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Bardhan M, Muneer MA, Khare A, Minesh Shah R, Kaur A, Vasipalli SS, Suresh V, Podder V, Ahluwalia M, Odia Y, Chen Z. Advances in stem cell-based therapeutic transfers for glioblastoma treatment. Expert Rev Neurother 2025:1-17. [PMID: 40245098 DOI: 10.1080/14737175.2025.2490543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/25/2025] [Accepted: 04/04/2025] [Indexed: 04/19/2025]
Abstract
INTRODUCTION Glioblastoma (GBM), a highly malignant brain tumor, has a poor prognosis despite standard treatments like surgery, chemotherapy, and radiation. Glioblastoma stem cells (GSCs) play a critical role in recurrence and therapy resistance. Stem cell-based therapies have emerged as innovative approaches, leveraging the tumor-targeting abilities of stem cells to deliver treatments directly to GBM. AREAS COVERED This review focuses on using intact stem cells or subtypes for GBM therapy, excluding antigenic characteristics. The stem cell-based therapies explored include neural, mesenchymal, glioblastoma, hematopoietic and adipose-derived stem cells that have been investigated in both clinical and preclinical settings. A systematic search in PubMed, EMBASE, ClinicalTrials.gov, and Scopus had identified research up until January 2024. Key mechanisms reviewed include immune modulation, angiogenesis inhibition, and apoptosis induction. Discussion of completed and ongoing trials include emphasis on safety, efficacy, challenges, and study design limitations. EXPERT OPINION Stem cell-based therapies hold promise for treating GBM by targeting GSCs and improving treatment outcomes. Despite some potential advantages, challenges such as tumorigenesis risks, delivery complexities, and sustained therapeutic effects persist. Future research should prioritize optimizing stem cell modifications, combining them with current treatments, and conducting large-scale trials to ensure safety and efficacy. Integrating stem cell therapies into GBM treatment could provide more effective and less invasive options for patients.
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Affiliation(s)
- Mainak Bardhan
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | | | - Abhinav Khare
- All India Institute of Medical Sciences, Gorakhpur, Uttar Pradesh, India
| | | | - Anmol Kaur
- Lady Hardinge Medical College, New Delhi, India
| | - Sonit Sai Vasipalli
- Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Vinay Suresh
- King George's Medical University, Lucknow, India
| | - Vivek Podder
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Manmeet Ahluwalia
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Yazmin Odia
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Zhijian Chen
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
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Zhu J, Ma J, Huang M, Deng H, Shi G. Emerging delivery strategy for oncolytic virotherapy. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200809. [PMID: 38845744 PMCID: PMC11153257 DOI: 10.1016/j.omton.2024.200809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/09/2024]
Abstract
Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which apparently limits their clinical application. For patients with advanced cancer with disseminated metastasis, systemic administration is considered the optimal approach. However, the direct delivery of naked viruses through intravenous injection presents challenges, including rapid clearance by the immune system, inadequate accumulation in tumors, and significant side effects. Consequently, the development of drug delivery strategies has led to the emergence of various bio-materials serving as viral vectors, thereby improving the anti-tumor efficacy of oncolytic virotherapy. This review provides an overview of innovative strategies for delivering OVs, with a focus on nanoparticle-based or cell-based delivery systems. Recent pre-clinical and clinical studies are examined to highlight the enhanced efficacy of systemic delivery using these novel platforms. In addition, prevalent challenges in current research are briefly discussed, and potential solutions are proposed.
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Affiliation(s)
- Jiao Zhu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinhu Ma
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meijuan Huang
- Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hongxin Deng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gang Shi
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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Zeng M, Zhang W, Li Y, Yu L. Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner. Biomark Res 2024; 12:36. [PMID: 38528632 DOI: 10.1186/s40364-024-00581-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/09/2024] [Indexed: 03/27/2024] Open
Abstract
Recombinant adenovirus (rAd) regimens, including replication-competent oncolytic adenovirus (OAV) and replication-deficient adenovirus, have been identified as potential cancer therapeutics. OAV presents advantages such as selective replication, oncolytic efficacy, and tumor microenvironment (TME) remodeling. In this perspective, the principles and advancements in developing OAV toolkits are reviewed. The burgeoning rAd may dictate efficacy of conventional cancer therapies as well as cancer immunotherapies, including cancer vaccines, synergy with adoptive cell therapy (ACT), and TME reshaping. Concurrently, we explored the potential of rAd hitchhiking to adoptive immune cells or stem cells, highlighting how this approach facilitates synergistic interactions between rAd and cellular therapeutics at tumor sites. Results from preclinical and clinical trials in which immune and stem cells were infected with rAd have been used to address significant oncological challenges, such as postsurgical residual tumor tissue and metastatic tissue. Briefly, rAd can eradicate tumors through various mechanisms, resulting from tumor immunogenicity, reprogramming of the TME, enhancement of cellular immunity, and effective tumor targeting. In this context, we argue that rAd holds immense potential for enhancing cellular immunity and synergistically improving antitumor effects in combination with novel cancer immunotherapies.
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Affiliation(s)
- Miao Zeng
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Wei Zhang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Yisheng Li
- Shenzhen Haoshi Biotechnology Co., Ltd. No, 155 Hongtian Road, Xinqiao Street, Bao'an District, Shenzhen, Guangdong, 518125, China.
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China.
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Yang J, Shi X, Kuang Y, Wei R, Feng L, Chen J, Wu X. Cell-nanocarrier drug delivery system: a promising strategy for cancer therapy. Drug Deliv Transl Res 2024; 14:581-596. [PMID: 37721694 DOI: 10.1007/s13346-023-01429-1] [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] [Accepted: 09/05/2023] [Indexed: 09/19/2023]
Abstract
Tumor targeting has been a great challenge for drug delivery systems. A number of nanotechnology-derived drug carriers have been developed for cancer treatment to improve efficacy and biocompatibility. Among them, the emergence of cell-nanocarriers has attracted great attention, which simulates cell function and has good biocompatibility. They can also escape the clearance of reticuloendothelial system, showing a long-cycle effect. The inherent tumor migration and tumor homing ability of cells increase their significance as tumor-targeting vectors. In this review, we focus on the combination of stem cells, immune cells, red blood cells, and cell membranes to nanocarriers, which enable chemotherapy agents to efficiently target lesion sites and improve drug distribution while being low toxic and safe. In addition, we discuss the pros and cons of these nanoparticles as well as the challenges and opportunities that lie ahead. Although research to address these limitations is still ongoing, this promising tumor-targeted drug delivery system will provide a safe and effective platform against cancer.
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Affiliation(s)
- Jiefen Yang
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China
- Shanghai Wei Er Lab, Shanghai, China
| | - Xiongxi Shi
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China
- Shanghai Wei Er Lab, Shanghai, China
| | - Yanting Kuang
- Shanghai Wei Er Lab, Shanghai, China
- Inner Mongolia Medical University, No. 5, Xinhua Road, Hohhot, Inner Mongolia, People's Republic of China
| | - Ruting Wei
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China
- Shanghai Wei Er Lab, Shanghai, China
| | - Lanni Feng
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China
- Shanghai Wei Er Lab, Shanghai, China
| | - Jianming Chen
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China.
- Shanghai Wei Er Lab, Shanghai, China.
| | - Xin Wu
- Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Fuzhou, Fujian, People's Republic of China.
- Shanghai Wei Er Lab, Shanghai, China.
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Volovat SR, Scripcariu DV, Vasilache IA, Stolniceanu CR, Volovat C, Augustin IG, Volovat CC, Ostafe MR, Andreea-Voichița SG, Bejusca-Vieriu T, Lungulescu CV, Sur D, Boboc D. Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy. Int J Mol Sci 2024; 25:1180. [PMID: 38256250 PMCID: PMC10816814 DOI: 10.3390/ijms25021180] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.
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Affiliation(s)
- Simona Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Dragos Viorel Scripcariu
- Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Ingrid Andrada Vasilache
- Department of Obstetrics and Gynecology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics—Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Constantin Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | | | - Madalina-Raluca Ostafe
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Slevoacă-Grigore Andreea-Voichița
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Toni Bejusca-Vieriu
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | - Daniel Sur
- 11th Department of Medical Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
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Zeng J, Zeng XX. Systems Medicine for Precise Targeting of Glioblastoma. Mol Biotechnol 2023; 65:1565-1584. [PMID: 36859639 PMCID: PMC9977103 DOI: 10.1007/s12033-023-00699-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/14/2023] [Indexed: 03/03/2023]
Abstract
Glioblastoma (GBM) is a malignant cancer that is fatal even after standard therapy and the effects of current available therapeutics are not promising due its complex and evolving epigenetic and genetic profile. The mysteries that lead to GBM intratumoral heterogeneity and subtype transitions are not entirely clear. Systems medicine is an approach to view the patient in a whole picture integrating systems biology and synthetic biology along with computational techniques. Since the GBM oncogenesis involves genetic mutations, various therapies including gene therapeutics based on CRISPR-Cas technique, MicroRNAs, and implanted synthetic cells endowed with synthetic circuits against GBM with neural stem cells and mesenchymal stem cells acting as potential vehicles carrying therapeutics via the intranasal route, avoiding the risks of invasive methods in order to reach the GBM cells in the brain are discussed and proposed in this review. Systems medicine approach is a rather novel strategy, and since the GBM of a patient is complex and unique, thus to devise an individualized treatment strategy to tailor personalized multimodal treatments for the individual patient taking into account the phenotype of the GBM, the unique body health profile of the patient and individual responses according to the systems medicine concept might show potential to achieve optimum effects.
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Affiliation(s)
- Jie Zeng
- Benjoe Institute of Systems Bio-Engineering, High Technology Park, Xinbei District, Changzhou, 213022 Jiangsu People’s Republic of China
| | - Xiao Xue Zeng
- Department of Health Management, Centre of General Practice, The Seventh Affiliated Hospital, Southern Medical University, No. 28, Desheng Road Section, Liguan Road, Lishui Town, Nanhai District, Foshan, 528000 Guangdong People’s Republic of China
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7
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Kim JH, Oh E, Song ES, Yun CW, Lee SH, Song YS. Carboxylesterase-overexpressing hTERT-immortalized human adipose stem cells in prostate tumor growth inhibition by irinotecan. J Cancer Res Ther 2023; 19:1731-1742. [PMID: 38376272 DOI: 10.4103/jcrt.jcrt_1019_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 07/23/2021] [Indexed: 02/21/2024]
Abstract
INTRODUCTION Effective chemotherapy has not yet to be developed for castration-resistant prostate cancer (CRPC). Cell-mediated enzyme prodrug therapy (EPT), including a combination of carboxylesterase (CE) and irinotecan (CPT-11), could be a possible treatment option. This study explored a cell-mediated EPT, including a combination of CE and irinotecan (CPT-11), to inhibit CRPC tumor growth using rabbit CE-overexpressing human TERT-immortalized adipose-derived stem cells (hTERT-ADSC.CE). MATERIALS AND METHODS An hTERT ADSC.CE cell line was established by transfection with a lentiviral vector (CLV-Ubic) encoding the rabbit CE gene. To determine the in vitro suicide effects of hTERT-ADSC.CE, cell cultures were performed using various concentrations of CPT-11 (0.01-5 μM), and to determine the in vitro cytotoxic effects of hTERT-ADSC.CE cells, PC3 and hTERT-ADSC.CE cells were co-cultured. For the in vivo model, PC3 cells (1 × 106 cells) were injected subcutaneously into the flanks of nude mice and hTERT-ADSC.CE cells were injected via an intracardiac route, followed by the continuous treatment using CPT-11 for 2 weeks. The final change in tumor volume was measured and immunohistochemical analysis was performed. RESULTS The directional and selective migration of hTERT-ADSC.CE cells toward PC3 cells was significantly stimulated by PC3 cells in vitro. The number of apoptotic PC3 cells significantly increased in the presence of hTERT-ADSC.CE and CPT-11 compared to CPT-11 alone. In the in vivo study, the inhibitory effects of hTERT-ADSC.CE combined with CPT-11 were higher than those of CPT-11 monotherapy. After treatment with CPT-11 alone or ADSC.CE in combination with CPT-11, the removed tumor tissues showed hyperchromatic nuclei and apoptotic bodies. CE-overexpressing ADSCs potentiated the inhibition of tumor growth in CRPC-bearing mice in the presence of CPT-11 prodrugs. CONCLUSIONS This report suggests that cell-mediated EPT including CE and CPT-11 may be efficacious in treating CRPC.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Republic of Korea
- Department of Microbiology, Soonchunhyang University School of Medicine, Cheonan, Republic of Korea
| | - Eunjeong Oh
- Department of Pharmacology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Eun Seop Song
- Department of Obstetrics and Gynecology, Korea Medical Dispute Mediation and Arbitration Agency, Seoul, Republic of Korea
| | - Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Republic of Korea
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Tamura R, Miyoshi H, Imaizumi K, Yo M, Kase Y, Sato T, Sato M, Morimoto Y, Sampetrean O, Kohyama J, Shinozaki M, Miyawaki A, Yoshida K, Saya H, Okano H, Toda M. Gene therapy using genome-edited iPS cells for targeting malignant glioma. Bioeng Transl Med 2023; 8:e10406. [PMID: 37693056 PMCID: PMC10487333 DOI: 10.1002/btm2.10406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/23/2022] [Accepted: 08/28/2022] [Indexed: 11/08/2022] Open
Abstract
Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) are an underlying cause of treatment failure. Despite the use of multimodal therapies, the prognosis remains dismal. New therapeutic approach targeting invasive GSCs is required. Here, we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human-induced pluripotent stem cell (hiPSC) expressing a suicide gene had higher tumor-trophic migratory capacity compared with mesenchymal stem cells (MSCs), leading to marked in vivo antitumor effects. High migratory capacity in iPSC-NSCs was related to self-repulsive action and pathotropism involved in EphB-ephrinB and CXCL12-CXCR4 signaling. The gene insertion to ACTB provided higher and stable transgene expression than other common insertion sites, such as GAPDH or AAVS1. Ferroptosis was associated with enhanced antitumor immune responses. The thymidylate synthase and dihydroprimidine dehydrogenase expressions predicted the treatment efficacy of therapeutic hiPSC-NSCs. Our results indicate the potential benefit of genome-edited iPS cells based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.
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Affiliation(s)
- Ryota Tamura
- Department of NeurosurgeryKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | | | - Kent Imaizumi
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Masahiro Yo
- Laboratory for Cell Function and Dynamics, RIKEN Center for Brain ScienceWako, SaitamaJapan
| | - Yoshitaka Kase
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
- Department of Geriatric MedicineGraduate School of Medicine, The University of TokyoBunkyo‐ku, TokyoJapan
| | - Tsukika Sato
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Mizuto Sato
- Department of NeurosurgeryKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Yukina Morimoto
- Department of NeurosurgeryKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Oltea Sampetrean
- Division of Gene RegulationKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Jun Kohyama
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Munehisa Shinozaki
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Atsushi Miyawaki
- Laboratory for Cell Function and Dynamics, RIKEN Center for Brain ScienceWako, SaitamaJapan
| | - Kazunari Yoshida
- Department of NeurosurgeryKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Hideyuki Saya
- Division of Gene RegulationKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Hideyuki Okano
- Department of PhysiologyKeio University School of MedicineShinjuku‐ku, TokyoJapan
| | - Masahiro Toda
- Department of NeurosurgeryKeio University School of MedicineShinjuku‐ku, TokyoJapan
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Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, Zekiy AO, Ansari MJ, Zabibah RS, Jawad MA, Al-Shalah SAJ, Rizaev JA, Alnassar YS, Mohammed NM, Mustafa YF, Darvishi M, Akhavan-Sigari R. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Commun Signal 2023; 21:43. [PMID: 36829187 PMCID: PMC9960453 DOI: 10.1186/s12964-022-01012-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/10/2022] [Indexed: 02/26/2023] Open
Abstract
Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers. MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer. Video Abstract.
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Affiliation(s)
| | - Anna I Gilmanova
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | | | - Angelina O Zekiy
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Saif A J Al-Shalah
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Mohammad Darvishi
- Department of Aerospace and Subaquatic Medicine, Infectious Diseases and Tropical Medicine Research Center (IDTMRC), AJA University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany.,Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Bernstock JD, Hoffman SE, Kappel AD, Valdes PA, Essayed WI, Klinger NV, Kang KD, Totsch SK, Olsen HE, Schlappi CW, Filipski K, Gessler FA, Baird L, Filbin MG, Hashizume R, Becher OJ, Friedman GK. Immunotherapy approaches for the treatment of diffuse midline gliomas. Oncoimmunology 2022; 11:2124058. [PMID: 36185807 PMCID: PMC9519005 DOI: 10.1080/2162402x.2022.2124058] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 12/14/2022] Open
Abstract
Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.
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Affiliation(s)
- Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Samantha E. Hoffman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital Cancer Center, Boston, MA, USA
| | - Ari D. Kappel
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Pablo A. Valdes
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Walid Ibn Essayed
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Neil V. Klinger
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kyung-Don Kang
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Stacie K. Totsch
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hannah E. Olsen
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Charles W. Schlappi
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital Cancer Center, Boston, MA, USA
| | - Katharina Filipski
- Neurological Institute (Edinger Institute), University Hospital, Frankfurt Am Main, Germany
- German Cancer Consortium (DKTK), Germany and German Cancer Research Center (DFKZ), Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- University Cancer Center (UCT), Frankfurt, Germany
| | - Florian A. Gessler
- Department of Neurosurgery, University Medicine Rostock, Rostock, Germany
| | - Lissa Baird
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Mariella G. Filbin
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital Cancer Center, Boston, MA, USA
| | - Rintaro Hashizume
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Oren J. Becher
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, the Mount Sinai Hospital, NY, NY, USA
| | - Gregory K. Friedman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
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11
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Cheng K, Zhang H, Guo Q, Zhai P, Zhou Y, Yang W, Wang Y, Lu Y, Shen Z, Wu H. Emerging trends and research foci of oncolytic virotherapy for central nervous system tumors: A bibliometric study. Front Immunol 2022; 13:975695. [PMID: 36148235 PMCID: PMC9486718 DOI: 10.3389/fimmu.2022.975695] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/16/2022] [Indexed: 12/19/2022] Open
Abstract
BackgroundCentral nervous system tumor (CNST) is one of the most complicated and lethal forms of human tumors with very limited treatment options. In recent years, growing evidence indicates that oncolytic virotherapy (OVT) has emerged as a promising therapeutic strategy for CNSTs. And a considerable amount of literature on OVT-CNSTs has been published. However, there are still no studies summarizing the global research trends and hotspots of this field through a bibliometric approach. To fulfill this knowledge gap, bibliometric analysis was conducted based on all publications relating to OVT-CNSTs since 2000s.MethodsWe searched the Web of Science Core Collection for all relevant studies published between 2000 and 2022. Four different tools (online analysis platform, R-bibliometrix, CiteSpace and VOSviewer) were used to perform bibliometric analysis and network visualization, including annual publication output, active journals, contribution of countries, institutions, and authors, references, as well as keywords.ResultsA total of 473 articles and reviews were included. The annual number of publications on OVT-CNSTs showed a significant increasing trend. Molecular Therapy and Cancer Research were the most active and co-cited journals, respectively. In terms of contributions, there is no doubt that the United States occupied a leading position with the most publications (n=307, 64.9%) and the highest H-index (57). The institution and author that contributed the largest number of publications were Ohio State University and Chiocca EA, respectively. As can be seen from citation analysis, the current studies mainly focused on preclinical and phase I/II clinical results of various oncolytic virus for CNSTs treatment. Keywords co-occurrence and burst analysis revealed that the following research topics including immunotherapy, T-cells, tumor microenvironment, vaccine, blood-brain-barrier, checkpoint inhibitors, macrophage, stem cell, and recurrent glioblastoma have been research frontiers of this field and also have great potential to continue to be research hotspots in the future.ConclusionThere has been increasing attention on oncolytic viruses for use as CNSTs therapeutics. Oncolytic immunotherapy is a topic of great concern in this field. This bibliometric study provides a comprehensive analysis of the knowledge base, research hotspots, development perspective in the field of OVT-CNSTs, which could become an essential reference for scholars in this area.
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Affiliation(s)
- Kunming Cheng
- Department of Intensive Care Unit, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huan Zhang
- Department of Neurosurgery, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
| | - Qiang Guo
- Department of Orhopaedic Surgery, Baodi Clinical College of Tianjin Medical University, Tianjin, China
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Pengfei Zhai
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of NeuroSpine Surgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Yan Zhou
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Weiguang Yang
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
| | - Yulin Wang
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
| | - Yanqiu Lu
- Department of Intensive Care Unit, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
| | - Zefeng Shen
- Department of Graduate School, Sun Yat-sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
| | - Haiyang Wu
- Department of Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
- Department of Graduate School, Tianjin Medical University, Tianjin, China
- *Correspondence: Yanqiu Lu, ; Zefeng Shen, ; Haiyang Wu,
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12
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Sababathy M, Ramanathan G, Tan SC. Targeted delivery of gold nanoparticles by neural stem cells to glioblastoma for enhanced radiation therapy: a review. AIMS Neurosci 2022; 9:303-319. [PMID: 36329899 PMCID: PMC9581732 DOI: 10.3934/neuroscience.2022017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/09/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma (GB) is the most malignant subtype of brain cancer derived from astrocytes in the brain. Radiotherapy is one of the standard treatments for GB patients, but its effectiveness is often limited by the radioresistance of aggressive GB cells. Higher dose of radiation needs to be applied to GB patients to eliminate these stubborn cells, but this also means more side effects on the adjacent healthy cells because the radiation beam could indistinguishably harm all cells exposed to it. In order to address this problem, various strategies have been studied to enhance the radiosensitivity among the radioresistant cell populations for targeted eradication of GB without harming other surrounding healthy cells. One of the promising strategies for radiosensitization is to use gold nanoparticles (AuNPs) which can enhance photoelectric effects within the radioresistant cells for higher killing efficiency even at low doses of radiation. Nonetheless, there is no evidence showing the capability of these nanoparticles to travel to brain tumor cells, therefore, the application of this nanotechnology is very much dependent on the development of a suitable carrier to deliver the AuNPs to the GB tumor sites specifically. In this review article, we discussed the potentials of neural stem cells (NSCs) as biological carriers to carry AuNPs to targeted GB tumor sites and provided new insights into the potential of NSC-based targeted delivery system for GB treatment. The information reported here may pave a new direction for clinical transformation of next-generation nanoparticle-assisted radiotherapy to optimize the efficacy of radiotherapy for GB treatment.
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Affiliation(s)
- Mogesh Sababathy
- Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Ghayathri Ramanathan
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
| | - Suat Cheng Tan
- School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
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13
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To Explore the Stem Cells Homing to GBM: The Rise to the Occasion. Biomedicines 2022; 10:biomedicines10050986. [PMID: 35625723 PMCID: PMC9138893 DOI: 10.3390/biomedicines10050986] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 12/13/2022] Open
Abstract
Multiple efforts are currently underway to develop targeted therapeutic deliveries to the site of glioblastoma progression. The use of carriers represents advancement in the delivery of various therapeutic agents as a new approach in neuro-oncology. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are used because of their capability in migrating and delivering therapeutic payloads to tumors. Two of the main properties that carrier cells should possess are their ability to specifically migrate from the bloodstream and low immunogenicity. In this article, we also compared the morphological and molecular features of each type of stem cell that underlie their migration capacity to glioblastoma. Thus, the major focus of the current review is on proteins and lipid molecules that are released by GBM to attract stem cells.
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14
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Recent advances in the therapeutic strategies of glioblastoma multiforme. Neuroscience 2022; 491:240-270. [PMID: 35395355 DOI: 10.1016/j.neuroscience.2022.03.030] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.
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15
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Zhang Y, Liu C, Wang T, Kong F, Zhang H, Yi J, Dong X, Duan H, Tao N, Yang Y, Wang H. Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model. Mol Ther Oncolytics 2022; 24:486-496. [PMID: 35229027 PMCID: PMC8850566 DOI: 10.1016/j.omto.2022.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 01/27/2022] [Indexed: 12/24/2022] Open
Abstract
Oncolytic adenoviruses (OAds) are alternative immune therapeutic strategies for tumors. However, liver uptake and antibody neutralization are two major barriers for systemic delivery during the treatment of tumor metastasis. Mesenchymal stem cells (MSCs) have emerged as potential vehicles to improve delivery. In this study, we loaded umbilical-cord-derived MSCs (UC-MSCs) with OAds expressing decorin (rAd.DCN) or without foreign genes (rAd.Null) to treat breast cancer lung metastasis. In vivo, rAd.Null, MSCs.Null, and rAd.DCN exhibited antitumor effects compared with other groups in a mouse model. Unexpectedly, MSCs.Null showed much greater antitumor responses than MSCs.DCN, including improved survival and reduced tumor burden. Compared with rAd.Null, both MSCs.Null and MSCs.DCN could improve the viral spread and distribution in metastatic tumor lesions in the lung. MSCs.DCN produced much more decorin in lungs than rAd.DCN; however, rAd.DCN reduced the downstream target genes of decorin much more strongly than MSCs.DCN, which was consistent with in vitro findings. In addition, rAd.DCN, MSCs.Null, and MSCs.DCN could reduce The cytokine levels in the lung. In conclusion, MSCs improved oncolytic adenoviral delivery and spread in tumor tissues and enhanced therapeutic effects. However, MSCs.DCN reduced OAd-evoked antitumor responses, possibly via a contact-dependent mechanism.
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16
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Nose-to-brain delivery: exploring newer domains for glioblastoma multiforme management. Drug Deliv Transl Res 2021; 10:1044-1056. [PMID: 32221847 DOI: 10.1007/s13346-020-00747-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive form of the primary brain tumors in humans. The intricate pathophysiology, the development of resistance by tumor cells, and the inability of the drugs to effectively cross the blood-brain and blood-tumor barriers result in poor prognosis for GBM patients, with a median survival time of only 1 to 2 years. Nose-to-brain delivery offers an attractive, noninvasive strategy to enhance drug penetration or transport novel drug/gene carriers into the brain. Although the exact mechanism of intranasal delivery remains elusive, the olfactory and trigeminal nerve pathways have been found to play a vital role in circumventing the traditional barriers of brain targeting. This review discusses the intranasal pathway as a novel domain for delivering drugs and nanocarriers encapsulating drugs/genes, as well as stem cell carriers specifically to the glioma cells. Considering the fact that most of these studies are still in preclinical stage, translating such intranasal delivery strategies from bench to bedside would be a critical step for better management and prognosis of GBM. Graphical abstract.
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17
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Zhang GL, Wang CF, Qian C, Ji YX, Wang YZ. Role and mechanism of neural stem cells of the subventricular zone in glioblastoma. World J Stem Cells 2021; 13:877-893. [PMID: 34367482 PMCID: PMC8316865 DOI: 10.4252/wjsc.v13.i7.877] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/16/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma multiforme (GBM), the most frequently occurring malignant brain tumor in adults, remains mostly untreatable. Because of the heterogeneity of invasive gliomas and drug resistance associated with the tumor microenvironment, the prognosis is poor, and the survival rate of patients is low. Communication between GBMs and non-glioma cells in the tumor microenvironment plays a vital role in tumor growth and recurrence. Emerging data have suggested that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells-of-origin of gliomas, and SVZ NSC involvement is associated with the progression and recurrence of GBM. This review highlights the interaction between SVZ NSCs and gliomas, summarizes current findings on the crosstalk between gliomas and other non-glioma cells, and describes the links between SVZ NSCs and gliomas. We also discuss the role and mechanism of SVZ NSCs in glioblastoma, as well as the interventions targeting the SVZ and their therapeutic implications in glioblastoma. Taken together, understanding the biological mechanism of glioma-NSC interactions can lead to new therapeutic strategies for GBM.
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Affiliation(s)
- Gui-Long Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Chuan-Fang Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Cheng Qian
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Yun-Xiang Ji
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Ye-Zhong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
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18
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Mercer-Smith AR, Findlay IA, Bomba HN, Hingtgen SD. Intravenously Infused Stem Cells for Cancer Treatment. Stem Cell Rev Rep 2021; 17:2025-2041. [PMID: 34138421 DOI: 10.1007/s12015-021-10192-0] [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] [Accepted: 05/24/2021] [Indexed: 01/14/2023]
Abstract
Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.
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Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Ingrid A Findlay
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Hunter N Bomba
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA. .,Department of Neurosurgery, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA.
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19
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Calinescu AA, Kauss MC, Sultan Z, Al-Holou WN, O'Shea SK. Stem cells for the treatment of glioblastoma: a 20-year perspective. CNS Oncol 2021; 10:CNS73. [PMID: 34006134 PMCID: PMC8162173 DOI: 10.2217/cns-2020-0026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma, the deadliest form of primary brain tumor, remains a disease without cure. Treatment resistance is in large part attributed to limitations in the delivery and distribution of therapeutic agents. Over the last 20 years, numerous preclinical studies have demonstrated the feasibility and efficacy of stem cells as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies, discuss mechanisms underlying their beneficial effect and highlight experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages brought by stem cells for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies. Glioblastoma is the deadliest and most common form of brain tumor, for which there is no cure. It is very difficult to deliver medicine to the tumor cells, because they spread out widely into the normal brain, and local blood vessels represent a barrier that most medicines cannot cross. It was shown, in many studies over the last 20 years, that stem cells are attracted toward the tumor and that they can deliver many kinds of therapeutic agents directly to brain cancer cells and shrink the tumor. In this review we analyze these studies and present new discoveries that can be used to make stem cell therapies for glioblastoma more effective to prolong the life of patients with brain tumors.
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Affiliation(s)
| | - McKenzie C Kauss
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,College of Literature Science & Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Zain Sultan
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,College of Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wajd N Al-Holou
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sue K O'Shea
- Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Seyed-Khorrami SM, Soleimanjahi H, Soudi S, Habibian A. MSCs loaded with oncolytic reovirus: migration and in vivo virus delivery potential for evaluating anti-cancer effect in tumor-bearing C57BL/6 mice. Cancer Cell Int 2021; 21:244. [PMID: 33933086 PMCID: PMC8088007 DOI: 10.1186/s12935-021-01848-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Background and aims Several oncolytic viruses applications have been approved in the clinic or in different phases of clinical trials. However, these methods have some rudimentary problems. Therefore, to enhance the delivery and quality of treatment, considering the advantage of cell carrier-based methods such as Mesenchymal Stem Cells (MSC) have been proposed. This study was designed to evaluate the performance and quality of cancer treatment based on MSCs loaded by oncolytic reovirus in the cancerous C57BL/6 mouse model. Also, we evaluated MSCs migration potency in vitro and in vivo following the oncolytic reovirus infection. Methods C57BL/6 mice were inoculated with TC-1 cell lines and tumors were established in the right flank. Mice were systemically treated with reovirus, MSCs-loaded with reovirus, MSCs, and PBS as a control in separated groups. Effects of infected AD-MSCs with reovirus on tumor growth and penetration in the tumor site were monitored. All groups of mice were monitored for two months in order to therapeutic and anticancer potential. After treatments, tumor size alteration and apoptosis rate, as well as cytokine release pattern was assessed. Results The results of the current study indicated that the effect of reovirus infection on AD-MSCs is not devastating the migration capacity especially in MOI 1 and 5 while intact cells remain. On the other hand, MSCs play an efficient role as a carrier to deliver oncolytic virus into the tumor site in comparison with systemic administration of reovirus alone. Apoptosis intensity relies on viral titration and passing time. Followed by systemic administration, treatment with oncolytic reovirus-infected AD-MSCs and MSCs alone had shown significant inhibition in tumor growth. Also, treatment by reovirus causes an increase in IFN-γ secretion. Conclusion The results of in vitro and in vivo study confirmed the tumor-homing properties of infected AD-MSCs and the significant antitumor activity of this platform. Hence, our results showed that the cell carrier strategy using oncolytic reovirus-loaded AD-MSCs enhanced virus delivery, infiltration, and antitumor activity can be effectively applied in most cancers.
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Affiliation(s)
| | - Hoorieh Soleimanjahi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ala Habibian
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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21
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Yang C, Hua N, Xie S, Wu Y, Zhu L, Wang S, Tong X. Oncolytic viruses as a promising therapeutic strategy for hematological malignancies. Biomed Pharmacother 2021; 139:111573. [PMID: 33894623 DOI: 10.1016/j.biopha.2021.111573] [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: 01/14/2021] [Revised: 03/23/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
The incidence of hematological malignancies such as multiple myeloma, leukemia, and lymphoma has increased over time. Although bone marrow transplantation, immunotherapy and chemotherapy have led to significant improvements in efficacy, poor prognosis in elderly patients, recurrence and high mortality among hematological malignancies remain major challenges, and innovative therapeutic strategies should be explored. Besides directly lyse tumor cells, oncolytic viruses can activate immune responses or be engineered to express therapeutic factors to increase antitumor efficacy, and have gradually been recognized as an appealing approach for fighting cancers. An increasing number of studies have applied oncolytic viruses in hematological malignancies and made progress. In particular, strategies combining immunotherapy and oncolytic virotherapy are emerging. Various phase I clinical trials of oncolytic reovirus with lenalidomide or programmed death 1(PD-1) immune checkpoint inhibitors in multiple myeloma are ongoing. Moreover, preclinical studies of combinations with chimeric antigen receptor T (CAR-T) cells are underway. Thus, oncolytic virotherapy is expected to be a promising approach to cure hematological malignancies. This review summarizes progress in oncolytic virus research in hematological malignancies. After briefly reviewing the development and oncolytic mechanism of oncolytic viruses, we focus on delivery methods of oncolytic viruses, especially systemic delivery that is suitable for hematological tumors. We then discuss the main types of oncolytic viruses applied for hematological malignancies and related clinical trials. In addition, we present several ways to improve the antitumor efficacy of oncolytic viruses. Finally, we discuss current challenges and provide suggestions for future studies.
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Affiliation(s)
- Chen Yang
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China; Department of Clinical Medicine, Qingdao University, Qingdao, PR China
| | - Nanni Hua
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China; The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, PR China
| | - Shufang Xie
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China; The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, PR China
| | - Yi Wu
- Phase I clinical research center, Zhejiang Provincial People's Hospital,Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Lifeng Zhu
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Shibing Wang
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China; The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital ,Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, PR China.
| | - Xiangmin Tong
- Molecular diagnosis laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China; The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital ,Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, PR China.
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Hicks WH, Bird CE, Traylor JI, Shi DD, El Ahmadieh TY, Richardson TE, McBrayer SK, Abdullah KG. Contemporary Mouse Models in Glioma Research. Cells 2021; 10:cells10030712. [PMID: 33806933 PMCID: PMC8004772 DOI: 10.3390/cells10030712] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/20/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023] Open
Abstract
Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.
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Affiliation(s)
- William H. Hicks
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (W.H.H.); (C.E.B.); (J.I.T.); (T.Y.E.A.)
| | - Cylaina E. Bird
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (W.H.H.); (C.E.B.); (J.I.T.); (T.Y.E.A.)
| | - Jeffrey I. Traylor
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (W.H.H.); (C.E.B.); (J.I.T.); (T.Y.E.A.)
| | - Diana D. Shi
- Department of Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA;
| | - Tarek Y. El Ahmadieh
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (W.H.H.); (C.E.B.); (J.I.T.); (T.Y.E.A.)
| | - Timothy E. Richardson
- Department of Pathology, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX 75229, USA;
| | - Samuel K. McBrayer
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harrold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
- Correspondence: (S.K.M.); (K.G.A.)
| | - Kalil G. Abdullah
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (W.H.H.); (C.E.B.); (J.I.T.); (T.Y.E.A.)
- Harrold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
- Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
- Correspondence: (S.K.M.); (K.G.A.)
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23
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Chastkofsky MI, Pituch KC, Katagi H, Zannikou M, Ilut L, Xiao T, Han Y, Sonabend AM, Curiel DT, Bonner ER, Nazarian J, Horbinski CM, James CD, Saratsis AM, Hashizume R, Lesniak MS, Balyasnikova IV. Mesenchymal Stem Cells Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma. Clin Cancer Res 2021; 27:1766-1777. [PMID: 33272983 PMCID: PMC7956061 DOI: 10.1158/1078-0432.ccr-20-1499] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/20/2020] [Accepted: 11/30/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors. EXPERIMENTAL DESIGN Here, we have explored the use of mesenchymal stem cells (MSC) for oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients' samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation. RESULTS Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone (P < 0.01). CONCLUSIONS Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment.
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Affiliation(s)
- Michael I Chastkofsky
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Katarzyna C Pituch
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Hiroaki Katagi
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Markella Zannikou
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Liliana Ilut
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Ting Xiao
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Yu Han
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Adam M Sonabend
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - David T Curiel
- Department of Radiation Oncology, University of Washington, St. Louis, Missouri
| | - Erin R Bonner
- Center for Genomics and Precision Medicine, Children's National Medical Center, Washington, D.C
- Institute for Biomedical Sciences, George Washington University School of Medicine and Health Sciences, Washington, D.C
| | - Javad Nazarian
- Center for Genomics and Precision Medicine, Children's National Medical Center, Washington, D.C
- Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, D.C
| | - Craig M Horbinski
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - C David James
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Amanda M Saratsis
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Division of Neurosurgery, Department of Pediatric Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Rintaro Hashizume
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Maciej S Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Irina V Balyasnikova
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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24
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Benmelouka AY, Munir M, Sayed A, Attia MS, Ali MM, Negida A, Alghamdi BS, Kamal MA, Barreto GE, Ashraf GM, Meshref M, Bahbah EI. Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges. Int J Mol Sci 2021; 22:2258. [PMID: 33668356 PMCID: PMC7956497 DOI: 10.3390/ijms22052258] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 02/05/2023] Open
Abstract
Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor's aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations.
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Affiliation(s)
| | - Malak Munir
- Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt; (M.M.); (A.S.)
| | - Ahmed Sayed
- Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt; (M.M.); (A.S.)
| | - Mohamed Salah Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Mohamad M. Ali
- Faculty of Medicine, Al-Azhar University, Damietta 34511, Egypt; (M.M.A.); (E.I.B.)
| | - Ahmed Negida
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK;
- Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Badrah S. Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; or
| | - Mohammad Amjad Kamal
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China;
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia
- Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia
| | - George E. Barreto
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago 32310, Chile
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; or
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | | | - Eshak I. Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta 34511, Egypt; (M.M.A.); (E.I.B.)
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25
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Wang X, Yang Y, Wang N, Wu X, Xu J, Zhou Y, Zhao X, He Z. Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia. Int Immunopharmacol 2021; 94:107437. [PMID: 33571747 DOI: 10.1016/j.intimp.2021.107437] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/21/2021] [Accepted: 01/24/2021] [Indexed: 12/12/2022]
Abstract
Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the therapeutic efficacy is modest, and most commonly manifests as relapse from remission. Thus, improving long-term AML survival is a crucial clinical challenge. In recent years, oncolytic virotherapy has provided an alternative approach for AML treatment. The use of oncolytic reoviruses has been explored in more than 30 clinical trials for safety and feasibility issues. However, like other oncolytic viruses, neutralizing antibodies (NAbs) reduce therapeutic efficacy. To tackle this problem, human umbilical cord mesenchymal stem cells (hUC-MSCs) were used to deliver reovirus using in vitro and in vivo models. Human UC-MSCs were successfully loaded with reovirus, without impairing biological function.We also observed in vitro protective effects of hUC-MSCs on reovirus in the presence of NAbs. In the immunocompromised AML mouse model, hUC-MSCs effectively carried reoviruses to tumor lesions and significantly prolonged the survival of AML xenografts in mice in the presence of a high titer anti-reovirus antibody (p = 0.001). However, reovirus-induced activation of AKT, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and NF-κB signaling led to the maintenance of intrinsic migratory properties and secretion of pro-inflammatory cytokines from hUC-MSCs, particularly CXCL10. In immuno-competent AML mice, MSCs carrying reovirus triggered immune responses, and eventually inhibited tumor growth. Therefore, these results suggest that MSCs as carriers of oncolytic reoviruses can enhance the antitumor efficacy of virotherapy.
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Affiliation(s)
- Xianyao Wang
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Yichen Yang
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China
| | - Nianxue Wang
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China
| | - Xijun Wu
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Jianwei Xu
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China; Department of Pharmacology, Guizhou Medical University, Guiyang 550025, China
| | - Yanhua Zhou
- Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China
| | - Xing Zhao
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Center for Tissue Engineering and Stem Cell Research , Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China.
| | - Zhixu He
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, China; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guiyang 550004, China; Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China.
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26
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Zhou YC, Zhang YN, Yang X, Wang SB, Hu PY. Delivery systems for enhancing oncolytic adenoviruses efficacy. Int J Pharm 2020; 591:119971. [PMID: 33059014 DOI: 10.1016/j.ijpharm.2020.119971] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 12/24/2022]
Abstract
Oncolytic adenovirus (OAds) has long been considered a promising biotherapeutic agent against various types of cancer owing to selectively replicate in and lyse cancer cells, while remaining dormant in healthy cells. In the last years, multiple (pre)clinical studies using genetic engineering technologies enhanced OAds anti-tumor effects in a broad range of cancers. However, poor targeting delivery, tropism toward healthy tissues, low-level expression of Ad receptors on tumor cells, and pre-existing neutralizing antibodies are major hurdles for systemic administration of OAds. Different vehicles have been developed for addressing these obstacles, such as stem cells, nanoparticles (NPs) and shielding polymers, extracellular vesicles (EVs), hydrogels, and microparticles (MPs). These carriers can enhance the therapeutic efficacy of OVs through enhancing transfection, circulatory longevity, cellular interactions, specific targeting, and immune responses against cancer. In this paper, we reviewed adenovirus structure and biology, different types of OAds, and the efficacy of different carriers in systemic administration of OAds.
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Affiliation(s)
- Yu-Cheng Zhou
- Gastroenterological & Pancreatic Surgery Department, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China; Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - You-Ni Zhang
- Clinical Laboratory, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People's Hospital), Taizhou 317200, Zhejiang Province, China
| | - Xue Yang
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China.
| | - Pei-Yang Hu
- Department of Traumatology, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People's Hospital), Taizhou 317200, Zhejiang Province, China.
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27
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McCrorie P, Vasey CE, Smith SJ, Marlow M, Alexander C, Rahman R. Biomedical engineering approaches to enhance therapeutic delivery for malignant glioma. J Control Release 2020; 328:917-931. [DOI: 10.1016/j.jconrel.2020.11.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 12/23/2022]
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28
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Howard F, Muthana M. Designer nanocarriers for navigating the systemic delivery of oncolytic viruses. Nanomedicine (Lond) 2020; 15:93-110. [PMID: 31868115 DOI: 10.2217/nnm-2019-0323] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Nanotechnology is paving the way for new carrier systems designed to overcome the greatest challenges of oncolytic virotherapy; systemic administration and subsequent implications of immune responses and specific cell binding and entry. Systemic administration of oncolytic agents is vital for disseminated neoplasms, however transition of nanoparticles (NP) to virotherapy has yielded modest results. Their success relies on how they navigate the merry-go-round of often-contradictory phases of NP delivery: circulatory longevity, tissue permeation and cellular interaction, with many studies postulating design features optimal for each phase. This review discusses the optimal design of NPs for the transport of oncolytic viruses within these phases, to determine whether improved virotherapeutic efficacy lies in the pharmacokinetic/pharmacodynamics characteristics of the NP-oncolytic viruses complexes rather than manipulation of the virus and targeting ligands.
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29
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Hammad M, Cornejo YR, Batalla-Covello J, Majid AA, Burke C, Liu Z, Yuan YC, Li M, Dellinger TH, Lu J, Chen NG, Fong Y, Aboody KS, Mooney R. Neural Stem Cells Improve the Delivery of Oncolytic Chimeric Orthopoxvirus in a Metastatic Ovarian Cancer Model. Mol Ther Oncolytics 2020; 18:326-334. [PMID: 32775617 PMCID: PMC7394740 DOI: 10.1016/j.omto.2020.07.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/01/2020] [Indexed: 12/22/2022] Open
Abstract
Oncolytic virotherapy represents a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance, which reduces viral delivery to the tumor. Patient-derived mesenchymal stem cells that home to tumors have been used as viral delivery tools, but variability associated with autologous cell isolations limits the clinical applicability of this approach. We previously developed an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) that can be used to deliver viral cargo. Here, we demonstrate that this NSC line can improve the delivery of a thymidine kinase gene-deficient conditionally replication-competent orthopoxvirus, CF33, in a preclinical cisplatin-resistant peritoneal ovarian metastases model. Overall, our findings provide the basis for using off-the-shelf allogeneic cell-based delivery platforms for oncolytic viruses, thus providing a more efficient delivery alternative compared with the free virus administration approach.
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Affiliation(s)
- Mohamed Hammad
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
| | - Yvonne R. Cornejo
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
- Irell & Manella Graduate School for Biological Sciences at the Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jennifer Batalla-Covello
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
- Irell & Manella Graduate School for Biological Sciences at the Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Asma Abdul Majid
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
| | - Connor Burke
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
| | - Zheng Liu
- Translational Bioinformatics Division, Center for Informatics, City of Hope, Duarte, CA 91010, USA
| | - Yate-Ching Yuan
- Translational Bioinformatics Division, Center for Informatics, City of Hope, Duarte, CA 91010, USA
| | - Min Li
- Department of Information Sciences, Division of Biostatistics at the Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Thanh H. Dellinger
- Division of Gynecologic Surgery, Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Jianming Lu
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Nanhai G. Chen
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
- Center for Gene Therapy, City of Hope, Duarte, CA 91010, USA
| | - Yuman Fong
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
- Center for Gene Therapy, City of Hope, Duarte, CA 91010, USA
| | - Karen S. Aboody
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
- Division of Neurosurgery, City of Hope, Duarte, CA 91010, USA
| | - Rachael Mooney
- Department of Developmental and Stem Cell Biology, City of Hope, Duarte, CA 91010, USA
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30
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Ebrahimi Z, Talaei S, Aghamiri S, Goradel NH, Jafarpour A, Negahdari B. Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours. IET Nanobiotechnol 2020; 14:441-448. [PMID: 32755952 PMCID: PMC8676526 DOI: 10.1049/iet-nbt.2019.0351] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/30/2020] [Accepted: 04/24/2020] [Indexed: 07/31/2023] Open
Abstract
Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide-based delivery, local delivery strategies, NP delivery, and cell-based delivery have been fully discussed.
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Affiliation(s)
- Zahra Ebrahimi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sam Talaei
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahin Aghamiri
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Jafarpour
- Students' Scientific Research Center, Virology Division, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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31
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Luzzi S, Giotta Lucifero A, Brambilla I, Trabatti C, Mosconi M, Savasta S, Foiadelli T. The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:51-60. [PMID: 32608375 PMCID: PMC7975826 DOI: 10.23750/abm.v91i7-s.9955] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/19/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. METHODS An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. RESULTS The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipotent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. CONCLUSION Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology.
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Affiliation(s)
- 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.
| | - Alice Giotta Lucifero
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| | - Ilaria Brambilla
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Chiara Trabatti
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Mario Mosconi
- c and Traumatology Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| | - Salvatore Savasta
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
| | - Thomas Foiadelli
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.
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Tong Q, Qiu N, Ji J, Ye L, Zhai G. Research Progress in Bioinspired Drug Delivery Systems. Expert Opin Drug Deliv 2020; 17:1269-1288. [PMID: 32543953 DOI: 10.1080/17425247.2020.1783235] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION To tackle challenges associated with traditional drug carriers, investigators have explored cells, cellular membrane, and macromolecular components including proteins and exosomes for the fabrication of delivery vehicles, owing to their excellent biocompatibility, lower toxicity, lower immunogenicity and similarities with the host. Biomacromolecule- and biomimetic nanoparticle (NP)-based drug/gene carriers are drawing immense attention, and biomimetic drug delivery systems (BDDSs) have been conceived and constructed. AREAS COVERED This review focuses on BDDS based on mammalian cells, including blood cells, cancer cells, adult stem cells, endogenous proteins, pathogens and extracellular vesicles (EVs). EXPERT OPINION Compared with traditional drug delivery systems (DDSs), BDDSs are based on biological nanocarriers, exhibiting superior biocompatibility, fewer side effects, natural targeting, and diverse modifications. In addition to directly employing natural biomaterials such as cells, proteins, pathogens and EVs as carriers, BDDSs offer these advantages by mimicking the structure of natural nanocarriers through bioengineering technologies. Furthermore, BDDSs demonstrate fewer limitations and irregularities than natural materials and can overcome several shortcomings associated with natural carriers. Although research remains ongoing to resolve these limitations, it is anticipated that BDDSs possess the potential to overcome challenges associated with traditional DDS, with a promising future in the treatment of human diseases.
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Affiliation(s)
- Qirong Tong
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China
| | - Na Qiu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China
| | - Lei Ye
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China
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Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy. Cancers (Basel) 2020; 12:cancers12051139. [PMID: 32370135 PMCID: PMC7281331 DOI: 10.3390/cancers12051139] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022] Open
Abstract
Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.
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Hossain JA, Marchini A, Fehse B, Bjerkvig R, Miletic H. Suicide gene therapy for the treatment of high-grade glioma: past lessons, present trends, and future prospects. Neurooncol Adv 2020; 2:vdaa013. [PMID: 32642680 PMCID: PMC7212909 DOI: 10.1093/noajnl/vdaa013] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Suicide gene therapy has represented an experimental cancer treatment modality for nearly 40 years. Among the various cancers experimentally treated by suicide gene therapy, high-grade gliomas have been the most prominent both in preclinical and clinical settings. Failure of a number of promising suicide gene therapy strategies in the clinic pointed toward a bleak future of this approach for the treatment of high-grade gliomas. Nevertheless, the development of new vectors and suicide genes, better prodrugs, more efficient delivery systems, and new combinatorial strategies represent active research areas that may eventually lead to better efficacy of suicide gene therapy. These trends are evident by the current increasing focus on suicide gene therapy for high-grade glioma treatment both in the laboratory and in the clinic. In this review, we give an overview of different suicide gene therapy approaches for glioma treatment and discuss clinical trials, delivery issues, and immune responses.
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Affiliation(s)
- Jubayer A Hossain
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Haukeland University Hospital, Bergen, Norway.,Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Antonio Marchini
- Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Boris Fehse
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Haukeland University Hospital, Bergen, Norway
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Lemos de Matos A, Franco LS, McFadden G. Oncolytic Viruses and the Immune System: The Dynamic Duo. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:349-358. [PMID: 32071927 PMCID: PMC7015832 DOI: 10.1016/j.omtm.2020.01.001] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oncolytic viruses (OVs) constitute a new and promising immunotherapeutic approach toward cancer treatment. This therapy takes advantage of the natural propensity of most tumor cells to be infected by specific OVs. Besides the direct killing potential (oncolysis), what makes OV administration attractive for the present cancer immunotherapeutic scenario is the capacity to induce two new overlapping, but distinct, immunities: anti-tumoral and anti-viral. OV infection and oncolysis naturally elicit both innate and adaptive immune responses (required for long-term anti-tumoral immunity); at the same time, the viral infection prompts an anti-viral response. In this review, we discuss the dynamic interaction between OVs and the triggered responses of the immune system. The anti-OV immunological events that lead to viral clearance and the strategies to deal with such potential loss of the therapeutic virus are discussed. Additionally, we review the immune stimulatory actions induced by OVs through different inherent strategies, such as modulation of the tumor microenvironment, the role of immunogenic cell death, and the consequences of genetically modifying OVs by arming them with therapeutic transgenes. An understanding of the balance between the OV-induced anti-tumoral versus anti-viral immunities will provide insight when choosing the appropriate virotherapy for any specific cancer.
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Affiliation(s)
- Ana Lemos de Matos
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy (B-CIVV), The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Lina S Franco
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy (B-CIVV), The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Grant McFadden
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy (B-CIVV), The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
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Kavari SL, Shah K. Engineered stem cells targeting multiple cell surface receptors in tumors. Stem Cells 2020; 38:34-44. [PMID: 31381835 PMCID: PMC6981034 DOI: 10.1002/stem.3069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 12/15/2022]
Abstract
Multiple stem cell types exhibit inherent tropism for cancer, and engineered stem cells have been used as therapeutic agents to specifically target cancer cells. Recently, stem cells have been engineered to target multiple surface receptors on tumor cells, as well as endothelial and immune cells in the tumor microenvironment. In this review, we discuss the rationales and strategies for developing multiple receptor-targeted stem cells, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics.
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Affiliation(s)
- Sanam L Kavari
- Center for Stem Cell Therapeutics and Imaging (CSTI), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging (CSTI), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials. Molecules 2019; 24:molecules24234312. [PMID: 31779126 PMCID: PMC6930669 DOI: 10.3390/molecules24234312] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/22/2019] [Accepted: 11/24/2019] [Indexed: 12/18/2022] Open
Abstract
Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood–brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.
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Fakiruddin KS, Lim MN, Nordin N, Rosli R, Zakaria Z, Abdullah S. Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer. Cancers (Basel) 2019; 11:cancers11091261. [PMID: 31466290 PMCID: PMC6770521 DOI: 10.3390/cancers11091261] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are emerging as vehicles for anti-tumor cytotherapy; however, investigation on its efficacy to target a specific cancer stem cell (CSC) population in non-small cell lung cancer (NSCLC) is lacking. Using assays to evaluate cell proliferation, apoptosis, and gene expression, we investigated the efficacy of MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) to target and destroy CD133+ (prominin-1 positive) NSCLC-derived CSCs. Characterization of TRAIL death receptor 5 (DR5) revealed that it was highly expressed in the CD133+ CSCs of both H460 and H2170 cell lines. The human MSC-TRAIL generated in the study maintained its multipotent characteristics, and caused significant tumor cell inhibition in NSCLC-derived CSCs in a co-culture. The MSC-TRAIL induced an increase in annexin V expression, an indicator of apoptosis in H460 and H2170 derived CD133+ CSCs. Through investigation of mitochondria membrane potential, we found that MSC-TRAIL was capable of inducing intrinsic apoptosis to the CSCs. Using pathway-specific gene expression profiling, we uncovered candidate genes such as NFKB1, BAG3, MCL1, GADD45A, and HRK in CD133+ CSCs, which, if targeted, might increase the sensitivity of NSCLC to MSC-TRAIL-mediated inhibition. As such, our findings add credibility to the utilization of MSC-TRAIL for the treatment of NSCLC through targeting of CD133+ CSCs.
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Affiliation(s)
- Kamal Shaik Fakiruddin
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor 43400, Malaysia.
- Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), National Institutes of Health (NIH), Ministry of Health Malaysia, Shah Alam 40170, Malaysia.
| | - Moon Nian Lim
- Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), National Institutes of Health (NIH), Ministry of Health Malaysia, Shah Alam 40170, Malaysia
| | - Norshariza Nordin
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Genetics and Regenerative Medicine Research Centre, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
| | - Rozita Rosli
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Genetics and Regenerative Medicine Research Centre, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
| | - Zubaidah Zakaria
- Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), National Institutes of Health (NIH), Ministry of Health Malaysia, Shah Alam 40170, Malaysia
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Genetics and Regenerative Medicine Research Centre, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
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Kwon S, Yoo KH, Sym SJ, Khang D. Mesenchymal stem cell therapy assisted by nanotechnology: a possible combinational treatment for brain tumor and central nerve regeneration. Int J Nanomedicine 2019; 14:5925-5942. [PMID: 31534331 PMCID: PMC6681156 DOI: 10.2147/ijn.s217923] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 07/11/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.
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Affiliation(s)
- Song Kwon
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea
| | - Kwai Han Yoo
- Department of Internal Medicine, Division of Hematology, School of Medicine, Gachon University Gil Medical Center, Incheon, 21565, South Korea
| | - Sun Jin Sym
- Department of Internal Medicine, Division of Hematology, School of Medicine, Gachon University Gil Medical Center, Incheon, 21565, South Korea
| | - Dongwoo Khang
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea.,Department of Gachon Advanced Institute for Health Science & Technology (Gaihst), Gachon University, Incheon 21999, South Korea.,Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea
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Guerrero-Fonseca CA, López-Baquero MA, Bedoya-Rodríguez AA. Virus oncolíticos: un arma contra el cáncer. REVISTA DE LA FACULTAD DE MEDICINA 2019. [DOI: 10.15446/revfacmed.v67n2.68347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introducción. Los virus oncolíticos son virus atenuados, mutados o que por naturaleza se dirigen y matan específicamente células tumorales, sin afectar a las células normales. La administración intratumoral del virus ofrece la oportunidad de tratar el tumor primario pero no focos metastásicos, los cuales pueden ser alcanzados mediante la administración intravenosa. Sin embargo, su eficiencia puede disminuir por la presencia de una respuesta inmunológica preexistente en los sujetos tratados.Objetivo. Exponer las técnicas utilizadas para envolver y transportar los virus con el fin de eludir el sistema inmunológico antes de que el virus llegue al tumor.Materiales y métodos. Se realizó una búsqueda narrativa de la literatura original y de revisión en las bases de datos PubMed, JSTOR y EBSCO sobre métodos o técnicas utilizadas para el tratamiento del cáncer mediante el uso de virus oncolíticos.Resultados. La formación de nanocomplejos entre los virus oncolíticos y biopolímeros —ya sea mediante la unión química o mediante la unión a través de interacciones electrostáticas o el uso de micropartículas, células transportadoras, liposomas, ultrasonido o terapias combinadas– es eficaz para evitar la respuesta inmunológica del huésped contra el virus.Conclusión. Para evitar la respuesta inmunológica del huésped contra los virus oncolíticos se han desarrollo diversos métodos que permiten la liberación controlada y especifica de los mismos. Sin embargo, debido a la diversidad de los virus, se debe tener en cuenta que la eficacia de los métodos de protección y transporte depende de las características bioquímicas tanto del biomaterial como del virus.
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Pirbhai M, Chandrasekar S, Zheng M, Ignatova T, Rotkin SV, Jedlicka SS. Augmentation of C17.2 Neural Stem Cell Differentiation via Uptake of Low Concentrations of ssDNA‐Wrapped Single‐Walled Carbon Nanotubes. ACTA ACUST UNITED AC 2019; 3:e1800321. [DOI: 10.1002/adbi.201800321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Massooma Pirbhai
- Department of Physics Susquehanna University 514 University Ave. Selinsgrove PA 17870 USA
| | - Swetha Chandrasekar
- Department of Bioengineering Lehigh University 111 Research Drive Bethlehem PA 18015 USA
| | - Ming Zheng
- National Institute of Standards and Technology 1000 Bureau Drive, M/S 8542 Gaithersburg MD 20899 USA
| | - Tetyana Ignatova
- Department of Nanoscience Joint School of Nanoscience and Nanoengineering University of North Carolina at Greensboro 2907 East Gate City Blvd. Greensboro NC 27401 USA
| | - Slava V. Rotkin
- Department of Engineering Science and Mechanics Materials Research Institute The Pennsylvania State University N‐332 Millennium Science Complex University Park PA 16802 USA
| | - Sabrina S. Jedlicka
- Department of Materials Science and Engineering Department of Bioengineering Lehigh University 5 E. Packer Ave. Bethlehem PA 18015 USA
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Mooney R, Majid AA, Batalla-Covello J, Machado D, Liu X, Gonzaga J, Tirughana R, Hammad M, Lesniak MS, Curiel DT, Aboody KS. Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for Treatment of Metastatic Ovarian Cancer. MOLECULAR THERAPY-ONCOLYTICS 2018; 12:79-92. [PMID: 30719498 PMCID: PMC6350263 DOI: 10.1016/j.omto.2018.12.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 12/06/2018] [Indexed: 12/23/2022]
Abstract
Oncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of the virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have been used to deliver virus to tumors, but variability associated with autologous cell isolations prevents this approach from being broadly clinically applicable. Here, we demonstrate the ability of an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) to protect oncolytic viral cargo from neutralizing antibodies within patient ascites fluid and to deliver it to tumors within preclinical peritoneal ovarian metastases models. The viral payload used is a conditionally replication-competent adenovirus driven by the survivin promoter (CRAd-S-pk7). Because the protein survivin is highly expressed in ovarian cancer, but not in normal differentiated cells, viral replication should occur selectively in ovarian tumor cells. We found this viral agent was effective against cisplatin-resistant ovarian tumors and could be used as an adjunct treatment with cisplatin to decrease tumor burden without increasing toxicity. Collectively, our data suggest NSC-delivered CRAd-S-pk7 virotherapy holds promise for improving clinical outcome, reducing toxicities, and improving quality of life for patients with advanced ovarian cancer.
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Affiliation(s)
- Rachael Mooney
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Asma Abdul Majid
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Jennifer Batalla-Covello
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Diana Machado
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Xueli Liu
- Department of Information Sciences, Division of Biostatistics at the Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Joanna Gonzaga
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Revathiswari Tirughana
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Mohamed Hammad
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Maciej S Lesniak
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 N. St. Clair Street, Suite 2210, Chicago, IL 60611, USA
| | - David T Curiel
- Division of Cancer Biology and Biologic Therapeutic Center, Department of Radiation Oncology, School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8224, St. Louis, MO 63110, USA
| | - Karen S Aboody
- Department of Stem Cell & Developmental Biology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.,Division of Neurosurgery, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
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Abstract
Objective: Gliomas are the most common neoplasm of the central nervous system (CNS); however, traditional imaging techniques do not show the boundaries of tumors well. Some researchers have found a new therapeutic mode to combine nanoparticles, which are nanosized particles with various properties for specific therapeutic purposes, and stem cells for tracing gliomas. This review provides an introduction of the basic understanding and clinical applications of the combination of stem cells and nanoparticles as a contrast agent for glioma imaging. Data Sources: Studies published in English up to and including 2017 were extracted from the PubMed database with the selected key words of “stem cell,” “glioma,” “nanoparticles,” “MRI,” “nuclear imaging,” and “Fluorescence imaging.” Study Selection: The selection of studies focused on both preclinical studies and basic studies of tracking glioma with nanoparticle-labeled stem cells. Results: Studies have demonstrated successful labeling of stem cells with multiple types of nanoparticles. These labeled stem cells efficiently migrated to gliomas of varies models and produced signals sensitively captured by different imaging modalities. Conclusion: The use of nanoparticle-labeled stem cells is a promising imaging platform for the tracking and treatment of gliomas.
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Affiliation(s)
- Shuang-Lin Deng
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yun-Qian Li
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Gang Zhao
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
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Fakiruddin KS, Ghazalli N, Lim MN, Zakaria Z, Abdullah S. Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour. Int J Mol Sci 2018; 19:ijms19082188. [PMID: 30060445 PMCID: PMC6121609 DOI: 10.3390/ijms19082188] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 06/30/2018] [Accepted: 07/02/2018] [Indexed: 02/06/2023] Open
Abstract
Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients.
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Affiliation(s)
- Kamal Shaik Fakiruddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
| | - Nadiah Ghazalli
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
| | - Moon Nian Lim
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
| | - Zubaidah Zakaria
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
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Bagó JR, Okolie O, Dumitru R, Ewend MG, Parker JS, Werff RV, Underhill TM, Schmid RS, Miller CR, Hingtgen SD. Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Sci Transl Med 2018; 9:9/375/eaah6510. [PMID: 28148846 DOI: 10.1126/scitranslmed.aah6510] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 07/26/2016] [Accepted: 10/05/2016] [Indexed: 12/13/2022]
Abstract
Engineered neural stem cells (NSCs) are a promising approach to treating glioblastoma (GBM). The ideal NSC drug carrier for clinical use should be easily isolated and autologous to avoid immune rejection. We transdifferentiated (TD) human fibroblasts into tumor-homing early-stage induced NSCs (h-iNSCTE), engineered them to express optical reporters and different therapeutic gene products, and assessed the tumor-homing migration and therapeutic efficacy of cytotoxic h-iNSCTE in patient-derived GBM models of surgical and nonsurgical disease. Molecular and functional analysis revealed that our single-factor SOX2 TD strategy converted human skin fibroblasts into h-iNSCTE that were nestin+ and expressed pathways associated with tumor-homing migration in 4 days. Time-lapse motion analysis showed that h-iNSCTE rapidly migrated to human GBM cells and penetrated human GBM spheroids, a process inhibited by blockade of CXCR4. Serial imaging showed that h-iNSCTE delivery of the proapoptotic agent tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) reduced the size of solid human GBM xenografts 250-fold in 3 weeks and prolonged median survival from 22 to 49 days. Additionally, h-iNSCTE thymidine kinase/ganciclovir enzyme/prodrug therapy (h-iNSCTE-TK) reduced the size of patient-derived GBM xenografts 20-fold and extended survival from 32 to 62 days. Mimicking clinical NSC therapy, h-iNSCTE-TK therapy delivered into the postoperative surgical resection cavity delayed the regrowth of residual GBMs threefold and prolonged survival from 46 to 60 days. These results suggest that TD of human skin into h-iNSCTE is a platform for creating tumor-homing cytotoxic cell therapies for cancer, where the potential to avoid carrier rejection could maximize treatment durability in human trials.
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Affiliation(s)
- Juli R Bagó
- Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Onyi Okolie
- Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Raluca Dumitru
- UNC Human Pluripotent Stem Cell Core Facility, Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Matthew G Ewend
- Department of Neurosurgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joel S Parker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ryan Vander Werff
- Department of Cellular and Physiological Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - T Michael Underhill
- Department of Cellular and Physiological Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - Ralf S Schmid
- Division of Neuropathology and Department of Pathology and Laboratory Medicine, Department of Neurology and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - C Ryan Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Division of Neuropathology and Department of Pathology and Laboratory Medicine, Department of Neurology and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shawn D Hingtgen
- Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. .,Department of Neurosurgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Mooney R, Abdul Majid A, Batalla J, Annala AJ, Aboody KS. Cell-mediated enzyme prodrug cancer therapies. Adv Drug Deliv Rev 2017; 118:35-51. [PMID: 28916493 DOI: 10.1016/j.addr.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/15/2017] [Accepted: 09/06/2017] [Indexed: 02/08/2023]
Abstract
Cell-directed gene therapy is a promising new frontier for the field of targeted cancer therapies. Here we discuss the current pre-clinical and clinical use of cell-mediated enzyme prodrug therapy (EPT) directed against solid tumors and avenues for further development. We also discuss some of the challenges encountered upon translating these therapies to clinical trials. Upon sufficient development, cell-mediated enzyme prodrug therapy has the potential to maximize the distribution of therapeutic enzymes within the tumor environment, localizing conversion of prodrug to active drug at the tumor sites thereby decreasing off-target toxicities. New combinatorial possibilities are also promising. For example, when combined with viral gene-delivery vehicles, this may result in new hybrid vehicles that attain heretofore unmatched levels of therapeutic gene expression within the tumor.
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Long W, Yi Y, Chen S, Cao Q, Zhao W, Liu Q. Potential New Therapies for Pediatric Diffuse Intrinsic Pontine Glioma. Front Pharmacol 2017; 8:495. [PMID: 28790919 PMCID: PMC5525007 DOI: 10.3389/fphar.2017.00495] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/11/2017] [Indexed: 12/20/2022] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is an extensively invasive malignancy with infiltration into other regions of the brainstem. Although large numbers of specific targeted therapies have been tested, no significant progress has been made in treating these high-grade gliomas. Therefore, the identification of new therapeutic approaches is of great importance for the development of more effective treatments. This article reviews the conventional therapies and new potential therapeutic approaches for DIPG, including epigenetic therapy, immunotherapy, and the combination of stem cells with nanoparticle delivery systems.
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Affiliation(s)
- Wenyong Long
- Department of Neurosurgery, Xiangya Hospital, Central South UniversityChangsha, China
| | - Yang Yi
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityGuangzhou, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou, China
| | - Shen Chen
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityGuangzhou, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou, China
| | - Qi Cao
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, HoustonTX, United States
| | - Wei Zhao
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityGuangzhou, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou, China
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital, Central South UniversityChangsha, China
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Filley AC, Dey M. Immune System, Friend or Foe of Oncolytic Virotherapy? Front Oncol 2017; 7:106. [PMID: 28589085 PMCID: PMC5440545 DOI: 10.3389/fonc.2017.00106] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/08/2017] [Indexed: 01/25/2023] Open
Abstract
Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune-mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus-expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies.
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Affiliation(s)
- Anna C Filley
- Department of Neurosurgery, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA
| | - Mahua Dey
- Department of Neurosurgery, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA
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