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Engineered cells as glioblastoma therapeutics. Cancer Gene Ther 2022; 29:156-166. [PMID: 33753869 PMCID: PMC8850190 DOI: 10.1038/s41417-021-00320-w] [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: 01/18/2021] [Revised: 02/17/2021] [Accepted: 03/02/2021] [Indexed: 02/01/2023]
Abstract
In spite of significant recent advances in our understanding of the genetics and cell biology of glioblastoma, to date, this has not led to improved treatments for this cancer. In addition to small molecule, antibody, and engineered virus approaches, engineered cells are also being explored as glioblastoma therapeutics. This includes CAR-T cells, CAR-NK cells, as well as engineered neural stem cells and mesenchymal stem cells. Here we review the state of this field, starting with clinical trial studies. These have established the feasibility and safety of engineered cell therapies for glioblastoma and show some evidence for activity. Next, we review the preclinical literature and compare the strengths and weaknesses of various starting cell types for engineered cell therapies. Finally, we discuss future directions for this nascent but promising modality for glioblastoma therapy.
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2
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Blood-Brain Barrier in Brain Tumors: Biology and Clinical Relevance. Int J Mol Sci 2021; 22:ijms222312654. [PMID: 34884457 PMCID: PMC8657947 DOI: 10.3390/ijms222312654] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/13/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.
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Hu XM, Zhang Q, Zhou RX, Wu YL, Li ZX, Zhang DY, Yang YC, Yang RH, Hu YJ, Xiong K. Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications. World J Stem Cells 2021; 13:386-415. [PMID: 34136072 PMCID: PMC8176847 DOI: 10.4252/wjsc.v13.i5.386] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.
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Affiliation(s)
- Xi-Min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rui-Xin Zhou
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yan-Lin Wu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Xin Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Dan-Yi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Chao Yang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rong-Hua Yang
- Department of Burns, Fo Shan Hospital of Sun Yat-Sen University, Foshan 528000, Guangdong Province, China
| | - Yong-Jun Hu
- Department of Cardiovascular Medicine, Hunan People's Hospital (the First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
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Das MK, Lunavat TR, Miletic H, Hossain JA. The Potentials and Pitfalls of Using Adult Stem Cells in Cancer Treatment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1326:139-157. [PMID: 33615422 DOI: 10.1007/5584_2021_619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Stem cells play a pivotal role in the developmental stages of an organism and in adulthood as well. Therefore, it is not surprising that stem cells constitute a focus of extensive research. Indeed, several decades of stem cell research have tremendously increased our knowledge on the mechanistic understandings of stem cell biology. Interestingly, revealing the fundamental principles of stem cell biology has also fostered its application for therapeutic purposes. Many of the attributes that the stem cells possess, some of which are unique, allow multifaceted exploitation of stem cells in the treatment of various diseases. Cancer, the leading cause of mortality worldwide, is one of the disease groups that has been benefited by the potentials of therapeutic applications of the stem cells. While the modi operandi of how stem cells contribute to cancer treatment are many-sided, two major principles can be conceived. One mode involves harnessing the regenerative power of the stem cells to promote the generation of blood-forming cells in cancer patients after cytotoxic regimens. A totally different kind of utility of stem cells has been exercised in another mode where the stem cells can potentially deliver a plethora of anti-cancer therapeutics in a tumor-specific manner. While both these approaches can improve the treatment of cancer patients, there exist several issues that warrant further research. This review summarizes the basic principles of the utility of the stem cells in cancer treatment along with the current trends and pinpoints the major obstacles to focus on in the future for further improvement.
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Affiliation(s)
- Mrinal K Das
- Department of Molecular Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Taral R Lunavat
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Jubayer A Hossain
- Department of Biomedicine, University of Bergen, Bergen, Norway. .,Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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5
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Arévalo-Soliz LM, Hardee CL, Fogg JM, Corman NR, Noorbakhsh C, Zechiedrich L. Improving therapeutic potential of non-viral minimized DNA vectors. CELL & GENE THERAPY INSIGHTS 2020; 6:1489-1505. [PMID: 33953961 PMCID: PMC8095377 DOI: 10.18609/cgti.2020.163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The tragic deaths of three patients in a recent AAV-based X-linked myotubular myopathy clinical trial highlight once again the pressing need for safe and reliable gene delivery vectors. Non-viral minimized DNA vectors offer one possible way to meet this need. Recent pre-clinical results with minimized DNA vectors have yielded promising outcomes in cancer therapy, stem cell therapy, stem cell reprograming, and other uses. Broad clinical use of these vectors, however, remains to be realized. Further advances in vector design and production are ongoing. An intriguing and promising potential development results from manipulation of the specific shape of non-viral minimized DNA vectors. By improving cellular uptake and biodistribution specificity, this approach could impact gene therapy, DNA nanotechnology, and personalized medicine.
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Affiliation(s)
- Lirio M Arévalo-Soliz
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cinnamon L Hardee
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jonathan M Fogg
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nathan R Corman
- Rural Medical Education Program, University of Illinois College of Medicine, Rockford, IL 61107, USA
| | - Cameron Noorbakhsh
- Weiss School of Natural Sciences, Rice University, Houston, TX 77005, USA
| | - Lynn Zechiedrich
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
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Wang D, Wang L, Bai L, Du Y, Liu L, Chen X. Effects of Inhibition of miR-155-5p in Neural Stem Cell Subarachnoid Transplant on Rats with Cerebral Infarction. Hum Gene Ther Methods 2020; 30:184-193. [PMID: 31618139 DOI: 10.1089/hgtb.2019.118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cerebral infarction is a leading cause of death, which calls for effective prevention and treatment. Transplant of neural stem cells (NSCs) is a potential therapeutic treatment to cerebral infarction although its efficacy still needs to be improved. Overexpression of hypoxia-inducible factor 1α (HIF-1α) has been shown to enhance the protective effects of stem cell transplant on cerebral infarction. The expression of HIF-1α is predicted to be regulated by miR-155-5p. Therefore, we regulated the expression of miR-155-5p in NSCs and evaluated the effects of miR-155-5p-regulated NSC transplant on cerebral infarction. We inhibited miR-155-5p expression in NSCs by overexpressing miR-155-5p inhibitor. HIF-1α expression, cell viability, and the expression of apoptosis markers were examined. We established the middle cerebral artery occlusion (MCAO) rat model, and the infarct volume, neurobehavioral outcomes, inflammation, and oxidative stress were evaluated after NSC transplant. miR-155-5p directly targeted HIF-1α and negatively regulated its expression. Inhibition of miR-155-5p enhanced cell viability and prevented cell apoptosis. Transplant of miR-155-5p-inhibited NSCs significantly decreased infarct volume and improved neurobehavioral outcomes of MCAO rats. Transplant of miR-155-5p-inhibited NSCs significantly inhibited inflammation and oxidative stress. Inhibition of miR-155-5p in NSCs resulted in enhanced protection against cerebral infarction after NSC transplant.
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Affiliation(s)
- Dong Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liang Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lin Bai
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuanyuan Du
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Luji Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiang Chen
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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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: 23] [Impact Index Per Article: 4.6] [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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8
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Wang D, Wang L, Bai L, Du Y, Liu L, Chen X. Effects of inhibition of miR-155-5p in neural stem cell subarachnoid transplant on rats with cerebral infarction. Hum Gene Ther Methods 2019. [DOI: 10.1089/hum.2019.118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Dong Wang
- Second Hospital of Hebei Medical University, 71213, the Second Hospital of Hebei Medical University, Shijiazhuang, China, 050000
| | - Liang Wang
- Second Hospital of Hebei Medical University, 71213, Shijiazhuang, Hebei, China
| | - Lin Bai
- Second Hospital of Hebei Medical University, 71213, Shijiazhuang, Hebei, China
| | - Yuanyuan Du
- Second Hospital of Hebei Medical University, 71213, Shijiazhuang, Hebei, China
| | - Luji Liu
- Second Hospital of Hebei Medical University, 71213, Shijiazhuang, Hebei, China
| | - Xiang Chen
- Second Hospital of Hebei Medical University, 71213, Shijiazhuang, Hebei, China
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9
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Mooney R, Hammad M, Batalla‐Covello J, Abdul Majid A, Aboody KS. Concise Review: Neural Stem Cell-Mediated Targeted Cancer Therapies. Stem Cells Transl Med 2018; 7:740-747. [PMID: 30133188 PMCID: PMC6186269 DOI: 10.1002/sctm.18-0003] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/28/2018] [Accepted: 04/24/2018] [Indexed: 12/27/2022] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide, with 1,688,780 new cancer cases and 600,920 cancer deaths projected to occur in 2017 in the U.S. alone. Conventional cancer treatments including surgical, chemo-, and radiation therapies can be effective, but are often limited by tumor invasion, off-target toxicities, and acquired resistance. To improve clinical outcomes and decrease toxic side effects, more targeted, tumor-specific therapies are being developed. Delivering anticancer payloads using tumor-tropic cells can greatly increase therapeutic distribution to tumor sites, while sparing non-tumor tissues therefore minimizing toxic side effects. Neural stem cells (NSCs) are tumor-tropic cells that can pass through normal organs quickly, localize to invasive and metastatic tumor foci throughout the body, and cross the blood-brain barrier to reach tumors in the brain. This review focuses on the potential use of NSCs as vehicles to deliver various anticancer payloads selectively to tumor sites. The use of NSCs in cancer treatment has been studied most extensively in the brain, but the findings are applicable to other metastatic solid tumors, which will be described in this review. Strategies include NSC-mediated enzyme/prodrug gene therapy, oncolytic virotherapy, and delivery of antibodies, nanoparticles, and extracellular vesicles containing oligonucleotides. Preclinical discovery and translational studies, as well as early clinical trials, will be discussed. Stem Cells Translational Medicine 2018;7:740-747.
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Affiliation(s)
- Rachael Mooney
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
- Irell and Manella Graduate, School of Biological SciencesBeckman Research InstituteCity of Hope DuarteCaliforniaUSA
| | - Mohamed Hammad
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
| | - Jennifer Batalla‐Covello
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
- Irell and Manella Graduate, School of Biological SciencesBeckman Research InstituteCity of Hope DuarteCaliforniaUSA
| | - Asma Abdul Majid
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
| | - Karen S. Aboody
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
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