since 2000s.MethodsWe searched the Web of Science Core Collection for all relevant studies published between 2000 and 2022. Four different tools (online analysis platform, R-bibliometrix, CiteSpace and VOSviewer) were used to perform bibliometric analysis and network visualization, including annual publication output, active journals, contribution of countries, institutions, and authors, references, as well as keywords.ResultsA total of 473 articles and reviews were included. The annual number of publications on OVT-CNSTs showed a significant increasing trend. Molecular Therapy and Cancer Research were the most active and co-cited journals, respectively. In terms of contributions, there is no doubt that the United States occupied a leading position with the most publications (n=307, 64.9%) and the highest H-index (57). The institution and author that contributed the largest number of publications were Ohio State University and Chiocca EA, respectively. As can be seen from citation analysis, the current studies mainly focused on preclinical and phase I/II clinical results of various oncolytic virus for CNSTs treatment. Keywords co-occurrence and burst analysis revealed that the following research topics including immunotherapy, T-cells, tumor microenvironment, vaccine, blood-brain-barrier, checkpoint inhibitors, macrophage, stem cell, and recurrent glioblastoma have been research frontiers of this field and also have great potential to continue to be research hotspots in the future.ConclusionThere has been increasing attention on oncolytic viruses for use as CNSTs therapeutics. Oncolytic immunotherapy is a topic of great concern in this field. This bibliometric study provides a comprehensive analysis of the knowledge base, research hotspots, development perspective in the field of OVT-CNSTs, which could become an essential reference for scholars in this area.
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Affiliation(s)
- Kunming Cheng
- Department of Intensive Care Unit, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huan Zhang
- Department of Neurosurgery, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
| | - Qiang Guo
- Department of Orhopaedic Surgery, Baodi Clinical College of Tianjin Medical University, Tianjin, China
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Pengfei Zhai
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of NeuroSpine Surgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Yan Zhou
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Weiguang Yang
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
| | - Yulin Wang
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
| | - Yanqiu Lu
- Department of Intensive Care Unit, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
| | - Zefeng Shen
- Department of Graduate School, Sun Yat-sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
| | - Haiyang Wu
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
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22
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Zhang Z, Conniot J, Amorim J, Jin Y, Prasad R, Yan X, Fan K, Conde J. Nucleic acid-based therapy for brain cancer: Challenges and strategies. J Control Release 2022; 350:80-92. [PMID: 35970297 DOI: 10.1016/j.jconrel.2022.08.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 07/26/2022] [Accepted: 08/09/2022] [Indexed: 10/15/2022]
Abstract
Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.
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Affiliation(s)
- Zixia Zhang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100408, China
| | - João Conniot
- ToxOmics, NOVA Medical School
- Faculdade de Ciências Médicas, NMS
- FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal
| | - Joana Amorim
- ToxOmics, NOVA Medical School
- Faculdade de Ciências Médicas, NMS
- FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal
| | - Yiliang Jin
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Rajendra Prasad
- Department of Mechanical Engineering, Tufts University, Medford, MA 02155, USA
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100408, China; Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - Kelong Fan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100408, China; Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - João Conde
- ToxOmics, NOVA Medical School
- Faculdade de Ciências Médicas, NMS
- FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
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23
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Li J, Zhang Y, Qu Z, Ding R, Yin X. ABCD3 is a prognostic biomarker for glioma and associated with immune infiltration: A study based on oncolysis of gliomas. Front Cell Infect Microbiol 2022; 12:956801. [PMID: 35959373 PMCID: PMC9358688 DOI: 10.3389/fcimb.2022.956801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Background Gliomas are the most lethal primary brain tumors and are still a major therapeutic challenge. Oncolytic virus therapy is a novel and effective means for glioma. However, little is known about gene expression changes during this process and their biological functions on glioma clinical characteristics and immunity. Methods The RNA-seq data after oncolytic virus EV-A71 infection on glioma cells were analyzed to screen significantly downregulated genes. Once ABCD3 was selected, The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) data were used to analyze the relationship between ABCD3 expression and clinical characteristics in glioma. We also evaluated the influence of ABCD3 on the survival of glioma patients. CIBERSORT and Tumor Immune Estimation Resource (TIMER) were also used to investigate the correlation between ABCD3 and cancer immune infiltrates. Gene set enrichment analysis (GSEA) was performed to functionally annotate the potential functions or signaling pathways related to ABCD3 expression. Results ABCD3 was among the top 5 downregulated genes in glioma cells after oncolytic virus EV-A71 infection and was significantly enriched in several GO categories. Both the mRNA and protein expression levels of ABCD3 were upregulated in glioma samples and associated with the prognosis and grades of glioma patients. The Kaplan–Meier (K-M) curve analysis revealed that patients with high ABCD3 expression had shorter disease-specific survival (DSS) and overall survival (OS) than those with low ABCD3 expression. Moreover, ABCD3 expression could affect the immune infiltration levels and diverse immune marker sets in glioma. A positive correlation was found between ABCD3 and macrophages and active dendritic cells in the microenvironment of both the GBM and LGG. Gene sets including the plk1 pathway, tyrobp causal network, ir-damage and cellular response, and interleukin-10 signaling showed significant differential enrichment in the high ABCD3 expression phenotype. Conclusion Our results suggested that ABCD3 could be a potential biomarker for glioma prognosis and immunotherapy response and also further enriched the theoretical and molecular mechanisms of oncolytic virus treatment for malignant gliomas.
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Affiliation(s)
- Jinchuan Li
- Department of Neurosurgery, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Neurosurgery, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhizhao Qu
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Rui Ding
- Department of Neurosurgery, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaofeng Yin
- Department of Neurosurgery, Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Xiaofeng Yin, ;
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24
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Maslinic Acid Inhibits the Growth of Malignant Gliomas by Inducing Apoptosis via MAPK Signaling. JOURNAL OF ONCOLOGY 2022; 2022:3347235. [PMID: 35799612 PMCID: PMC9256398 DOI: 10.1155/2022/3347235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022]
Abstract
Background Gliomas are primary malignant brain tumors. Despite recent advances in surgery and clinical neuro-oncology, the prognosis of patients with glioma is still poor. Therefore, there is an urgent need to find new therapeutic drugs. Methods Here, we have studied the anticancer effect of maslinic acid in glioma and explored its potential molecular mechanism. CCK-8, Ki67 immunofluorescence, and colony formation tests are used to detect the proliferation of glioma cells. Transwell and migration experiments are used to detect the function of cell invasion and migration, and RNA-seq was performed to identify differentially expressed genes. Western blot analysis helps us identify important signaling pathways. Finally, the anticancer effect of maslinic acid was confirmed in vivo through tumor xenografting experiments. Results Our experiments obtained high-throughput data on the treatment of maslinic acid in glioma. We found that maslinic acid significantly inhibits the proliferation, invasion, and migration of glioma cells and promotes the apoptosis of glioma cells via suppressing MAPK signaling. Conclusions This is the first time to analyze the mechanism of maslinic acid against glioma based on transcription. Our experiments show that maslinic acid may be a useful natural product for the treatment of glioma.
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25
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Ljubimov VA, Ramesh A, Davani S, Danielpour M, Breunig JJ, Black KL. Neurosurgery at the crossroads of immunology and nanotechnology. New reality in the COVID-19 pandemic. Adv Drug Deliv Rev 2022; 181:114033. [PMID: 34808227 PMCID: PMC8604570 DOI: 10.1016/j.addr.2021.114033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/19/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022]
Abstract
Neurosurgery as one of the most technologically demanding medical fields rapidly adapts the newest developments from multiple scientific disciplines for treating brain tumors. Despite half a century of clinical trials, survival for brain primary tumors such as glioblastoma (GBM), the most common primary brain cancer, or rare ones including primary central nervous system lymphoma (PCNSL), is dismal. Cancer therapy and research have currently shifted toward targeted approaches, and personalized therapies. The orchestration of novel and effective blood-brain barrier (BBB) drug delivery approaches, targeting of cancer cells and regulating tumor microenvironment including the immune system are the key themes of this review. As the global pandemic due to SARS-CoV-2 virus continues, neurosurgery and neuro-oncology must wrestle with the issues related to treatment-related immune dysfunction. The selection of chemotherapeutic treatments, even rare cases of hypersensitivity reactions (HSRs) that occur among immunocompromised people, and number of vaccinations they have to get are emerging as a new chapter for modern Nano neurosurgery.
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Affiliation(s)
- Vladimir A Ljubimov
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | | | | | - Moise Danielpour
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Joshua J Breunig
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Keith L Black
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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26
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Fernández-Ruiz M. Overview of the Risk of Infection Associated with Biologic and Target Therapies. INFECTIOUS COMPLICATIONS IN BIOLOGIC AND TARGETED THERAPIES 2022:3-15. [DOI: 10.1007/978-3-031-11363-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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27
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Wang EJ, Chen JS, Jain S, Morshed RA, Haddad AF, Gill S, Beniwal AS, Aghi MK. Immunotherapy Resistance in Glioblastoma. Front Genet 2021; 12:750675. [PMID: 34976006 PMCID: PMC8718605 DOI: 10.3389/fgene.2021.750675] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/27/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.
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Affiliation(s)
- Elaina J. Wang
- Department of Neurological Surgery, The Warren Alpert School of Medicine, Brown University, Providence, RI, United States
| | - Jia-Shu Chen
- Department of Neurological Surgery, The Warren Alpert School of Medicine, Brown University, Providence, RI, United States
| | - Saket Jain
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Ramin A. Morshed
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Alexander F. Haddad
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Sabraj Gill
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Angad S. Beniwal
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
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28
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Zwernik SD, Adams BH, Raymond DA, Warner CM, Kassam AB, Rovin RA, Akhtar P. AXL receptor is required for Zika virus strain MR-766 infection in human glioblastoma cell lines. Mol Ther Oncolytics 2021; 23:447-457. [PMID: 34901388 PMCID: PMC8626839 DOI: 10.1016/j.omto.2021.11.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/13/2021] [Accepted: 11/08/2021] [Indexed: 12/28/2022] Open
Abstract
Recent reports have shown that Zika virus (ZIKV) has oncolytic potential against human glioblastoma (GBM); however, the mechanisms underlying its tropism and cell entry are not completely understood. The receptor tyrosine kinase AXL has been identified as an entry receptor for ZIKV in a cell-type-specific manner. Interestingly, AXL is frequently overexpressed in GBM patients. Using commercially available GBM cell lines, we first show that cells expressing AXL are permissive for ZIKV infection, while cells that do not express AXL are not. Furthermore, inhibition of AXL kinase using R428 and antibody blockade of AXL receptor strongly attenuated virus entry in GBM cell lines. Additionally, CRISPR knockout of the AXL gene in GBM cell lines completely abolished ZIKV infection, significantly inhibited viral replication, and significantly reduced apoptosis compared with parental lines. Lastly, introduction of AXL receptor into non-expressing cell lines renders the cells susceptible to ZIKV infection. Together, these findings demonstrate that ZIKV entry into GBM cells in vitro is mediated by the AXL receptor and that following cell entry, productive infection is cytotoxic. Thus, ZIKV is a potential oncolytic virus for GBM.
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Affiliation(s)
- Samuel D Zwernik
- Advocate Aurora Research Institute, Advocate Aurora Health, Milwaukee, WI 53233, USA
| | - Beau H Adams
- Advocate Aurora Research Institute, Advocate Aurora Health, Milwaukee, WI 53233, USA
| | - Daniel A Raymond
- Advocate Aurora Research Institute, Advocate Aurora Health, Milwaukee, WI 53233, USA
| | - Catherine M Warner
- Advocate Aurora Research Institute, Advocate Aurora Health, Milwaukee, WI 53233, USA
| | - Amin B Kassam
- Aurora Neuroscience Innovation Institute, Advocate Aurora Health, Milwaukee, WI 53215, USA
| | - Richard A Rovin
- Aurora Neuroscience Innovation Institute, Advocate Aurora Health, Milwaukee, WI 53215, USA
| | - Parvez Akhtar
- Advocate Aurora Research Institute, Advocate Aurora Health, Milwaukee, WI 53233, USA
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The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors. NANOMATERIALS 2021; 11:nano11113018. [PMID: 34835785 PMCID: PMC8623458 DOI: 10.3390/nano11113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
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Zeng J, Li X, Sander M, Zhang H, Yan G, Lin Y. Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas. Front Immunol 2021; 12:721830. [PMID: 34675919 PMCID: PMC8524046 DOI: 10.3389/fimmu.2021.721830] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/16/2021] [Indexed: 01/17/2023] Open
Abstract
The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.
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Affiliation(s)
- Jiayi Zeng
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xiangxue Li
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Max Sander
- Department of International Cooperation, Guangzhou Virotech Pharmaceutical Co., Ltd., Guangzhou, China
| | - Haipeng Zhang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Guangmei Yan
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuan Lin
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Vasileva N, Ageenko A, Dmitrieva M, Nushtaeva A, Mishinov S, Kochneva G, Richter V, Kuligina E. Double Recombinant Vaccinia Virus: A Candidate Drug against Human Glioblastoma. Life (Basel) 2021; 11:life11101084. [PMID: 34685455 PMCID: PMC8538059 DOI: 10.3390/life11101084] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 11/26/2022] Open
Abstract
Glioblastoma is one of the most aggressive brain tumors. Given the poor prognosis of this disease, novel methods for glioblastoma treatment are needed. Virotherapy is one of the most actively developed approaches for cancer therapy today. VV-GMCSF-Lact is a recombinant vaccinia virus with deletions of the viral thymidine kinase and growth factor genes and insertions of the granulocyte–macrophage colony-stimulating factor and oncotoxic protein lactaptin genes. The virus has high cytotoxic activity against human cancer cells of various histogenesis and antitumor efficacy against breast cancer. In this work, we show VV-GMCSF-Lact to be a promising therapeutic agent for glioblastoma treatment. VV-GMCSF-Lact effectively decreases the viability of glioblastoma cells of both immortalized and patient-derived cultures in vitro, crosses the blood–brain barrier, selectively replicates into orthotopically transplanted human glioblastoma when intravenously injected, and inhibits glioblastoma xenograft and metastasis growth when injected intratumorally.
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Affiliation(s)
- Natalia Vasileva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
- LLC “Oncostar”, R&D Department, Ingenernaya Street 23, 630090 Novosibirsk, Russia
- Correspondence: ; Tel.: +7-(913)-949-6585
| | - Alisa Ageenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
| | - Maria Dmitrieva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
| | - Anna Nushtaeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
| | - Sergey Mishinov
- Novosibirsk Research Institute of Traumatology and Orthopedics n.a. Ya.L. Tsivyan, Department of Neurosurgery, Frunze Street 17, 630091 Novosibirsk, Russia;
| | - Galina Kochneva
- The State Research Center of Virology and Biotechnology “VECTOR”, Department of Molecular Virology of Flaviviruses and Viral Hepatitis, Novosibirsk Region, 630559 Koltsovo, Russia;
| | - Vladimir Richter
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
| | - Elena Kuligina
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Akad. Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; (A.A.); (M.D.); (A.N.); (V.R.); (E.K.)
- LLC “Oncostar”, R&D Department, Ingenernaya Street 23, 630090 Novosibirsk, Russia
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Ghonime MG, Saini U, Kelly MC, Roth JC, Wang PY, Chen CY, Miller K, Hernandez-Aguirre I, Kim Y, Mo X, Stanek JR, Cripe T, Mardis E, Cassady KA. Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy. J Immunother Cancer 2021; 9:jitc-2021-002939. [PMID: 34599026 PMCID: PMC8488720 DOI: 10.1136/jitc-2021-002939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/26/2021] [Indexed: 12/02/2022] Open
Abstract
Background Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection. Methods We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice. Results Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations. Conclusions Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.
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Affiliation(s)
- Mohammed G Ghonime
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Uksha Saini
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Michael C Kelly
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Justin C Roth
- The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Pin-Yi Wang
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Chun-Yu Chen
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Katherine Miller
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | | | - Yeaseul Kim
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Xiaokui Mo
- Biostatistics, The Ohio State University, Columbus, Ohio, USA
| | - Joseph R Stanek
- Biostatistics Resource, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Tim Cripe
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Elaine Mardis
- Pediatrics, The Ohio State University, Columbus, Ohio, USA.,The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kevin A Cassady
- Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA .,Pediatrics, The Ohio State University, Columbus, Ohio, USA
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Sokolov AV, Dostdar SA, Attwood MM, Krasilnikova AA, Ilina AA, Nabieva AS, Lisitsyna AA, Chubarev VN, Tarasov VV, Schiöth HB. Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies. Pharmacol Rev 2021; 73:1-32. [PMID: 34663683 DOI: 10.1124/pharmrev.121.000317] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.
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Affiliation(s)
- Aleksandr V Sokolov
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Samira A Dostdar
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Misty M Attwood
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Aleksandra A Krasilnikova
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Anastasia A Ilina
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Amina Sh Nabieva
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Anna A Lisitsyna
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vladimir N Chubarev
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vadim V Tarasov
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Helgi B Schiöth
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
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Burster T, Traut R, Yermekkyzy Z, Mayer K, Westhoff MA, Bischof J, Knippschild U. Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells. Front Cell Dev Biol 2021; 9:695325. [PMID: 34485282 PMCID: PMC8415230 DOI: 10.3389/fcell.2021.695325] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/29/2021] [Indexed: 12/28/2022] Open
Abstract
According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.
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Affiliation(s)
- Timo Burster
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Rebecca Traut
- Department of General and Visceral Surgery, Surgery Center, Ulm University Hospital, Ulm, Germany
| | - Zhanerke Yermekkyzy
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Katja Mayer
- Department of General and Visceral Surgery, Surgery Center, Ulm University Hospital, Ulm, Germany
| | - Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Joachim Bischof
- Department of General and Visceral Surgery, Surgery Center, Ulm University Hospital, Ulm, Germany
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Surgery Center, Ulm University Hospital, Ulm, Germany
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Kasten BB, Houson HA, Coleman JM, Leavenworth JW, Markert JM, Wu AM, Salazar F, Tavaré R, Massicano AVF, Gillespie GY, Lapi SE, Warram JM, Sorace AG. Positron emission tomography imaging with 89Zr-labeled anti-CD8 cys-diabody reveals CD8 + cell infiltration during oncolytic virus therapy in a glioma murine model. Sci Rep 2021; 11:15384. [PMID: 34321569 PMCID: PMC8319402 DOI: 10.1038/s41598-021-94887-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/13/2021] [Indexed: 12/17/2022] Open
Abstract
Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p < 0.001). Radioactive probe accumulation in brains was consistent with CD8+ cell trafficking patterns after oHSV treatment. This PET imaging strategy could aid in distinguishing responders from non-responders during immunotherapy of GBM.
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Affiliation(s)
- Benjamin B Kasten
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hailey A Houson
- Department of Radiology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35294, USA
| | - Jennifer M Coleman
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jianmei W Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Anna M Wu
- Department of Immunology and Theranostics, City of Hope, Duarte, CA, USA
- Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
| | - Felix Salazar
- Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
| | | | - Adriana V F Massicano
- Department of Radiology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35294, USA
| | - G Yancey Gillespie
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Suzanne E Lapi
- Department of Radiology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35294, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jason M Warram
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Otolaryngology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35294, USA.
| | - Anna G Sorace
- Department of Radiology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35294, USA.
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA.
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Patel V, Shah J. The current and future aspects of glioblastoma: Immunotherapy a new hope? Eur J Neurosci 2021; 54:5120-5142. [PMID: 34107127 DOI: 10.1111/ejn.15343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is the most perilous and highly malignant in all the types of brain tumor. Regardless of the treatment, the diagnosis of the patients in GBM is very poor. The average survival rate is only 21 months after multimodal combinational therapies, which include chemotherapy, radiation, and surgery. Due to the intrusive and infiltrative nature of GBM, it requires elective therapy for specific targeting of tumor cells. Tumor vaccine in a form of immunotherapy has potential to address this need. Nanomedicine-based immunotherapies have clutch the trigger of systemic and specific immune response against tumor cells, which might be the approach to eliminating the unrelieved cancer. In this mechanism, combination of immunomodulators with specific target and appropriate strategic vaccines can stifle tumor anti-immune defense system and/or increase the capabilities of the body to move up immunity against the tumor. Here, we explore the different types of immunotherapies and vaccines for brain tumor treatment and their clinical trials, which bring the feasibility of the future of personalized vaccine of nanomedicine-based immunotherapies for the brain tumor. We believe that immunotherapy could result in a significantly more stable reaction in GBM patients.
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Affiliation(s)
- Vimal Patel
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | - Jigar Shah
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
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Chianese A, Santella B, Ambrosino A, Stelitano D, Rinaldi L, Galdiero M, Zannella C, Franci G. Oncolytic Viruses in Combination Therapeutic Approaches with Epigenetic Modulators: Past, Present, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13112761. [PMID: 34199429 PMCID: PMC8199618 DOI: 10.3390/cancers13112761] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Cancer rates have been accelerating significantly in recent years. Despite notable advances having been made in cancer therapy, and numerous studies being currently conducted in clinical trials, research is always looking for new treatment. Novel and promising anticancer therapies comprise combinations of oncolytic viruses and epigenetic modulators, including chromatin modifiers, such as DNA methyltransferase and histone deacetylases, and microRNA. Combinatorial treatments have several advantages: they enhance viral entry, replication, and spread between proximal cells and, moreover, they strengthen the immune response. In this review we summarize the main combination of therapeutic approaches, giving an insight into past, present, and future perspectives. Abstract According to the World Cancer Report, cancer rates have been increased by 50% with 15 million new cases in the year 2020. Hepatocellular carcinoma (HCC) is the only one of the most common tumors to cause a huge increase in mortality with a survival rate between 40% and 70% at 5 years, due to the high relapse and limitations associated with current therapies. Despite great progress in medicine, oncological research is always looking for new therapies: different technologies have been evaluated in clinical trials and others have been already used in clinics. Among them, oncolytic virotherapy represents a therapeutic option with a widespread possibility of approaches and applications. Oncolytic viruses are naturally occurring, or are engineered, viruses characterized by the unique features of preferentially infecting, replicating, and lysing malignant tumor cells, as well as activating the immune response. The combination of oncolytic virotherapy and chemical drugs are arousing great interest in the tumor treatment. In this scenario, novel and promising anticancer therapies comprise combinations of oncolytic viruses and epigenetic modulators or inhibitors of the signalling pathways. Combination treatments are required to improve the immune response and allow viral entry, replication, and diffusion between proximal cells. In this review, we summarize all combination therapies associated with virotherapy, including co-administered inhibitors of chromatin modifiers (combination strategies) and inserted target sites for miRNAs (recombination or arming strategies).
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Affiliation(s)
- Annalisa Chianese
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Biagio Santella
- Section of Microbiology and Virology, University Hospital “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Annalisa Ambrosino
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Debora Stelitano
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Massimiliano Galdiero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
- Section of Microbiology and Virology, University Hospital “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Carla Zannella
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
- Correspondence: (C.Z.); (G.F.)
| | - Gianluigi Franci
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
- Correspondence: (C.Z.); (G.F.)
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38
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Calinescu AA, Kauss MC, Sultan Z, Al-Holou WN, O'Shea SK. Stem cells for the treatment of glioblastoma: a 20-year perspective. CNS Oncol 2021; 10:CNS73. [PMID: 34006134 PMCID: PMC8162173 DOI: 10.2217/cns-2020-0026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma, the deadliest form of primary brain tumor, remains a disease without cure. Treatment resistance is in large part attributed to limitations in the delivery and distribution of therapeutic agents. Over the last 20 years, numerous preclinical studies have demonstrated the feasibility and efficacy of stem cells as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies, discuss mechanisms underlying their beneficial effect and highlight experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages brought by stem cells for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies. Glioblastoma is the deadliest and most common form of brain tumor, for which there is no cure. It is very difficult to deliver medicine to the tumor cells, because they spread out widely into the normal brain, and local blood vessels represent a barrier that most medicines cannot cross. It was shown, in many studies over the last 20 years, that stem cells are attracted toward the tumor and that they can deliver many kinds of therapeutic agents directly to brain cancer cells and shrink the tumor. In this review we analyze these studies and present new discoveries that can be used to make stem cell therapies for glioblastoma more effective to prolong the life of patients with brain tumors.
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Affiliation(s)
| | - McKenzie C Kauss
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,College of Literature Science & Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Zain Sultan
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,College of Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wajd N Al-Holou
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sue K O'Shea
- Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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39
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Li J, Wang W, Wang J, Cao Y, Wang S, Zhao J. Viral Gene Therapy for Glioblastoma Multiforme: A Promising Hope for the Current Dilemma. Front Oncol 2021; 11:678226. [PMID: 34055646 PMCID: PMC8155537 DOI: 10.3389/fonc.2021.678226] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/29/2021] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma multiforme (GBM), as one of the most common malignant brain tumors, was limited in its treatment effectiveness with current options. Its invasive and infiltrative features led to tumor recurrence and poor prognosis. Effective treatment and survival improvement have always been a challenge. With the exploration of genetic mutations and molecular pathways in neuro-oncology, gene therapy is becoming a promising therapeutic approach. Therapeutic genes are delivered into target cells with viral vectors to act specific antitumor effects, which can be used in gene delivery, play an oncolysis effect, and induce host immune response. The application of engineering technology makes the virus vector used in genetics a more prospective future. Recent advances in viral gene therapy offer hope for treating brain tumors. In this review, we discuss the types and designs of viruses as well as their study progress and potential applications in the treatment of GBM. Although still under research, viral gene therapy is promising to be a new therapeutic approach for GBM treatment in the future.
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Affiliation(s)
- Junsheng Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Wen Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Jia Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Yong Cao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Shuo Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Jizong Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.,Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China.,Savaid Medical School, University of the Chinese Academy of Sciences, Beijing, China
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40
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Zhang DY, Singer L, Sonabend AM, Lukas RV. Gene Therapy for the Treatment of Malignant Glioma. ADVANCES IN ONCOLOGY 2021; 1:189-202. [PMID: 37476488 PMCID: PMC10358332 DOI: 10.1016/j.yao.2021.02.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Affiliation(s)
- Daniel Y. Zhang
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 303 East Superior Street SQ-601, Chicago, IL 60611, USA
| | - Lauren Singer
- Department of Neurology, Rush University Medical Center, Rush University, 1725 West Harrison Street Suite #1106, Chicago, IL 60612, USA
| | - Adam M. Sonabend
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 259 East Erie Street Suite #1950, Chicago, IL 60611, USA
- Lou and Jean Malnati Brain Tumor Institute, Chicago, IL, USA
| | - Rimas V. Lukas
- Lou and Jean Malnati Brain Tumor Institute, Chicago, IL, USA
- Department of Neurology, Northwestern University Feinberg School of Medicine, 710 North Lake Shore Drive, Abbott Hall 1114, Chicago, IL 60611, USA
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Abedalthagafi M, Mobark N, Al-Rashed M, AlHarbi M. Epigenomics and immunotherapeutic advances in pediatric brain tumors. NPJ Precis Oncol 2021; 5:34. [PMID: 33931704 PMCID: PMC8087701 DOI: 10.1038/s41698-021-00173-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 04/05/2021] [Indexed: 12/15/2022] Open
Abstract
Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.
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Affiliation(s)
- Malak Abedalthagafi
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia.
| | - Nahla Mobark
- Department of Paediatric Oncology Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - May Al-Rashed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Musa AlHarbi
- Department of Paediatric Oncology Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
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42
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Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, Kachurak K, Nan L, Kang KD, Totsch S, Schlappi C, Martin AM, Pastakia D, McNall-Knapp R, Farouk Sait S, Khakoo Y, Karajannis MA, Woodling K, Palmer JD, Osorio DS, Leonard J, Abdelbaki MS, Madan-Swain A, Atkinson TP, Whitley RJ, Fiveash JB, Markert JM, Gillespie GY. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N Engl J Med 2021; 384:1613-1622. [PMID: 33838625 PMCID: PMC8284840 DOI: 10.1056/nejmoa2024947] [Citation(s) in RCA: 226] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
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Affiliation(s)
- Gregory K Friedman
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - James M Johnston
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Asim K Bag
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Joshua D Bernstock
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Rong Li
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Inmaculada Aban
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Kara Kachurak
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Li Nan
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Kyung-Don Kang
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Stacie Totsch
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Charles Schlappi
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Allison M Martin
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Devang Pastakia
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Rene McNall-Knapp
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Sameer Farouk Sait
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Yasmin Khakoo
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Matthias A Karajannis
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Karina Woodling
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Joshua D Palmer
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Diana S Osorio
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Jeffrey Leonard
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Mohamed S Abdelbaki
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Avi Madan-Swain
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - T Prescott Atkinson
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - Richard J Whitley
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - John B Fiveash
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - James M Markert
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
| | - G Yancey Gillespie
- From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.)
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Lu K, Wang F, Ma B, Cao W, Guo Q, Wang H, Rodriguez R, Wang Z. Teratogenic Toxicity Evaluation of Bladder Cancer-Specific Oncolytic Adenovirus on Mice. Curr Gene Ther 2021; 21:160-166. [PMID: 33334289 DOI: 10.2174/1566523220999201217161258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue-specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer. The virus biodistribution and body toxicity in nude mice have also been investigated. However, the safety of the bladder cancer-specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation. OBJECTIVE In order to evaluate the teratogenic toxicity of bladder cancer-specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue-specific adenovirus Ad-PSCAE- UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials. METHODS On the sixth day of being fertilized, the pregnant mice began to be intramuscularly administrated with AD (1×107VP, 1×108VP, 1×109VP) every other day for ten days. The pregnant mice were then divided into two groups. One group was euthanized on the seventeenth day; the fetal mice were taken out, and the bone structure of the infants was observed. The other group was observed until natural childbirth. The Filial Generation (F1) is fed for 30 days; the variations in the growth progress and development were assessed. The mice were then euthanized; The tissues from major organs were harvested and observed under the microscope. RESULTS In the process of teratogenic toxicity test, the Placenta weight, fetal mice weight, body length, and a tail length of mice fetal in adenovirus treated group did not reveal any alteration. Meanwhile, comparing with the PBS group, there is no obvious change in the skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes in mice weight show statistical significance. However, in the progress of the growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs. CONCLUSION Our study demonstrated that bladder cancer-specific adenovirus Ad-PSCAE-UPII- E1A-AR appears safe in pregnant mice without any discernable effects on fetal mice and F1 development. Hence, it is relatively safe for tumor gene therapy.
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Affiliation(s)
- Keqing Lu
- Gansu Nephro-Urological Clinical Center, Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University), Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou730000, China
| | - Fang Wang
- Center of Medical Experiments, School of Basic Medical Sciences, Lanzhou University, Gansu Province, Lanzhou730000, China
| | - Baoliang Ma
- Gansu Nephro-Urological Clinical Center, Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University), Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou730000, China
| | - Wenjuan Cao
- Gansu Nephro-Urological Clinical Center, Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University), Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou730000, China
| | - Qi Guo
- Gansu Nephro-Urological Clinical Center, Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University), Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou730000, China
| | - Hanzhang Wang
- Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States
| | - Ronald Rodriguez
- Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States
| | - Zhiping Wang
- Gansu Nephro-Urological Clinical Center, Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University), Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou730000, China
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Physiological Imaging Methods for Evaluating Response to Immunotherapies in Glioblastomas. Int J Mol Sci 2021; 22:ijms22083867. [PMID: 33918043 PMCID: PMC8069140 DOI: 10.3390/ijms22083867] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 12/19/2022] Open
Abstract
Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive multi-modal therapy. Immunotherapy is currently being evaluated as an alternate treatment modality for recurrent GBMs in clinical trials. These immunotherapeutic approaches harness the patient's immune response to fight and eliminate tumor cells. Standard MR imaging is not adequate for response assessment to immunotherapy in GBM patients even after using refined response assessment criteria secondary to amplified immune response. Thus, there is an urgent need for the development of effective and alternative neuroimaging techniques for accurate response assessment. To this end, some groups have reported the potential of diffusion and perfusion MR imaging and amino acid-based positron emission tomography techniques in evaluating treatment response to different immunotherapeutic regimens in GBMs. The main goal of these techniques is to provide definitive metrics of treatment response at earlier time points for making informed decisions on future therapeutic interventions. This review provides an overview of available immunotherapeutic approaches used to treat GBMs. It discusses the limitations of conventional imaging and potential utilities of physiologic imaging techniques in the response assessment to immunotherapies. It also describes challenges associated with these imaging methods and potential solutions to avoid them.
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Janjua TI, Rewatkar P, Ahmed-Cox A, Saeed I, Mansfeld FM, Kulshreshtha R, Kumeria T, Ziegler DS, Kavallaris M, Mazzieri R, Popat A. Frontiers in the treatment of glioblastoma: Past, present and emerging. Adv Drug Deliv Rev 2021; 171:108-138. [PMID: 33486006 DOI: 10.1016/j.addr.2021.01.012] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/13/2020] [Accepted: 01/09/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is one of the most aggressive cancers of the brain. Despite extensive research over the last several decades, the survival rates for GBM have not improved and prognosis remains poor. To date, only a few therapies are approved for the treatment of GBM with the main reasons being: 1) significant tumour heterogeneity which promotes the selection of resistant subpopulations 2) GBM induced immunosuppression and 3) fortified location of the tumour in the brain which hinders the delivery of therapeutics. Existing therapies for GBM such as radiotherapy, surgery and chemotherapy have been unable to reach the clinical efficacy necessary to prolong patient survival more than a few months. This comprehensive review evaluates the current and emerging therapies including those in clinical trials that may potentially improve both targeted delivery of therapeutics directly to the tumour site and the development of agents that may specifically target GBM. Particular focus has also been given to emerging delivery technologies such as focused ultrasound, cellular delivery systems nanomedicines and immunotherapy. Finally, we discuss the importance of developing novel materials for improved delivery efficacy of nanoparticles and therapeutics to reduce the suffering of GBM patients.
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Podshivalova ES, Semkina AS, Kravchenko DS, Frolova EI, Chumakov SP. Efficient delivery of oncolytic enterovirus by carrier cell line NK-92. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:110-118. [PMID: 33981827 PMCID: PMC8065264 DOI: 10.1016/j.omto.2021.03.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 03/26/2021] [Indexed: 02/07/2023]
Abstract
Many members of the enterovirus family are considered as promising oncolytic agents; however, their systemic administration is largely inefficient due to the rapid neutralization of the virus in the circulation and the barrier functions of the endothelium. We aimed to evaluate natural killer cells as carriers for the delivery of oncolytic enteroviruses, which would combine the effects of cell immunotherapy with virotherapy. We tested four strains of nonpathogenic enteroviruses against the glioblastoma cell line panel and evaluated the produced infectious titers. Next, we explored whether these virus strains could be delivered to the tumor by natural killer cell line NK-92, which is being actively evaluated as a clinically acceptable therapeutic. Several strains of enteroviruses demonstrated oncolytic properties, but only coxsackievirus A7 (CVA7) could replicate in NK-92 cells efficiently. We compared the delivery efficiency of CVA7 in vivo, using NK-92 cells and direct intravenous administration, and found significant advantages of cell delivery even after a single injection. This suggests that the NK-92 cell line can be utilized as a vehicle for the delivery of the oncolytic strain of CVA7, which would improve the clinical potential of this viral oncolytic for the treatment of glioblastoma multiforme and other forms of cancer.
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Affiliation(s)
| | - Alevtina Sergeevna Semkina
- Department of Medical Nanobiotechnologies, Pirogov Russian National Research Medical University, Ostrovityanova 1, Moscow 117997, Russia.,Department of Basic and Applied Neurobiology, Serbsky National Medical Research Center for Psychiatry and Narcology, Kropotkinskiy 23, Moscow 119991, Russia
| | - Dmitry Sergeevich Kravchenko
- Department of Peptide and Protein Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
| | - Elena Ivanovna Frolova
- Department of Peptide and Protein Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
| | - Stepan Petrovich Chumakov
- Department of Peptide and Protein Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
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Zeng F, Li G, Liu X, Zhang K, Huang H, Jiang T, Zhang Y. Plasminogen Activator Urokinase Receptor Implies Immunosuppressive Features and Acts as an Unfavorable Prognostic Biomarker in Glioma. Oncologist 2021; 26:e1460-e1469. [PMID: 33687124 DOI: 10.1002/onco.13750] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 02/25/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Clinical outcomes of patients with glioma are still poor, even after standard treatments, including surgery combined with radiotherapy and chemotherapy. New therapeutic strategies and targets for glioma are urgently needed. Plasminogen activator urokinase receptor (PLAUR), a highly glycosylated integral membrane protein, is reported to modulate plasminogen activation and extracellular matrix degradation in many malignant cancers, but its role in gliomas remains unclear. METHODS Glioma samples with mRNA sequencing data and clinical information from the Chinese Glioma Genome Atlas (n = 310) data set and The Cancer Genome Atlas (n = 611) data set were collected for this study. Analyses using Kaplan-Meier plots, time-dependent receiver operating characteristic curves, Cox regression, and nomograms were conducted to evaluate the prognostic performance of PLAUR expression. Analyses using Metascape, ESTIMATE, EPIC, and immunohistochemical staining were performed to reveal the potential biological mechanism. The statistical analysis and graphical work were completed using SPSS, R language, and GraphPad Prism. RESULTS PLAUR was highly expressed in phenotypes associated with glioma malignancy and could serve as an independent prognostic indicator. Functional analysis revealed the correlation between PLAUR and immune response. Further studies found that samples with higher PLAUR expression were infiltrated with fewer CD8 T cells and many more M2 macrophages. Strong positive correlation was demonstrated between PLAUR expression and some immunosuppressive markers, including immune checkpoints and cytokines. These findings were also confirmed in patient samples. CONCLUSION Our results elucidated the clinical significance and immunosuppressive effect of PLAUR in gliomas, which might provide some clues in glioma immunotherapy. IMPLICATIONS FOR PRACTICE Although the efficacy of immunotherapy has been verified in other tumors, its application in glioma is impeded because of the unique microenvironment. Tumor-associated macrophages, which are particularly abundant in a glioma mass, contribute much to the immunosuppressive microenvironment and offer new opportunities in glioma immunotherapy. The results of this study identified plasminogen activator urokinase receptor (PLAUR) expression as a potential marker to predict the infiltration of macrophages and the status of immune microenvironment in patients with glioma, suggesting that treatment decisions could be based on PLAUR level when administering immunotherapeutics. The soluble PLAUR in blood and other body fluids would make this approach easy to implement in the clinic.
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Affiliation(s)
- Fan Zeng
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Guanzhang Li
- Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Xiu Liu
- Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Kenan Zhang
- Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Hua Huang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Tao Jiang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Ying Zhang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
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Banerjee K, Núñez FJ, Haase S, McClellan BL, Faisal SM, Carney SV, Yu J, Alghamri MS, Asad AS, Candia AJN, Varela ML, Candolfi M, Lowenstein PR, Castro MG. Current Approaches for Glioma Gene Therapy and Virotherapy. Front Mol Neurosci 2021; 14:621831. [PMID: 33790740 PMCID: PMC8006286 DOI: 10.3389/fnmol.2021.621831] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
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Affiliation(s)
- Kaushik Banerjee
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Felipe J. Núñez
- Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, Buenos Aires, Argentina
| | - Santiago Haase
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Brandon L. McClellan
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Syed M. Faisal
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Stephen V. Carney
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Cancer Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Jin Yu
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Mahmoud S. Alghamri
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Antonela S. Asad
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro J. Nicola Candia
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Maria Luisa Varela
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Marianela Candolfi
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Pedro R. Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria G. Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
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Yang H, Wei L, Xun Y, Yang A, You H. BRD4: An emerging prospective therapeutic target in glioma. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:1-14. [PMID: 33851008 PMCID: PMC8010576 DOI: 10.1016/j.omto.2021.03.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite advances in treatment, the prognosis for glioma patients remains poor. Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) protein family, plays an important role in controlling oncogene expression and genome stability. In recent years, numerous BRD4 inhibitors have entered clinical trials and achieved exciting results in tumor treatment. Recent clinical studies have shown that BRD4 expression in glioma is significantly higher than in the adjacent normal brain tissue. BRD4 inhibitors effectively penetrate the blood-brain barrier and target glioma tumor tissues but have little effect on normal brain tissues. Thus, BRD4 is a target for the treatment of glioma. In this study, we discuss the progress in the use of BRD4 inhibitors for glioma treatment, their mechanism of action, and their broad potential clinical application.
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Affiliation(s)
- Hua Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan 528000, Guangdong Province, China
| | - Li Wei
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong Province, China
| | - Yang Xun
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan 528000, Guangdong Province, China
| | - Anping Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan 528000, Guangdong Province, China
| | - Hua You
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong Province, China
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50
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Nguyen HM, Saha D. The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment. Oncolytic Virother 2021; 10:1-27. [PMID: 33659221 PMCID: PMC7917312 DOI: 10.2147/ov.s268426] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) is a lethal primary malignant brain tumor with no current effective treatments. The recent emergence of immuno-virotherapy and FDA approval of T-VEC have generated a great expectation towards oncolytic herpes simplex viruses (oHSVs) as a promising treatment option for GBM. Since the generation and testing of the first genetically engineered oHSV in glioma in the early 1990s, oHSV-based therapies have shown a long way of great progress in terms of anti-GBM efficacy and safety, both preclinically and clinically. Here, we revisit the literature to understand the recent advancement of oHSV in the treatment of GBM. In addition, we discuss current obstacles to oHSV-based therapies and possible strategies to overcome these pitfalls.
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Affiliation(s)
- Hong-My Nguyen
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, School of Pharmacy, Abilene, TX, 79601, USA
| | - Dipongkor Saha
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, School of Pharmacy, Abilene, TX, 79601, USA
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