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Saini S, Gadet JAMA, Freeman GJ, Chiocca EA, Mineo M. Improving IL12 immunotherapy in glioblastoma by targeting the long noncoding RNA INCR1. J Neurooncol 2025; 173:205-216. [PMID: 40035950 PMCID: PMC12041012 DOI: 10.1007/s11060-025-04978-2] [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: 01/14/2025] [Accepted: 02/12/2025] [Indexed: 03/06/2025]
Abstract
PURPOSE The potent antitumor effects of interleukin 12 (IL12) gene therapy in glioblastoma (GBM) are significantly attenuated by the highly immunosuppressive microenvironment and the upregulation of the PD-1/PD-L1 immune checkpoint. However, combining IL12 gene therapy with PD-1/PD-L1 inhibitors failed to improve efficacy. This study aims to assess the effects of silencing the immunosuppressive long noncoding RNA INCR1 when combined with IL12 therapy. METHODS RNAscope in situ hybridization was performed to analyze INCR1 and PD-L1 expression in tumor tissues from GBM patients pre- and post-IL12 gene therapy. Quantitative PCR was used to analyze immunosuppressive gene expression in patient-derived GBM cells co-cultured with immune cells stimulated with IL12. The effects of INCR1 and PD-L1 silencing on the expression of immunosuppressive genes were evaluated by RNA sequencing. 3D-cytotoxicity assays were performed to assess the activity of immune cells against GBM tumor cells. RESULTS INCR1 and PD-L1 expression was upregulated in tumor tissue from GBM patients treated with IL12 gene therapy compared to the tumor tissue of the same patients before the IL12 treatment. Co-culture of patient-derived GBM cells with IL12-stimulated immune cells increased the expression of several immunosuppressive genes. Knocking down INCR1 was more effective than silencing PD-L1 in reducing the expression of multiple immunosuppressive genes. INCR1 silencing improved IL12-mediated immune cell antitumor activity compared to monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint signaling. CONCLUSION INCR1 silencing affects more immune evasive pathways than PD-L1. Targeting INCR1 may represent a valid approach to improve the efficacy of IL12 therapy in GBM.
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Affiliation(s)
- Shikha Saini
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Josephina A M A Gadet
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
- Faculty of Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Gordon J Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - E Antonio Chiocca
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Marco Mineo
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.
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Chen H, Koul D, Zhang Y, Ghobadi SN, Zhu Y, Hou Q, Chang E, Habte FG, Paulmurugan R, Khan S, Zheng Y, Graeber MB, Herschmann I, Lee KS, Wintermark M. Pulsed focused ultrasound alters the proteomic profile of the tumor microenvironment in a syngeneic mouse model of glioblastoma. J Neurooncol 2024; 170:347-361. [PMID: 39180641 DOI: 10.1007/s11060-024-04801-4] [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: 06/17/2024] [Accepted: 08/09/2024] [Indexed: 08/26/2024]
Abstract
PURPOSE Glioblastoma (GBM), a lethal primary adult malignancy, is difficult to treat because of the restrictive nature of the blood-brain barrier (BBB), blood-tumor barrier (BTB), and the immunosuppressive tumor microenvironment (TME). Since pulsed focused ultrasound (pFUS) is currently used to improve therapeutic deliveries across these barriers, this study aims to characterize the impact of pFUS on the TME proteomics upon opening the BBB and BTB. METHODS We utilized MRI-guided, pFUS with ultrasound contrast microbubbles (termed 'pFUS' herein) to selectively and transiently open the BBB and BTB investigating proteomic modifications in the TME. Utilizing an orthotopically-allografted mouse GL26 GBM model (Ccr2RFP/wt - Cx3cr1GFP/wt), pFUS's effect on glioma proteomics was evaluated using a Luminex 48-plex assay. RESULTS pFUS treated tumors exhibited increases in pro-inflammatory cytokines, chemokines, and trophic factors (CCTFs). Proteomic changes in tumors tend to peak at 24 h after single pFUS session (1x), with levels then plateauing or declining over the subsequent 24 h. Tumors receiving three pFUS sessions (3x) showed elevated CCTFs levels peaking as early as 6 h after the third session. CONCLUSIONS pFUS together with microbubbles induces a sterile inflammatory response in the TME of a mouse GBM tumor. Moreover, this proinflammatory shift can be sustained and perhaps primed for more rapid responses upon multiple sessions of pFUS. These findings raise the intriguing potential that pFUS-induced BBB and BTB opening may not only be effective in facilitating the therapeutic agent delivery, but also be harnessed to modify the TME to assist immunotherapies in overcoming immune evasion in GBM.
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Affiliation(s)
- Hui Chen
- Department of Neuroradiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1482, Houston, TX, 77030, USA
| | - Dimpy Koul
- Department of Neuroradiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1482, Houston, TX, 77030, USA
| | - Yanrong Zhang
- Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA
| | - Sara Natasha Ghobadi
- Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA
| | - Yayu Zhu
- Salpointe Catholic High School, Tucson, AZ, USA
| | - Qingyi Hou
- Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA
| | - Edwin Chang
- Department of Radiology, Molecular Imaging Program, Stanford University, Stanford, CA, USA
| | - Frezghi G Habte
- Department of Radiology, Molecular Imaging Program, Stanford University, Stanford, CA, USA
| | - Ramasamy Paulmurugan
- Department of Radiology, Molecular Imaging Program, Stanford University, Stanford, CA, USA
| | - Sabbir Khan
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuqi Zheng
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Manuel B Graeber
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2050, Australia
- University of Sydney Association of Professors (USAP), University of Sydney, Camperdown, NSW, 2006, Australia
| | - Iris Herschmann
- The Human Immune Monitoring Center (HIMC), Stanford University, Stanford, CA, USA
| | - Kevin S Lee
- Departments of Neuroscience and Neurosurgery, Center for Brain Immunology and Glia, School of Medicine, University of Virginia, 409 Lane Road, MR4 Building, PO Box 801392, Charlottesville, VA, 22903, USA.
| | - Max Wintermark
- Department of Neuroradiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1482, Houston, TX, 77030, USA.
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3
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Ataei A, Azizi M, Hajisadeghi S, Madani M, Khorami M, Hassantash S, Saeidpour Masouleh S, Barati G. The Therapeutic Effects of Mesenchymal Stem Cells and their Secretome on Oral Squamous Cell Carcinoma. Curr Mol Med 2024; 24:1195-1207. [PMID: 37366360 DOI: 10.2174/1566524023666230627151809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023]
Abstract
Oral cancers are prevalent in the human population, particularly in unindustrialized countries. In 90 % of oral cancers, the tumors arise from squamous cells, which is called oral squamous cell carcinoma (OSCC). Despite new treatment strategies, the morbidity and mortality rates are still high. Current treatment options including surgery, chemotherapy, and radiotherapy are not effective in the treatment of the tumor. Cell therapy with mesenchymal stem cells (MSCs) is considered one of the leading strategies in cancer treatment. However, the field of MSC therapy in OSCC is immature and ongoing studies are being conducted in experimental and pre-clinical studies. Here, we reviewed these studies to figure out whether the use of MSCs could be worthwhile in OSCC therapy or not. Both native and engineered MSCs as well as their secretome have been used in the treatment of OSCC. It seems that genetically modified MSCs or their secretome could inhibit the tumorigenesis of OSCC. However, further pre-clinical studies are required to come to a conclusion.
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Affiliation(s)
- Atefe Ataei
- Department of Periodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Majid Azizi
- Department of Periodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Samira Hajisadeghi
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Qom University of Medical Sciences, Qom, Iran
| | - Mojan Madani
- Orthodontics Department, Dental Faculty, Arak UNDUniversity of Medical Sciences, Arak, Iran
| | - Mozhgan Khorami
- Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Hassantash
- Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ghasem Barati
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Stem Cell Technology Research Center, Tehran, Iran
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Onnockx S, Baldo A, Pauwels K. Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment. Vaccines (Basel) 2023; 11:1448. [PMID: 37766125 PMCID: PMC10535390 DOI: 10.3390/vaccines11091448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Attenuated and/or genetically modified oncolytic viruses (OV) gain increasing interest as a promising approach for cancer therapy. Beside the assessment of subject safety, quality and efficacy aspects of medicinal products for human use, genetically modified viruses are also governed by EU regulatory frameworks requiring an environmental risk assessment (ERA). An important element to be assessed as part of the ERA is the incidence of exposure to OV of individuals, other than the trial subjects, and the environment. The evidence-based evaluation of shedding data is considered to be decisive in that context, as it may impact the OV capacity to be transmitted. This is particularly true for OV still able to (conditionally) replicate as opposed to replication-defective viral vectors commonly used in gene therapy or vaccination. To our knowledge, this article presents the most extensive and up-to-date review of shedding data reported with OV employed in clinics. Besides the identification of a topical need for improving the collection of shedding data, this article aims at providing an aid to the design of an appropriate shedding study, thereby relying on and further complementing principles described in existing guidelines issued by European and international institutions.
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Affiliation(s)
- Sheela Onnockx
- Sciensano, Service Biosafety and Biotechnology, Rue Juliette Wytsmanstraat 14, B-1050 Brussels, Belgium; (A.B.); (K.P.)
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Bernstock JD, Ling A, Chiocca EA. Combined gene therapies for high-grade glioma. Lancet Oncol 2023; 24:949-950. [PMID: 37657467 DOI: 10.1016/s1470-2045(23)00389-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 08/02/2023] [Indexed: 09/03/2023]
Affiliation(s)
- Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alexander Ling
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - E Antonio Chiocca
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Blomberg E, Silginer M, Roth P, Weller M. Differential roles of type I interferon signaling in tumor versus host cells in experimental glioma models. Transl Oncol 2023; 28:101607. [PMID: 36571986 PMCID: PMC9800198 DOI: 10.1016/j.tranon.2022.101607] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/11/2022] [Accepted: 12/17/2022] [Indexed: 12/25/2022] Open
Abstract
Despite multimodal treatment approaches including surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma remains in the range of one year and thus poor. Type I interferons (IFN) are involved in immune responses to viral infection and exhibit anti-tumor activity in certain cancers. Here we explored the biological relevance of constitutive type I IFN signaling in murine glioma models in vitro and in vivo. CT-2A, GL-261, SMA-497, SMA-540 and SMA-560 murine glioma cells expressed IFN type I receptors IFNAR1 and IFNAR2 and were responsive to exogenous IFN stimulation. CRISPR/Cas9-mediated deletion of IFNAR1 decreased the baseline expression of type I IFN response genes in GL-261 cells, but neither in CT-2A nor in SMA-560 cells. IFNAR1 deletion slowed growth in GL-261 and SMA-560, but not in CT-2A cells. However, only the growth of IFNAR1-depleted GL-261 tumors and not that of SMA-560 tumors was delayed in vivo upon orthotopic tumor cell implantation into syngeneic mice. This survival gain was no longer detected when the IFNAR1-depleted GL-261 cells were inoculated into IFNAR1-deficient mice. Altogether these data suggest that constitutive type I IFN signaling in gliomas may be pro-tumorigenic, but only in a microenvironment that is proficient for type I IFN signaling in the host.
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Affiliation(s)
- Evelina Blomberg
- Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Zürich
| | - Manuela Silginer
- Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Patrick Roth
- Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Zürich; Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Michael Weller
- Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Zürich; Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
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Varela ML, Comba A, Faisal SM, Argento A, Franson A, Barissi MN, Sachdev S, Castro MG, Lowenstein PR. Gene Therapy for High Grade Glioma: The Clinical Experience. Expert Opin Biol Ther 2023; 23:145-161. [PMID: 36510843 PMCID: PMC9998375 DOI: 10.1080/14712598.2022.2157718] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of ~18 months. The standard of care (SOC) is maximal safe surgical resection, and radiation therapy with concurrent and adjuvant temozolomide. This protocol remains unchanged since 2005, even though HGG median survival has marginally improved. AREAS COVERED Gene therapy was developed as a promising approach to treat HGG. Here, we review completed and ongoing clinical trials employing viral and non-viral vectors for adult and pediatric HGG, as well as the key supporting preclinical data. EXPERT OPINION These therapies have proven safe, and pre- and post-treatment tissue analyses demonstrated tumor cell lysis, increased immune cell infiltration, and increased systemic immune function. Although viral therapy in clinical trials has not yet significantly extended the survival of HGG, promising strategies are being tested. Oncolytic HSV vectors have shown promising results for both adult and pediatric HGG. A recently published study demonstrated that HG47Δ improved survival in recurrent HGG. Likewise, PVSRIPO has shown survival improvement compared to historical controls. It is likely that further analysis of these trials will stimulate the development of new administration protocols, and new therapeutic combinations that will improve HGG prognosis.
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Affiliation(s)
- 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
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Comba
- 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
- Rogel Cancer Center, 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
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Anna Argento
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Franson
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Marcus N Barissi
- 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
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sean Sachdev
- Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL USA
| | - 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
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - 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
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States
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Giotta Lucifero A, Luzzi S. Emerging immune-based technologies for high-grade gliomas. Expert Rev Anticancer Ther 2022; 22:957-980. [PMID: 35924820 DOI: 10.1080/14737140.2022.2110072] [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] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The selection of a tailored and successful strategy for high-grade gliomas (HGGs) treatment is still a concern. The abundance of aberrant mutations within the heterogenic genetic landscape of glioblastoma strongly influences cell expansion, proliferation, and therapeutic resistance. Identification of immune evasion pathways opens the way to novel immune-based strategies. This review intends to explore the emerging immunotherapies for HGGs. The immunosuppressive mechanisms related to the tumor microenvironment and future perspectives to overcome glioma immunity barriers are also debated. AREAS COVERED An extensive literature review was performed on the PubMed/Medline and ClinicalTrials.gov databases. Only highly relevant articles in English and published in the last 20 years were selected. Data about immunotherapies coming from preclinical and clinical trials were summarized. EXPERT OPINION The overall level of evidence about the efficacy and safety of immunotherapies for HGGs is noteworthy. Monoclonal antibodies have been approved as second-line treatment, while peptide vaccines, viral gene strategies, and adoptive technologies proved to boost a vivid antitumor immunization. Malignant brain tumor-treating fields are ever-changing in the upcoming years. Constant refinements and development of new routes of drug administration will permit to design of novel immune-based treatment algorithms thus improving the overall survival.
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Affiliation(s)
- Alice Giotta Lucifero
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Chiocca EA, Gelb AB, Chen CC, Rao G, Reardon DA, Wen PY, Bi WL, Peruzzi P, Amidei C, Triggs D, Seften L, Park G, Grant J, Truman K, Buck JY, Hadar N, Demars N, Miao J, Estupinan T, Loewy J, Chadha K, Tringali J, Cooper L, Lukas RV. Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: An open-label, multi-institutional phase I trial. Neuro Oncol 2022; 24:951-963. [PMID: 34850166 PMCID: PMC9159462 DOI: 10.1093/neuonc/noab271] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. METHODS An open-label, multi-institutional, dose-escalation phase I trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). Nivolumab was administered 7 (±3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. RESULTS Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related, and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post-treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. CONCLUSION The safety of this combination immunotherapy was established and has led to an ongoing phase II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).
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Affiliation(s)
- E Antonio Chiocca
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Clark C Chen
- University of Minnesota, Minneapolis, Minnesota, USA
| | - Ganesh Rao
- Baylor College of Medicine, Houston, Texas, USA
| | | | - Patrick Y Wen
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Wenya Linda Bi
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Pierpaolo Peruzzi
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Dan Triggs
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Leah Seften
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Grace Park
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - James Grant
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kyla Truman
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jill Y Buck
- Ziopharm Oncology, Inc., Boston, Massachusetts, USA
| | - Nira Hadar
- Ziopharm Oncology, Inc., Boston, Massachusetts, USA
| | | | - John Miao
- Ziopharm Oncology, Inc., Boston, Massachusetts, USA
| | | | - John Loewy
- Ziopharm Oncology, Inc., Boston, Massachusetts, USA
| | - Kamal Chadha
- Ziopharm Oncology, Inc., Boston, Massachusetts, USA
| | | | | | - Rimas V Lukas
- Northwestern Memorial Hospital, Chicago, Illinois, USA
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Cytokine Responses to Adenovirus and Adenovirus Vectors. Viruses 2022; 14:v14050888. [PMID: 35632630 PMCID: PMC9145601 DOI: 10.3390/v14050888] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022] Open
Abstract
The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine storm are known clinical phenomena observed following naturally disseminated adenovirus infection in immunocompromised hosts as well as when extremely high doses of adenovirus vectors are injected intravenously. This dose-dependent, cytokine-mediated toxicity compromises the safety of adenovirus-based vectors and represents a critical problem, limiting their utility for gene therapy applications and the therapy of disseminated cancer, where intravenous injection of adenovirus vectors may provide therapeutic benefits. The mechanisms triggering severe cytokine response are not sufficiently understood, prompting efforts to further investigate this phenomenon, especially in clinically relevant settings. In this review, we summarize the current knowledge on cytokine and chemokine activation in response to adenovirus- and adenovirus-based vectors and discuss the underlying mechanisms that may trigger acute cytokine storm syndrome. First, we review profiles of cytokines and chemokines that are activated in response to adenovirus infection initiated via different routes. Second, we discuss the molecular mechanisms that lead to cytokine and chemokine transcriptional activation. We further highlight how immune cell types in different organs contribute to synthesis and systemic release of cytokines and chemokines in response to adenovirus sensing. Finally, we review host factors that can limit cytokine and chemokine expression and discuss currently available and potential future interventional approaches that allow for the mitigation of the severity of the cytokine storm syndrome. Effective cytokine-targeted interventional approaches may improve the safety of systemic adenovirus delivery and thus broaden the potential clinical utility of adenovirus-based therapeutic vectors.
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Lechpammer M, Rao R, Shah S, Mirheydari M, Bhattacharya D, Koehler A, Toukam DK, Haworth KJ, Pomeranz Krummel D, Sengupta S. Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers. Cancers (Basel) 2022; 14:1627. [PMID: 35406398 PMCID: PMC8997081 DOI: 10.3390/cancers14071627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12-15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood-brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.
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Affiliation(s)
- Mirna Lechpammer
- Foundation Medicine, Inc., Cambridge, MA 02141, USA;
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Rohan Rao
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
| | - Sanjit Shah
- Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA;
| | - Mona Mirheydari
- Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (M.M.); (K.J.H.)
| | - Debanjan Bhattacharya
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
| | - Abigail Koehler
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
| | - Donatien Kamdem Toukam
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
| | - Kevin J. Haworth
- Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (M.M.); (K.J.H.)
| | - Daniel Pomeranz Krummel
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
| | - Soma Sengupta
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (R.R.); (D.B.); (A.K.); (D.K.T.)
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12
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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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13
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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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14
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Wang JL, Scheitler KM, Wenger NM, Elder JB. Viral therapies for glioblastoma and high-grade gliomas in adults: a systematic review. Neurosurg Focus 2021; 50:E2. [PMID: 33524943 DOI: 10.3171/2020.11.focus20854] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/09/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE High-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically favorable adjuvant modality that might overcome intrinsic factors of HGGs that confer treatment resistance. METHODS The authors present the results of systematic searches of the MEDLINE and ClinicalTrials.gov databases that were performed for clinical trials published or registered up to July 15, 2020. RESULTS Fifty-one completed clinical trials were identified that made use of a virus-based therapeutic strategy to treat HGG. The two main types of viral therapies were oncolytic viruses and viral vectors for gene therapy. Among clinical trials that met inclusion criteria, 20 related to oncolytic viruses and 31 to gene therapy trials. No oncolytic viruses have progressed to phase III clinical trial testing, although there have been many promising early-phase results and no reported cases of encephalitis or death due to viral therapy. Three phase III trials in which viral gene therapy was used have been completed but have not resulted in any FDA-approved therapy. Recent efforts in this area have been focused on the delivery of suicide genes such as herpes simplex virus thymidine kinase and cytosine deaminase. CONCLUSIONS Decades of research efforts and an improving understanding of the immunomodulatory effects of viral therapies for gliomas are informing ongoing clinical efforts aimed at improving outcomes in patients with HGG. The available clinical data reveal varied efficacy among different virus-based treatment strategies.
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Affiliation(s)
- Joshua L Wang
- 1Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | | | - Nicole M Wenger
- 3Department of Neurosurgery, University of Maryland, Baltimore, Maryland
| | - J Bradley Elder
- 1Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
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15
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Lu VM, Shah AH, Vallejo FA, Eichberg DG, Luther EM, Shah SS, Komotar RJ, Ivan ME. Clinical trials using oncolytic viral therapy to treat adult glioblastoma: a progress report. Neurosurg Focus 2021; 50:E3. [PMID: 33524946 DOI: 10.3171/2020.11.focus20860] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/13/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Adult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date. METHODS The ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector-based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials. RESULTS A total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13-108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1-15), via industry funding (n = 18 trials, 62%). CONCLUSIONS There are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials.
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Mozhei O, G. Teschemacher A, Kasparov S. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers (Basel) 2020; 12:E3724. [PMID: 33322507 PMCID: PMC7764372 DOI: 10.3390/cancers12123724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 01/02/2023] Open
Abstract
In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells.
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Affiliation(s)
- Oleg Mozhei
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
| | - Anja G. Teschemacher
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
| | - Sergey Kasparov
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
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17
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Udayakumar TS, Betancourt DM, Ahmad A, Tao W, Totiger TM, Patel M, Marples B, Barber G, Pollack A. Radiation Attenuates Prostate Tumor Antiviral Responses to Vesicular Stomatitis Virus Containing IFNβ, Resulting in Pronounced Antitumor Systemic Immune Responses. Mol Cancer Res 2020; 18:1232-1243. [PMID: 32366674 DOI: 10.1158/1541-7786.mcr-19-0836] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 11/26/2019] [Accepted: 04/30/2020] [Indexed: 11/16/2022]
Abstract
Vesicular stomatitis virus (VSV) expressing IFNβ induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNβ is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNβ (hIFNβ) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective when used in combination with radiotherapy (RT). We investigated the synergistic effects of RT and VSV-hIFNβ in the subcutaneous PC3 and orthotopic LNCaP prostate xenograft models and a syngeneic RM9 prostate tumor model. VSV-IFNβ combined with RT amplified tumor killing for PC3 and LNCaP xenografts, and RM9 tumors. This was attributed to the induction of proapoptotic genes leading to increased VSV-IFNβ infection and replication, VSV expression, and oncolysis. In the RM9 tumors, combination therapy resulted in a robust antitumor immune response. Treated RM9 tumor-bearing mice demonstrated an increase in CD8+ and CD4+ T-cell numbers, 100% resistance to tumor rechallenge, and reduced resistance to reimplantation challenge with CD8+ knockdown. RT enhanced the activity of VSV-mediated oncolysis via attenuation of the innate antiviral response, resulting in increased VSV replication and the generation of an adaptive immune response earmarked by an increase in CD8+ lymphocyte numbers and antitumor activity. Local tumor irradiation combined with VSV-IFNβ affects tumor cell death through direct and systemic activity in conjunction with pronounced antitumor immunity. IMPLICATIONS: Radiotherapy enhances VSV-mediated oncolysis and anti-tumor immunity, indicating that the ombination has promise for very high risk prostate cancer.
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Affiliation(s)
- Thirupandiyur S Udayakumar
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Dillon M Betancourt
- Department of Cell Biology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Anis Ahmad
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Wensi Tao
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Tulasigeri M Totiger
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Mausam Patel
- Department of Radiology, Memorial Health, Savannah, Georgia
| | - Brian Marples
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Glen Barber
- Department of Cell Biology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Alan Pollack
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
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Altshuler DB, Kadiyala P, Núñez FJ, Núñez FM, Carney S, Alghamri MS, Garcia-Fabiani MB, Asad AS, Nicola Candia AJ, Candolfi M, Lahann J, Moon JJ, Schwendeman A, Lowenstein PR, Castro MG. Prospects of biological and synthetic pharmacotherapies for glioblastoma. Expert Opin Biol Ther 2020; 20:305-317. [PMID: 31959027 PMCID: PMC7059118 DOI: 10.1080/14712598.2020.1713085] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 01/06/2020] [Indexed: 01/05/2023]
Abstract
Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas.Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches.Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials.
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Affiliation(s)
- David B. Altshuler
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Padma Kadiyala
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Felipe J. Núñez
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Fernando M. Núñez
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Stephen Carney
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Mahmoud S. Alghamri
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Maria B. Garcia-Fabiani
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Antonela S. Asad
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires. Argentina
| | - Alejandro J. Nicola Candia
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires. Argentina
| | - Marianela Candolfi
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires. Argentina
| | - Joerg Lahann
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - James J. Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Pedro R. Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Maria G. Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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19
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Belcaid Z, Berrevoets C, Choi J, van Beelen E, Stavrakaki E, Pierson T, Kloezeman J, Routkevitch D, van der Kaaij M, van der Ploeg A, Mathios D, Sleijfer S, Dirven C, Lim M, Debets R, Lamfers MLM. Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy. Neurooncol Adv 2020; 2:vdaa011. [PMID: 32642679 PMCID: PMC7212906 DOI: 10.1093/noajnl/vdaa011] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The tumor-selective human adenovirus Delta24-RGD is currently under investigation in phase II clinical trials for patients with recurrent glioblastoma (GBM). To improve treatments for patients with GBM, we explored the potential of combining Delta24-RGD with antibodies targeting immune checkpoints. METHODS C57BL/6 mice were intracranially injected with GL261 cells and treated with a low dose of Delta24-RGD virus. The expression dynamics of 10 co-signaling molecules known to affect immune activity was assessed in tumor-infiltrating immune cells by flow cytometry after viral injection. The antitumor activity was measured by tumor cell killing and IFNγ production in co-cultures. Efficacy of the combination viro-immunotherapy was tested in vitro and in the GL261 and CT2A orthotopic mouse GBM models. Patient-derived GBM cell cultures were treated with Delta24-RGD to assess changes in PD-L1 expression induced by virus infection. RESULTS Delta24-RGD therapy increased intratumoral CD8+ T cells expressing Inducible T-cell co-stimulator (ICOS) and PD-1. Functionality assays confirmed a significant positive correlation between tumor cell lysis and IFNγ production in ex vivo cultures (Spearman r = 0.9524; P < .01). Co-cultures significantly increased IFNγ production upon treatment with PD-1 blocking antibodies. In vivo, combination therapy with low-dose Delta24-RGD and anti-PD-1 antibodies significantly improved outcome compared to single-agent therapy in both syngeneic mouse glioma models and increased PD-1+ tumor-infiltrating CD8+ T cells. Delta24-RGD infection induced tumor-specific changes in PD-L1 expression in primary GBM cell cultures. CONCLUSIONS This study demonstrates the potential of using low-dose Delta24-RGD therapy to sensitize glioma for combination with anti-PD-1 antibody therapy.
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Affiliation(s)
- Zineb Belcaid
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Cor Berrevoets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - John Choi
- Department of Neurosurgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Edward van Beelen
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Eftychia Stavrakaki
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tessa Pierson
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jenneke Kloezeman
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Denis Routkevitch
- Department of Neurosurgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mariëlle van der Kaaij
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Alicia van der Ploeg
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dimitrios Mathios
- Department of Neurosurgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stefan Sleijfer
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Clemens Dirven
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michael Lim
- Department of Neurosurgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Reno Debets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Martine L M Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands
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20
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Tsujimura M, Kusamori K, Katsumi H, Sakane T, Yamamoto A, Nishikawa M. Cell-based interferon gene therapy using proliferation-controllable, interferon-releasing mesenchymal stem cells. Sci Rep 2019; 9:18869. [PMID: 31827180 PMCID: PMC6906518 DOI: 10.1038/s41598-019-55269-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/25/2019] [Indexed: 01/14/2023] Open
Abstract
An important safety concern on cell-based gene therapy is that few methods have been available to control the proliferation and functioning of therapeutic protein-expressing cells after transplantation. We previously reported that the proliferation and functioning of the cells transfected with herpes simplex virus thymidine kinase (HSVtk) gene, a suicide gene, can be controlled by administration of ganciclovir. In this study, we tried to control the amount of murine interferon-γ (IFN-γ) secreted from transplanted murine mesenchymal stem cell line C3H10T1/2 cells to achieve safe cell-based IFN-γ gene therapy for cancer. C3H10T1/2 cells were transfected with HSVtk- and murine IFN-γ-expressing plasmid vectors to obtain C3H10T1/2/HSVtk/IFN-γ cells. C3H10T1/2/HSVtk/IFN-γ cells released IFN-γ and were sensitive to ganciclovir. C3H10T1/2/HSVtk/IFN-γ cells significantly suppressed the proliferation of murine adenocarcinoma cell line colon26 cells both in vitro and in vivo. Moreover, subcutaneous administration of ganciclovir to mice transplanted with NanoLuc luciferase-expressing C3H10T1/2/HSVtk cells for three consecutive days reduced the luminescence signals from the transplanted cells. These results indicate that the cell regulation system using HSVtk gene and ganciclovir can be useful for safe and efficient cell-based IFN-γ gene therapy for cancer.
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Affiliation(s)
- Mari Tsujimura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan
| | - Kosuke Kusamori
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
| | - Hidemasa Katsumi
- Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Toshiyasu Sakane
- Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Akira Yamamoto
- Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan
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21
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Loya J, Zhang C, Cox E, Achrol AS, Kesari S. Biological intratumoral therapy for the high-grade glioma part II: vector- and cell-based therapies and radioimmunotherapy. CNS Oncol 2019; 8:CNS40. [PMID: 31747784 PMCID: PMC6880300 DOI: 10.2217/cns-2019-0002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two part review will provide an overview of biological intratumoral therapies that have been evaluated in human clinical trials in HGGs, and summarize key advances and remaining challenges in the development of these therapies as a potential new paradigm in the management of HGGs. Part II discusses vector-based therapies, cell-based therapies and radioimmunotherapy.
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Affiliation(s)
- Joshua Loya
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Charlie Zhang
- Buffalo School of Medicine, State University of New York, Buffalo, NY 14202, USA
| | - Emily Cox
- Providence Medical Research Center, Spokane, WA 99204, USA
| | - Achal S Achrol
- John Wayne Cancer Institute, Pacific Neuroscience Institute, Santa Monica, CA 90404, USA
| | - Santosh Kesari
- John Wayne Cancer Institute, Pacific Neuroscience Institute, Santa Monica, CA 90404, USA
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22
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Lukas RV, Wainwright DA, Horbinski CM, Iwamoto FM, Sonabend AM. Immunotherapy Against Gliomas: is the Breakthrough Near? Drugs 2019; 79:1839-1848. [PMID: 31598900 PMCID: PMC6868342 DOI: 10.1007/s40265-019-01203-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Immunotherapeutic approaches have been, and continue to be, aggressively investigated in the treatment of infiltrating gliomas. While the results of late-phase clinical studies have been disappointing in this disease space thus far, the success of immunotherapies in other malignancies as well as the incremental gains in our understanding of immune-tumour interactions in gliomas has fuelled a strong continued interest of their evaluation in these tumours. We discuss a range of immunotherapeutic approaches including, but not limited to, vaccines, checkpoint inhibitors, oncolytic viruses, and gene therapies. Potential biomarkers under investigation to help elucidate which patients may respond or not respond to immunotherapeutic regimens are reviewed. Directions for future investigations are also noted.
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Affiliation(s)
- Rimas V Lukas
- Department of Neurology, Northwestern University, 710 N. Lake Shore Drive, Abbott Hall 1114, Chicago, IL, 60611, USA.
- Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA.
| | - Derek A Wainwright
- Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA
- Department of Neurological Surgery, Northwestern University, Chicago, USA
- Department of Microbiology-Immunology, Northwestern University, Chicago, USA
- Department of Medicine-Hematology/Oncology, Northwestern University, Chicago, USA
| | - Craig M Horbinski
- Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA
- Department of Neurological Surgery, Northwestern University, Chicago, USA
- Department of Pathology, Northwestern University, Chicago, USA
| | | | - Adam M Sonabend
- Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA
- Department of Neurological Surgery, Northwestern University, Chicago, USA
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23
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Luzzi S, Crovace AM, Del Maestro M, Giotta Lucifero A, Elbabaa SK, Cinque B, Palumbo P, Lombardi F, Cimini A, Cifone MG, Crovace A, Galzio R. The cell-based approach in neurosurgery: ongoing trends and future perspectives. Heliyon 2019; 5:e02818. [PMID: 31844735 PMCID: PMC6889232 DOI: 10.1016/j.heliyon.2019.e02818] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/11/2019] [Accepted: 11/06/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Examination of the current trends and future perspectives of the cell-based therapies in neurosurgery. METHODS A PubMed/MEDLINE-based systematic review has been performed combining the main Medical Subject Headings (MeSH) regarding the cell- and tissue-based therapies with the "Brain", "Spinal Cord", "Spine" and "Skull" MeSH terms. Only articles in English published in the last 10 years and pertinent to neurosurgery have been selected. RESULTS A total of 1,173 relevant articles have been chosen. Somatic cells and gene-modification technologies have undergone the greatest development. Immunotherapies and gene therapies have been tested for the cure of glioblastoma, stem cells mainly for brain and spinal cord traumatic injuries. Stem cells have also found a rationale in the treatment of the cranial and spinal bony defects, and of the intervertebral disc degeneration, as well.Most of the completed or ongoing trials concerning the cell-based therapies in neurosurgery are on phase 2. Future perspectives involve the need to overcome issues related to immunogenicity, oncogenicity and routes for administration. Refinement and improvement of vector design and delivery are required within the gene therapies. CONCLUSION The last decade has been characterised by a progressive evolution of neurosurgery from a purely mechanical phase to a new biological one. This trend has followed the rapid and parallel development of translational medicine and nanotechnologies.The introduction of new technologies, the optimisation of the already existing ones, and the reduction of costs are among the main challenges of the foreseeable future.
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Affiliation(s)
- Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
| | - Alberto Maria Crovace
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Piazza G. Cesare, 11 – Policlinico di Bari, Bari, 70124, Italy
| | - Mattia Del Maestro
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
- PhD School in Experimental Medicine, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
| | - Alice Giotta Lucifero
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
| | - Samer K. Elbabaa
- Pediatric Neurosurgery, Pediatric Neuroscience Center of Excellence, Arnold Palmer Hospital for Children, 1222 S. Orange Avenue, 2nd Floor, MP 154, Orlando, FL, 32806, USA
| | - Benedetta Cinque
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Paola Palumbo
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Francesca Lombardi
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Annamaria Cimini
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Maria Grazia Cifone
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Antonio Crovace
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Piazza G. Cesare, 11 – Policlinico di Bari, Bari, 70124, Italy
| | - Renato Galzio
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
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24
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Zhang H, Wang R, Yu Y, Liu J, Luo T, Fan F. Glioblastoma Treatment Modalities besides Surgery. J Cancer 2019; 10:4793-4806. [PMID: 31598150 PMCID: PMC6775524 DOI: 10.7150/jca.32475] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 07/04/2019] [Indexed: 01/04/2023] Open
Abstract
Glioblastoma multiforme (GBM) is commonly known as the most aggressive primary CNS tumor in adults. The mean survival of it is 14 to 15 months, following the standard therapy from surgery, chemotherapy, to radiotherapy. Efforts in recent decades have brought many novel therapies to light, however, with limitations. In this paper, authors reviewed current treatments for GBM besides surgery. In the past decades, only radiotherapy, temozolomide (TMZ), and tumor treating field (TTF) were approved by FDA. Though promising in preclinical experiments, therapeutic effects of other novel treatments including BNCT, anti-angiogenic therapy, immunotherapy, epigenetic therapy, oncolytic virus therapy, and gene therapy are still either uncertain or discouraging in clinical results. In this review, we went through current clinical trials, underlying causes, and future therapy designs to present neurosurgeons and researchers a sketch of this field.
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Affiliation(s)
- Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Ruizhe Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yuanqiang Yu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Jinfang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Tianmeng Luo
- Department of Medical Affairs, Xiangya Hospital, Central South University, Chang Sha, Hunan Province, China
| | - Fan Fan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University Changsha, China
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25
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Chiocca EA, Yu JS, Lukas RV, Solomon IH, Ligon KL, Nakashima H, Triggs DA, Reardon DA, Wen P, Stopa BM, Naik A, Rudnick J, Hu JL, Kumthekar P, Yamini B, Buck JY, Demars N, Barrett JA, Gelb AB, Zhou J, Lebel F, Cooper LJN. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci Transl Med 2019; 11:eaaw5680. [PMID: 31413142 PMCID: PMC7286430 DOI: 10.1126/scitranslmed.aaw5680] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 07/01/2019] [Indexed: 12/22/2022]
Abstract
Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad-RTS-hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.
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Affiliation(s)
- E Antonio Chiocca
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - John S Yu
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Rimas V Lukas
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
- University of Chicago, Chicago, IL 60637, USA
| | - Isaac H Solomon
- Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Keith L Ligon
- Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Hiroshi Nakashima
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel A Triggs
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - David A Reardon
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Patrick Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Brittany M Stopa
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Ajay Naik
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jeremy Rudnick
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jethro L Hu
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Priya Kumthekar
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
| | | | - Jill Y Buck
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - Nathan Demars
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - John A Barrett
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - Arnold B Gelb
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - John Zhou
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - Francois Lebel
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
| | - Laurence J N Cooper
- Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
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26
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Du L, Liang Q, Ge S, Yang C, Yang P. The growth inhibitory effect of human gingiva-derived mesenchymal stromal cells expressing interferon-β on tongue squamous cell carcinoma cells and xenograft model. Stem Cell Res Ther 2019; 10:224. [PMID: 31358054 PMCID: PMC6664557 DOI: 10.1186/s13287-019-1320-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/17/2019] [Accepted: 06/30/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interferon-β (IFN-β) is a cytokine with pleiotropic cellular functions, including antiviral, antiproliferative, and immunomodulatory activities. IFN-β inhibits multiple tumor cell growth in vitro. However, the contradiction between the therapeutic dose of IFN-β and its maximally tolerated dose is still inextricable in vivo. Human gingiva-derived mesenchymal stromal cells (GMSCs) represent promising vehicles for cancer gene therapy. This study evaluated the potential of GMSCs genetically engineered to produce IFN-β as a targeted gene delivery system to treat tongue squamous cell carcinoma (TSCC) in vitro and in vivo. METHODS A lentiviral vector encoding IFN-β was constructed and transfected into GMSCs to obtain IFN-β gene-modified GMSCs (GMSCs/IFN-β). Enzyme-linked immunosorbent assay (ELISA) was used to measure the IFN-β concentration in conditioned medium (CM) from GMSCs/IFN-β. The Cell Counting Kit-8 (CCK8), colony formation assay, and flow cytometry were used to detect the effects of GMSCs/IFN-β on TSCC cell line CAL27 cell growth and apoptosis in vitro. TSCC xenograft model was developed by subcutaneous injection of CAL27 cells into BALB/c nude mouse, and the role of intravenously injected GMSCs/IFN-β in engrafting in TSCC and controlling tumor progression was measured in vivo. RESULTS GMSCs/IFN-β expressed a high level of IFN-β. Both CCK8 and colony forming assay showed that GMSCs/IFN-β significantly inhibited the proliferation of CAL27 cells compared with the GMSCs, GMSCs/vector, or DMEM group. Flow cytometry analysis demonstrated that the CAL27 cell apoptosis rate was higher in the GMSCs/IFN-β group than in the other three groups. The in vivo experiment revealed that GMSCs/IFN-β engrafted selectively in TSCC xenograft and expressed a high level of IFN-β. There were smaller tumor volume and lower number of Ki67-positive cells in the GMSCs/IFN-β group than in the GMSCs, GMSCs/vector, or phosphate-buffered saline (PBS) group. Interestingly, GMSCs and GMSCs/vector also presented the potential of CAL27 cell growth inhibition in vitro and in vivo, although such an effect was weaker than GMSCs/IFN-β. CONCLUSIONS GMSCs/IFN-β inhibits the proliferation of TSCC cells in vitro and in vivo. These results provide evidence that delivery of IFN-β by GMSCs may be a promising approach to develop an effective treatment option for TSCC therapy.
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Affiliation(s)
- Lingqian Du
- Department of Stomatology, The Second Hospital of Shandong University, Jinan, 250033 Shandong People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
| | - Qianyu Liang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
| | - Chengzhe Yang
- Department of Oral & Maxillofacial Surgery, Qilu Hospital and Institute of Stomatology, Shandong University, 107 Wenhua Road West, Jinan, 250012 Shandong People’s Republic of China
| | - Pishan Yang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
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Chiocca EA, Nassiri F, Wang J, Peruzzi P, Zadeh G. Viral and other therapies for recurrent glioblastoma: is a 24-month durable response unusual? Neuro Oncol 2019; 21:14-25. [PMID: 30346600 PMCID: PMC6303472 DOI: 10.1093/neuonc/noy170] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
A phase I trial of an engineered poliovirus for the treatment of recurrent glioblastoma (GBM) has attracted attention due to 8 survivors reaching the 24-month and 5 reaching the 36-month survival landmarks.1 Genetically engineered viruses (oncolytic viruses) have been in trials for GBM for almost two decades.2 These replication-competent (tumor-selective, oncolytic, replication-conditional) viruses or replication-defective viral vectors (gene therapy) deliver cytotoxic payloads to tumors, leading to immunogenic death and intratumoral inflammatory responses. This transforms the tumor microenvironment from immunologically naïve ("cold") to inflamed ("hot"), increasing immune cell recognition of tumor antigens and the durable responses observed in virotherapy.3,4 Several current and past virotherapy trials have reported a "tail" of apparent responders at the 24-month landmark. Other modalities have also reported a "tail" of seemingly long-term survivors. These trials seem to show that these responder "tails" characterize a defined subset of GBM patients.
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Affiliation(s)
- E Antonio Chiocca
- Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Farshad Nassiri
- Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
| | - Justin Wang
- Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
| | - Pierpaolo Peruzzi
- Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gelareh Zadeh
- Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
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Hitti FL, Gonzalez-Alegre P, Lucas TH. Gene Therapy for Neurologic Disease: A Neurosurgical Review. World Neurosurg 2019; 121:261-273. [DOI: 10.1016/j.wneu.2018.09.097] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/10/2018] [Accepted: 09/12/2018] [Indexed: 01/01/2023]
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Abstract
PURPOSE OF REVIEW More effective therapies for glioblastoma are urgently needed. Immunotherapeutic strategies appear particularly promising and are therefore intensively studied. This article reviews the current understanding of the immunosuppressive glioblastoma microenvironment, discusses the rationale behind various immunotherapies, and outlines the findings of several recently published clinical studies. RECENT FINDINGS The results of CheckMate-143 indicated that nivolumab is not superior to bevacizumab in patients with recurrent glioblastoma. A first-in man exploratory study evaluating EGFRvIII-specific CAR T cells for patients with newly diagnosed glioblastoma demonstrated overall safety of CAR T cell therapy and effective target recognition. A pilot study evaluating treatment with adoptively transferred CMV-specific T cells combined with a CMV-specific DC vaccine was found to be safe and resulted in increased polyclonality of CMV-specific T cells in vivo. Despite the success of immunotherapies in many cancers, clinical evidence supporting their efficacy for patients with glioblastoma is still lacking. Nevertheless, the recently published studies provide important proof-of-concept in several areas of immunotherapy research. The careful and critical interpretation of these results will enhance our understanding of the opportunities and challenges of immunotherapies for high-grade gliomas and improve the immunotherapeutic strategies investigated in future clinical trials.
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Affiliation(s)
- Sylvia C Kurz
- Perlmutter Cancer Institute, Brain Tumor Program, NYU Langone Medical Center, 240 E. 38th Street, 19th floor, New York, NY, 10016, USA
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
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30
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Shah AH, Jusué-Torres I, Ivan ME, Komotar RJ, Kasahara N. Pathogens and glioma: a history of unexpected discoveries ushering in novel therapy. J Neurosurg 2018; 128:1139-1146. [DOI: 10.3171/2016.12.jns162123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley’s toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology.
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Affiliation(s)
| | | | | | | | - Noriyuki Kasahara
- 2Cell Biology, and
- 3Pathology, University of Miami Miller School of Medicine, Miami, Florida
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31
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Kamran N, Alghamri MS, Nunez FJ, Shah D, Asad AS, Candolfi M, Altshuler D, Lowenstein PR, Castro MG. Current state and future prospects of immunotherapy for glioma. Immunotherapy 2018; 10:317-339. [PMID: 29421984 PMCID: PMC5810852 DOI: 10.2217/imt-2017-0122] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/30/2017] [Indexed: 12/14/2022] Open
Abstract
There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy.
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Affiliation(s)
- Neha Kamran
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Mahmoud S Alghamri
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Felipe J Nunez
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Diana Shah
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Antonela S Asad
- Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Marianela Candolfi
- Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - David Altshuler
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Pedro R Lowenstein
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
| | - Maria G Castro
- Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
- Department of Cell & Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA
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Gene-Based Neuromodulation. Neuromodulation 2018. [DOI: 10.1016/b978-0-12-805353-9.00030-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Bardakjian T, Gonzalez-Alegre P. Towards precision medicine. HANDBOOK OF CLINICAL NEUROLOGY 2018; 147:93-102. [DOI: 10.1016/b978-0-444-63233-3.00008-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Medrano RF, Hunger A, Mendonça SA, Barbuto JAM, Strauss BE. Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy. Oncotarget 2017; 8:71249-71284. [PMID: 29050360 PMCID: PMC5642635 DOI: 10.18632/oncotarget.19531] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-α and IFN-β, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-α/β share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-α/β, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-α/β has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-α/β have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.
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Affiliation(s)
- Ruan F.V. Medrano
- Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of São Paulo/LIM 24, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Aline Hunger
- Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of São Paulo/LIM 24, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Samir Andrade Mendonça
- Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of São Paulo/LIM 24, University of São Paulo School of Medicine, São Paulo, Brazil
| | - José Alexandre M. Barbuto
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Cell and Molecular Therapy Center, NUCEL-NETCEM, University of São Paulo, São Paulo, Brazil
| | - Bryan E. Strauss
- Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of São Paulo/LIM 24, University of São Paulo School of Medicine, São Paulo, Brazil
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Galani V, Papadatos SS, Alexiou G, Galani A, Kyritsis AP. In Vitro and In Vivo Preclinical Effects of Type I IFNs on Gliomas. J Interferon Cytokine Res 2017; 37:139-146. [PMID: 28387596 DOI: 10.1089/jir.2016.0094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The interferons (IFNs) are a family of cytokines with diverse cellular actions such as control of cell proliferation and regulation of immune responses; therefore, they have been extensively studied as antitumor agents for a variety of malignancies, including gliomas. Type I IFNs exert their antitumor effects either directly, by targeting the tumor cells or the tumor stem cells, or indirectly, by regulating the anticancer activities of the immune system. More specifically, IFN-beta and IFN-alpha exhibit antiproliferative effects by p53 induction, CD8+ T-lymphocyte and macrophage activation, chemokine secretion, and miR-21 downregulation. In vitro and in vivo studies provide evidence that immunotherapy could have a role in glioma treatment, especially when first-line therapeutic interventions fail to produce durable responses. These effects are more obvious when combining IFN-beta with classical antitumor therapies such as temozolamide, an oral chemotherapeutic, for both newly diagnosed and recurrent gliomas. However, further clinical studies are needed to determine whether IFNs will have a definite place in the management of gliomas.
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Affiliation(s)
- Vasiliki Galani
- 1 Department of Anatomy-Histology-Embryology, Faculty of Medicine, University of Ioannina , Ioannina, Greece
| | - Stamatis S Papadatos
- 2 3rd Department of Internal Medicine, Athens School of Medicine, National and Kapodistrian University of Athens , Sotiria General Hospital, Athens, Greece
| | - George Alexiou
- 3 Neurosurgical Institute, University of Ioannina , Ioannina, Greece
| | - Angeliki Galani
- 4 Department of Environmental and Natural Resources Management, University of Patras , Patra, Greece
| | - Athanasios P Kyritsis
- 3 Neurosurgical Institute, University of Ioannina , Ioannina, Greece .,5 Department of Neurology, Faculty of Medicine, University of Ioannina , Ioannina, Greece
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Hamana A, Takahashi Y, Nishikawa M, Takakura Y. Interferon-Inducible Mx Promoter-Driven, Long-Term Transgene Expression System of Interferon-β for Cancer Gene Therapy. Hum Gene Ther 2016; 27:936-945. [DOI: 10.1089/hum.2016.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Atsushi Hamana
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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Kamran N, Calinescu A, Candolfi M, Chandran M, Mineharu Y, Asad AS, Koschmann C, Nunez FJ, Lowenstein PR, Castro MG. Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther 2016; 16:1245-64. [PMID: 27411023 PMCID: PMC5014608 DOI: 10.1080/14712598.2016.1212012] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/08/2016] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. AREAS COVERED Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. EXPERT OPINION Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.
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Affiliation(s)
- Neha Kamran
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Alexandra Calinescu
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Marianela Candolfi
- c Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina , Universidad de Buenos Aires , Buenos Aires , Argentina
| | - Mayuri Chandran
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Yohei Mineharu
- d Department of Neurosurgery , Kyoto University Graduate School of Medicine , Kyoto , Japan
| | - Antonela S Asad
- c Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina , Universidad de Buenos Aires , Buenos Aires , Argentina
| | - Carl Koschmann
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Felipe J Nunez
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Pedro R Lowenstein
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
| | - Maria G Castro
- a Department of Neurosurgery , The University of Michigan School of Medicine , Ann Arbor , MI , USA
- b Department of Cell and Developmental Biology , The University of Michigan School of Medicine , Ann Arbor , MI , USA
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Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma. Ther Deliv 2016; 5:975-90. [PMID: 25375341 DOI: 10.4155/tde.14.58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The incipient development of gene therapy for cancer has fuelled its progression from bench to bedside in mere decades. Of all malignancies that exist, gliomas are the largest class of brain tumors, and are renowned for their aggressiveness and resistance to therapy. In order for gene therapy to achieve clinical success, a multitude of barriers ranging from glioma tumor physiology to vector biology must be overcome. Many viral gene delivery systems have been subjected to clinical investigation; however, with highly limited success. In this review, the current progress and challenges of gene therapy for malignant glioma are discussed. Moreover, we highlight the hybrid adeno-associated virus and bacteriophage vector as a potential candidate for targeted gene delivery to brain tumors.
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Buijs PRA, Verhagen JHE, van Eijck CHJ, van den Hoogen BG. Oncolytic viruses: From bench to bedside with a focus on safety. Hum Vaccin Immunother 2016; 11:1573-84. [PMID: 25996182 DOI: 10.1080/21645515.2015.1037058] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents. Several viruses have undergone evaluation in clinical trials in the last decades, and the first agent is about to be approved to be used as a novel cancer therapy modality. In the current review, an overview is presented on recent (pre)clinical developments in the field of oncolytic viruses that have previously been or currently are being evaluated in clinical trials. Special attention is given to possible safety issues like toxicity, environmental shedding, mutation and reversion to wildtype virus.
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Key Words
- CAR, Coxsackie Adenovirus receptor
- CD, cytosine deaminase
- CEA, carcinoembryonic antigen
- CVA, Coxsackievirus type A
- DAF, decay accelerating factor
- DNA, DNA
- EEV, extracellular enveloped virus
- EGF, epidermal growth factor
- EGF-R, EGF receptor
- EMA, European Medicines Agency
- FDA, Food and Drug Administration
- GBM, glioblastoma multiforme
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- HA, hemagglutinin
- HAdV, Human (mast)adenovirus
- HER2, human epidermal growth factor receptor 2
- HSV, herpes simplex virus
- ICAM-1, intercellular adhesion molecule 1
- IFN, interferon
- IRES, internal ribosome entry site
- KRAS, Kirsten rat sarcoma viral oncogene homolog
- Kb, kilobase pairs
- MeV, Measles virus
- MuLV, Murine leukemia virus
- NDV, Newcastle disease virus
- NIS, sodium/iodide symporter
- NSCLC, non-small cell lung carcinoma
- OV, oncolytic virus
- PEG, polyethylene glycol
- PKR, protein kinase R
- PV, Polio virus
- RCR, replication competent retrovirus
- RCT, randomized controlled trial
- RGD, arginylglycylaspartic acid (Arg-Gly-Asp)
- RNA, ribonucleic acid
- Rb, retinoblastoma
- SVV, Seneca Valley virus
- TGFα, transforming growth factor α
- VGF, Vaccinia growth factor
- VSV, Vesicular stomatitis virus
- VV, Vaccinia virus
- cancer
- crHAdV, conditionally replicating HAdV
- dsDNA, double stranded DNA
- dsRNA, double stranded RNA
- environment
- hIFNβ, human IFN β
- immunotherapy
- mORV, Mammalian orthoreovirus
- mORV-T3D, mORV type 3 Dearing
- oHSV, oncolytic HSV
- oncolytic virotherapy
- oncolytic virus
- rdHAdV, replication-deficient HAdV
- review
- safety
- shedding
- ssRNA, single stranded RNA
- tk, thymidine kinase
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Affiliation(s)
- Pascal R A Buijs
- a Department of Surgery; Erasmus MC; University Medical Center ; Rotterdam , The Netherlands
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Lagogianni C, Thomas S, Lincoln N. Examining the relationship between fatigue and cognition after stroke: A systematic review. Neuropsychol Rehabil 2016; 28:57-116. [PMID: 26787096 DOI: 10.1080/09602011.2015.1127820] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many stroke survivors experience fatigue, which is associated with a variety of factors including cognitive impairment. A few studies have examined the relationship between fatigue and cognition and have obtained conflicting results. The aim of the current study was to review the literature on the relationship between fatigue and cognition post-stroke. The following databases were searched: EMBASE (1980-February, 2014), PsycInfo (1806-February, 2014), CINAHL (1937-February, 2014), MEDLINE (1946-February, 2014), Ethos (1600-February, 2014) and DART (1999-February, 2014). Reference lists of relevant papers were screened and the citation indices of the included papers were searched using Web of Science. Studies were considered if they were on adult stroke patients and assessed the following: fatigue with quantitative measurements (≥ 3 response categories), cognition using objective measurements, and the relationship between fatigue and cognition. Overall, 413 papers were identified, of which 11 were included. Four studies found significant correlations between fatigue and memory, attention, speed of information processing and reading speed (r = -.36 to .46) whereas seven studies did not. Most studies had limitations; quality scores ranged from 9 to 14 on the Critical Appraisal Skills Programme Checklists. There was insufficient evidence to support or refute a relationship between fatigue and cognition post-stroke. More robust studies are needed.
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Affiliation(s)
- Christodouli Lagogianni
- a Division of Rehabilitation & Ageing, Medical School , University of Nottingham , Nottingham , UK.,b Queens Medical Centre , Nottingham , UK
| | - Shirley Thomas
- a Division of Rehabilitation & Ageing, Medical School , University of Nottingham , Nottingham , UK.,b Queens Medical Centre , Nottingham , UK
| | - Nadina Lincoln
- a Division of Rehabilitation & Ageing, Medical School , University of Nottingham , Nottingham , UK.,b Queens Medical Centre , Nottingham , UK
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Hulou MM, Cho CF, Chiocca EA, Bjerkvig R. Experimental therapies: gene therapies and oncolytic viruses. HANDBOOK OF CLINICAL NEUROLOGY 2016; 134:183-197. [PMID: 26948355 DOI: 10.1016/b978-0-12-802997-8.00011-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Glioblastoma is the most common and aggressive primary brain tumor in adults. Over the past three decades, the overall survival time has only improved by a few months, therefore novel alternative treatment modalities are needed to improve clinical management strategies. Such strategies should ultimately extend patient survival. At present, the extensive insight into the molecular biology of gliomas, as well as into genetic engineering techniques, has led to better decision processes when it comes to modifying the genome to accommodate suicide genes, cytokine genes, and tumor suppressor genes that may kill cancer cells, and boost the host defensive immune system against neoantigenic cytoplasmic and nuclear targets. Both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment. Stem cells, microRNAs, nanoparticles, and viruses have also been designed. These have been armed with transgenes or peptides, and have been used both in laboratory-based experiments as well as in clinical trials, with the aim of improving selective killing of malignant glioma cells while sparing normal brain tissue. This chapter reviews the current status of gene therapies for malignant gliomas and highlights the most promising viral and cell-based strategies under development.
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Affiliation(s)
- M Maher Hulou
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Choi-Fong Cho
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Rolf Bjerkvig
- NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg; Department of Biomedicine, University of Bergen, Norway
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Nakashima H, Nguyen T, Chiocca EA. Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy. Oncolytic Virother 2015; 4:183-91. [PMID: 27512681 PMCID: PMC4918398 DOI: 10.2147/ov.s66081] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.
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Affiliation(s)
- Hiroshi Nakashima
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
| | - Tran Nguyen
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
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A New Approach in Gene Therapy of Glioblastoma Multiforme: Human Olfactory Ensheathing Cells as a Novel Carrier for Suicide Gene Delivery. Mol Neurobiol 2015; 53:5118-28. [DOI: 10.1007/s12035-015-9412-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 08/27/2015] [Indexed: 12/23/2022]
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Dendritic cell immunotherapy for brain tumors. J Neurooncol 2015; 123:425-32. [PMID: 26037466 DOI: 10.1007/s11060-015-1830-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 05/25/2015] [Indexed: 12/15/2022]
Abstract
Glioblastomas are characterized by immunosuppression, rapid proliferation, angiogenesis, and invasion into the surrounding brain parenchyma. Limitations in current therapeutic approaches have spurred the development of personalized, patient-specific treatments. Among these, active immunotherapy has emerged as a viable option for glioma treatment. The ability to generate an immune response utilizing patient-derived dendritic cells (DCs) (professional antigen-presenting cells) is especially attractive. This approach to glioma treatment allows for the immunologic targeting and destruction of malignant cells. Data acquired in multiple pre-clinical models and clinical trials have shown significant responses and prolonged survival. Here we provide an overview of the current status of DC vaccination for the treatment of gliomas.
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Calinescu AA, Kamran N, Baker G, Mineharu Y, Lowenstein PR, Castro MG. Overview of current immunotherapeutic strategies for glioma. Immunotherapy 2015; 7:1073-104. [PMID: 26598957 PMCID: PMC4681396 DOI: 10.2217/imt.15.75] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints.
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Affiliation(s)
| | - Neha Kamran
- Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Gregory Baker
- Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Yohei Mineharu
- Department of Neurosurgery, Kyoto University, Kyoto, Japan
| | - Pedro Ricardo Lowenstein
- Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Maria Graciela Castro
- Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
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Martinez-Quintanilla J, He D, Wakimoto H, Alemany R, Shah K. Encapsulated stem cells loaded with hyaluronidase-expressing oncolytic virus for brain tumor therapy. Mol Ther 2014; 23:108-18. [PMID: 25352242 DOI: 10.1038/mt.2014.204] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 10/17/2014] [Indexed: 02/08/2023] Open
Abstract
Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications.
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Affiliation(s)
- Jordi Martinez-Quintanilla
- 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Derek He
- 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hiroaki Wakimoto
- 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ramon Alemany
- Laboratori de Recerca Traslacional IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Catalonia, Spain
| | - Khalid Shah
- 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [4] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
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Okura H, Smith CA, Rutka JT. Gene therapy for malignant glioma. MOLECULAR AND CELLULAR THERAPIES 2014; 2:21. [PMID: 26056588 PMCID: PMC4451964 DOI: 10.1186/2052-8426-2-21] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 06/27/2014] [Indexed: 01/01/2023]
Abstract
Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.
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Affiliation(s)
- Hidehiro Okura
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada ; Department of Neurosurgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Christian A Smith
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada
| | - James T Rutka
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada ; Department of Surgery, University of Toronto, 149 College Street, 5th Floor, Toronto, Ontario M5T 1P5 Canada ; Division of Neurosurgery, The Hospital for Sick Children, Suite 1503, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada
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Castro MG, Candolfi M, Wilson TJ, Calinescu A, Paran C, Kamran N, Koschmann C, Moreno-Ayala MA, Assi H, Lowenstein PR. Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther 2014; 14:1241-57. [PMID: 24773178 DOI: 10.1517/14712598.2014.915307] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.
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Affiliation(s)
- Maria G Castro
- University of Michigan Medical School, Department of Neurosurgery , 4570 MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689 , USA +734 764 0850 ; +734 764 7051 ;
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Castro MG, Candolfi M, Wilson TJ, Calinescu A, Paran C, Kamran N, Koschmann C, Moreno-Ayala MA, Assi H, Lowenstein PR. Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther 2014. [PMID: 24773178 DOI: 10.1517/14712598.2014.91530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.
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Affiliation(s)
- Maria G Castro
- University of Michigan Medical School, Department of Neurosurgery , 4570 MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689 , USA +734 764 0850 ; +734 764 7051 ;
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