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1
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Otero JG, Belmonte-Beitia J, Jiménez-Sánchez J. Exploring neuroblastoma's cellular microenvironment: A novel approach using cellular automata to model Celyvir treatment. Comput Biol Med 2025; 188:109782. [PMID: 39946782 DOI: 10.1016/j.compbiomed.2025.109782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025]
Abstract
Neuroblastoma is a significant health concern in children, as it is one of the most common types of cancer among this age group and is associated with poor survival rates. Currently, there are no effective therapies that significantly improve outcomes for these patients. This study explores the efficacy of Celyvir - an advanced therapy comprising mesenchymal stem cells (MSCs) carrying the oncolytic virus ICOVIR 5 - against neuroblastoma, by means of an individual-based model. A probabilistic cellular automaton was developed to implement the dynamic interactions between neuroblastoma cells, T lymphocytes, and the therapeutic agent Celyvir. The model examines various sizes, shapes, and positions of the tumour within a lattice, along with different infection probabilities associated with the action of Celyvir and various treatment schedules. This analysis identifies the most influential infection probabilities according to the cellular automaton model, and demonstrates that different treatment regimens can effectively eradicate the tumour, in contrast to standard clinical approaches. Additionally, Kaplan-Meier curves have been generated to assess different treatment schedules under specific tumour scenarios, highlighting the importance of precise treatment scheduling to optimise therapeutic outcomes. This study provides insights into the potential of Celyvir in neuroblastoma treatment, emphasising the need to understand tumour dynamics and strategically implement treatment schemes to improve clinical outcomes.
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Affiliation(s)
- José García Otero
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain.
| | - Juan Belmonte-Beitia
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain.
| | - Juan Jiménez-Sánchez
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain; Dipartimento di Scienze Matematiche Giuseppe Luigi Lagrange, Politecnico di Torino, Corso Duca degli Abruzzi, 24, 10129, Turin, Italy.
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2
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Karadimas T, Huynh TH, Chose C, Zervoudakis G, Clampitt B, Lapp S, Joyce D, Letson GD, Metts J, Binitie O, Mullinax JE, Lazarides A. Oncolytic Viral Therapy in Osteosarcoma. Viruses 2024; 16:1139. [PMID: 39066301 PMCID: PMC11281467 DOI: 10.3390/v16071139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/13/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
Primary bone malignancies, including osteosarcoma (OS), are rare but aggressive. Current OS treatment, involving surgical resection and chemotherapy, has improved survival for non-metastatic cases but remains ineffective for recurrent or metastatic OS. Oncolytic viral therapy (OVT) is a promising alternative, using naturally occurring or genetically modified viruses to selectively target and lyse cancer cells and induce a robust immune response against remaining OS cells. Various oncolytic viruses (OVs), such as adenovirus, herpes simplex virus, and measles virus, have demonstrated efficacy in preclinical OS models. Combining OVT with other therapeutics, such as chemotherapy or immunotherapy, may further improve outcomes. Despite these advances, challenges in reliability of preclinical models, safety, delivery, and immune response must be addressed to optimize OVT for clinical use. Future research should focus on refining delivery methods, exploring combination treatments, and clinical trials to ensure OVT's efficacy and safety for OS. Overall, OVT represents a novel approach with the potential to drastically improve survival outcomes for patients with OS.
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Affiliation(s)
- Thomas Karadimas
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Thien Huong Huynh
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Chloe Chose
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Guston Zervoudakis
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Bryan Clampitt
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Sean Lapp
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - David Joyce
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - George Douglas Letson
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Jonathan Metts
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Odion Binitie
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - John E. Mullinax
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Alexander Lazarides
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
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3
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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4
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Gil-Chinchilla JI, Zapata AG, Moraleda JM, García-Bernal D. Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects. Biomolecules 2024; 14:734. [PMID: 39062449 PMCID: PMC11275142 DOI: 10.3390/biom14070734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.
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Affiliation(s)
- Jesús I. Gil-Chinchilla
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
| | - Agustín G. Zapata
- Department of Cell Biology, Complutense University, 28040 Madrid, Spain;
| | - Jose M. Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, 30120 Murcia, Spain
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5
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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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Karami Fath M, Bagherzadeh Torbati SM, Saqagandomabadi V, Yousefi Afshar O, Khalilzad M, Abedi S, Moliani A, Daneshdoust D, Barati G. The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2024; 187:51-60. [PMID: 38373516 DOI: 10.1016/j.pbiomolbio.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/04/2023] [Accepted: 02/16/2024] [Indexed: 02/21/2024]
Abstract
Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Vahid Saqagandomabadi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | | | - Mohammad Khalilzad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Abedi
- Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Afshin Moliani
- Isfahan Medical Students Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Danyal Daneshdoust
- Faculty of Medicine, Babol University of Medical Sciences, Mazandaran, Iran
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Duan S, Wang S, Qiao L, Yu X, Wang N, Chen L, Zhang X, Zhao X, Liu H, Wang T, Wu Y, Li N, Liu F. Oncolytic Virus-Driven Biotherapies from Bench to Bedside. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206948. [PMID: 36879416 DOI: 10.1002/smll.202206948] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/17/2023] [Indexed: 06/08/2023]
Abstract
With advances in cancer biology and an ever-deepening understanding of molecular virology, oncolytic virus (OV)-driven therapies have developed rapidly and become a promising alternative to traditional cancer therapies. In recent years, satisfactory results for oncolytic virus therapy (OVT) are achieved at both the cellular and organismal levels, and efforts are being increasingly directed toward clinical trials. Unfortunately, OVT remains ineffective in these trials, especially when performed using only a single OV reagent. In contrast, integrated approaches, such as using immunotherapy, chemotherapy, or radiotherapy, alongside OVT have demonstrated considerable efficacy. The challenges of OVT in clinical efficacy include the restricted scope of intratumoral injections and poor targeting of intravenous administration. Further optimization of OVT delivery is needed before OVs become a viable therapy for tumor treatment. In this review, the development process and antitumor mechanisms of OVs are introduced. The advances in OVT delivery routes to provide perspectives and directions for the improvement of OVT delivery are highlighted. This review also discusses the advantages and limitations of OVT monotherapy and combination therapy through the lens of recent clinical trials and aims to chart a course toward safer and more effective OVT strategies.
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Affiliation(s)
- Shijie Duan
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shuhang Wang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Qiao
- Colorectal and Henia Minimally Invasive Surgery Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xinbo Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Nan Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Liting Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xinyuan Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xu Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Hongyu Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Tianye Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ying Wu
- Phase I Clinical Trials Center, The First Hospital of China Medical University, Department of General Practice, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ning Li
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
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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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9
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Osum M, Kalkan R. Cancer Stem Cells and Their Therapeutic Usage. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1436:69-85. [PMID: 36689167 DOI: 10.1007/5584_2022_758] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Cancer stem cells (CSC) have unique characteristics which include self-renewal, multi-directional differentiation capacity, quiescence/dormancy, and tumor-forming capability. These characteristics are referred to as the "stemness" properties. Tumor microenvironment contributes to CSC survival, function, and remaining them in an undifferentiated state. CSCs can form malignant tumors with heterogeneous phenotypes mediated by the tumor microenvironment. Therefore, the crosstalk between CSCs and tumor microenvironment can modulate tumor heterogeneity. CSCs play a crucial role in several biological processes, epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. In this chapter, we focused characteristics of cancer stem cells, reprogramming strategies cells into CSCs, and then we highlighted the contribution of CSCs to therapy resistance and cancer relapse and their potential of therapeutic targeting of CSCs.
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Affiliation(s)
- Meryem Osum
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Near East University, Nicosia, Cyprus
| | - Rasime Kalkan
- Department of Medical Genetics, Faculty of Medicine, Cyprus Health and Social Sciences University, Guzelyurt, Cyprus.
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10
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Cloquell A, Mateo I, Gambera S, Pumarola M, Alemany R, García-Castro J, Perisé-Barrios AJ. Systemic cellular viroimmunotherapy for canine high-grade gliomas. J Immunother Cancer 2022; 10:jitc-2022-005669. [PMID: 36600663 PMCID: PMC9772696 DOI: 10.1136/jitc-2022-005669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Oncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors. METHODS Ten dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment. RESULTS The treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells. CONCLUSIONS These findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.
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Affiliation(s)
- Ana Cloquell
- Servicio de Neurología, Hospital Clínico Veterinario, Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain
| | - Isidro Mateo
- Servicio de Neurología, Hospital Clínico Veterinario, Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain,Servicio de Neurología, Hospital Veterinario VETSIA, Leganés, Spain
| | - Stefano Gambera
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain,Molecular Genetics of Angiogenesis Group, Spanish National Centre for Cardiovascular Research (CNIC), Madrid, Spain
| | - Martí Pumarola
- Unitat de Patologia Murina i Comparada (UPMiC), Departament de Medicina i Cirurgia Animals, Facultat de Veterinaria, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ramon Alemany
- IDIBELL, Institut Català d'Oncologia, Barcelona, Spain
| | | | - Ana Judith Perisé-Barrios
- Unidad de Investigación Biomédica (UIB-UAX), Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain
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11
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 451] [Impact Index Per Article: 150.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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12
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Nilson R, Lübbers O, Schmidt CQ, Rojewski M, Zeplin PH, Funk W, Schrezenmeier H, Kritzinger A, Kochanek S, Krutzke L. Hexon modification of human adenovirus type 5 vectors enables efficient transduction of human multipotent mesenchymal stromal cells. Mol Ther Methods Clin Dev 2022; 25:96-110. [PMID: 35402633 PMCID: PMC8956844 DOI: 10.1016/j.omtm.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/04/2022] [Indexed: 11/29/2022]
Abstract
In adenovirus type 5 (HAdV-5)-derived viral vectors, the fiber protein has been the preferred locale for modifications to alter the natural viral tropism. Hexon, the most abundant capsid protein, has rarely been used for retargeting purposes, likely because the insertion of larger targeting peptides into Hexon often interferes with the assembly of the viral capsid. We previously observed that positively charged molecules enhance the transduction of human multipotent mesenchymal stromal cells (hMSCs)—a cell type of significant interest for clinical development but inefficiently transduced by unmodified HAdV-5-based vectors. As efficient HAdV-5-mediated gene transfer would greatly increase the therapeutic potential of hMSCs, we tested the hypothesis that introducing positively charged amino acids into Hexon might enhance the transduction of hMSCs, enabling efficient expression of selected transgenes. From the constructs that could be rescued as functional virions, one (HAdV-5-HexPos3) showed striking transduction of hMSCs with up to 500-fold increased efficiency. Evaluation of the underlying mechanism identified heparan sulfate proteoglycans (HSPGs) to be essential for virus uptake by the cells. The ease and efficiency of transduction of hMSCs with this vector will facilitate the development of genetically modified hMSCs as therapeutic vehicles in different disciplines, including oncology or regenerative medicine.
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Affiliation(s)
- Robin Nilson
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Olivia Lübbers
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Christoph Q Schmidt
- Department of Applied Immunology and Immunopharmacology, University Medical Center Ulm, Ulm, Germany
| | - Markus Rojewski
- Institute for Transfusion Medicine, University Medical Center Ulm, Ulm, Germany.,Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, Ulm, Germany
| | - Philip Helge Zeplin
- Schlosspark Klinik Ludwigsburg, Privatklinik für Plastische und Ästhetische Chirurgie, Ludwigsburg, Germany
| | | | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Medical Center Ulm, Ulm, Germany.,Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, Ulm, Germany
| | - Astrid Kritzinger
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Stefan Kochanek
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Lea Krutzke
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
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13
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Chen XT, Dai SY, Zhan Y, Yang R, Chen DQ, Li Y, Zhou EQ, Dong R. Progress of oncolytic virotherapy for neuroblastoma. Front Pediatr 2022; 10:1055729. [PMID: 36467495 PMCID: PMC9716318 DOI: 10.3389/fped.2022.1055729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022] Open
Abstract
As a neuroendocrine tumor derived from the neural crest, neuroblastoma (NB) is the most common extracranial solid tumor in children. The prognosis in patients with low- and intermediate-risk NB is favorable while that in high-risk patients is often detrimental. However, the management of the considerably large proportion of high-risk patients remains challenging in clinical practice. Among various new approaches, oncolytic virus (OV) therapy offers great advantages in tumor treatment, especially for high-risk NB. Genetic modified OVs can target NB specifically without affecting normal tissue and avoid the widespread drug resistance issue in anticancer monotherapy. Meanwhile, its safety profile provides great potential in combination therapy with chemo-, radio-, and immunotherapy. The therapeutic efficacy of OV for NB is impressive from bench to bedside. The effectiveness and safety of OVs have been demonstrated and reported in studies on children with NB. Furthermore, clinical trials on some OVs (Celyvir, Pexa-Vec (JX-594) and Seneca Valley Virus (NTX-010)) have reported great results. This review summarizes the latest evidence in the therapeutic application of OVs in NB, including those generated in cell lines, animal models and clinical trials.
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Affiliation(s)
- Xiao-Tong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Shu-Yang Dai
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yong Zhan
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Ran Yang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - De-Qian Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yi Li
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - En-Qing Zhou
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
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14
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Niknam MR, Attari F. The Potential Applications of Stem Cells for Cancer Treatment. Curr Stem Cell Res Ther 2022; 17:26-42. [PMID: 35048802 DOI: 10.2174/1574888x16666210810100858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/26/2021] [Accepted: 06/01/2021] [Indexed: 01/10/2023]
Abstract
:
Scientists encounter many obstacles in traditional cancer therapies, including the side effects
on the healthy cells, drug resistance, tumor relapse, the short half-life of employed drugs in
the blood circulation, and the improper delivery of drugs toward the tumor site. The unique traits of
stem cells (SCs) such as self-renewal, differentiation, tumor tropism, the release of bioactive
molecules, and immunosuppression have opened a new window for utilizing SCs as a novel tool in
cancer treatment. In this regard, engineered SCs can secrete anti-cancer proteins or express enzymes
used in suicide gene therapy which locally induce apoptosis in neoplastic cells via the bystander
effect. These cells also stand as proper candidates to serve as careers for drug-loaded nanoparticles
or to play suitable hosts for oncolytic viruses. Moreover, they harbor great potential to be
employed in immunotherapy and combination therapy. However, tactful strategies should be devised
to allow easier transplantation and protection of SCs from in vivo immune responses. In spite
of the great hope concerning SCs application in cancer therapy, there are shortcomings and challenges
to be addressed. This review tends to elaborate on recent advances on the various applications
of SCs in cancer therapy and existing challenges in this regard.
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Affiliation(s)
- Malikeh Rad Niknam
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farnoosh Attari
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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15
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Alyami EM, Tarar A, Peng CA. Less phagocytosis of viral vectors by tethering with CD47 ectodomain. J Mater Chem B 2021; 10:64-77. [PMID: 34846059 DOI: 10.1039/d1tb01815a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Many viral vectors, which are effective when administrated in situ, lack efficacy when delivered intravenously. The key reason for this is the rapid clearance of the viruses from the blood circulation via the immune system before they reach target sites. Therefore, avoiding their clearance by the immune system is essential. In this study, lentiviral vectors were tethered with the ectodomain of self-marker protein CD47 to suppress phagocytosis via interacting with SIRPα on the outer membrane of macrophage cells. CD47 ectodomain and core-streptavidin fusion gene (CD47ED-coreSA) was constructed into pET-30a(+) plasmid and transformed into Lemo21 (DE3) competent E. coli cells. The expressed CD47ED-coreSA chimeric protein was purified by cobalt-nitrilotriacetate affinity column and characterized by SDS-PAGE and western blot. The purified chimeric protein was anchored on biotinylated lentivirus via biotin-streptavidin binding. The CD47ED-capped lentiviruses encoding GFP were used to infect J774A.1 macrophage cells to assess the impact on phagocytosis. Our results showed that the overexpressed CD47ED-coreSA chimeric protein was purified and bound on the surface of biotinylated lentivirus which was confirmed via immunoblotting assay. The process to produce biotinylated lentivirus did not affect native viral infectivity. It was shown that the level of GFP expression in J774A.1 macrophages transduced with CD47ED-lentiviruses was threefold lower in comparison to control lentiviruses, indicating an antiphagocytic effect triggered by the interaction of CD47ED and SIRPα. Through the test of blocking antibodies against CD47ED and/or SIRPα, it was confirmed that the phagocytosis inhibition was mediated through the CD47ED-SIRPα axis signaling. In conclusion, surface immobilization of CD47ED on lentiviral vectors inhibits their phagocytosis by macrophages. The chimeric protein of CD47 ectodomain and core-streptavidin is effective in mediating the surface binding and endowing the lentiviral nanoparticles with the antiphagocytic property.
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Affiliation(s)
- Esmael M Alyami
- Department of Chemical and Biological Engineering, University of Idaho, Engineering Physics Building 410, 875 Perimeter Drive, Moscow, ID 83844-0904, USA.
| | - Ammar Tarar
- Department of Chemical and Biological Engineering, University of Idaho, Engineering Physics Building 410, 875 Perimeter Drive, Moscow, ID 83844-0904, USA.
| | - Ching-An Peng
- Department of Chemical and Biological Engineering, University of Idaho, Engineering Physics Building 410, 875 Perimeter Drive, Moscow, ID 83844-0904, USA.
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16
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El-Kadiry AEH, Rafei M, Shammaa R. Cell Therapy: Types, Regulation, and Clinical Benefits. Front Med (Lausanne) 2021; 8:756029. [PMID: 34881261 PMCID: PMC8645794 DOI: 10.3389/fmed.2021.756029] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
Cell therapy practices date back to the 19th century and continue to expand on investigational and investment grounds. Cell therapy includes stem cell- and non-stem cell-based, unicellular and multicellular therapies, with different immunophenotypic profiles, isolation techniques, mechanisms of action, and regulatory levels. Following the steps of their predecessor cell therapies that have become established or commercialized, investigational and premarket approval-exempt cell therapies continue to provide patients with promising therapeutic benefits in different disease areas. In this review article, we delineate the vast types of cell therapy, including stem cell-based and non-stem cell-based cell therapies, and create the first-in-literature compilation of the different "multicellular" therapies used in clinical settings. Besides providing the nuts and bolts of FDA policies regulating their use, we discuss the benefits of cell therapies reported in 3 therapeutic areas-regenerative medicine, immune diseases, and cancer. Finally, we contemplate the recent attention shift toward combined therapy approaches, highlighting the factors that render multicellular therapies a more attractive option than their unicellular counterparts.
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Affiliation(s)
- Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Center, Montreal, QC, Canada
- Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada
| | - Moutih Rafei
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada
- Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Riam Shammaa
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
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17
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Fathi E, Vandghanooni S, Montazersaheb S, Farahzadi R. Mesenchymal stem cells promote caspase-3 expression of SH-SY5Y neuroblastoma cells via reducing telomerase activity and telomere length. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1583-1589. [PMID: 35317118 PMCID: PMC8917842 DOI: 10.22038/ijbms.2021.59400.13187] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/26/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVES The use of mesenchymal stem cells in malignancies has attracted much attention due to their ability to deliver anticancer agents to tumors, including cytokines, chemokines, etc. This study aimed to investigate the effect of MSCs on the neuroblastoma SH-SY5Y cells through proliferation/apoptosis, senescence assessment, telomere length, and telomerase activity in vitro. BAX and BCL2 were also examined as potential signaling pathways in this process. MATERIALS AND METHODS For this reason, two cell populations (MSCs and SH-SY5Y cells) were co-cultured on trans-well plates for 7 days. In a subsequent step, SH-SY5Y cells were harvested from both control and experimental groups and subjected to flow cytometry, ELISA, real-time PCR, PCR-ELISA TRAP assay, and Western blotting assay for Ki67/Caspase3 investigation, β-Galactosidase assessment, telomere length, and telomerase activity assay. Also, expression of genes and proteins through real-time PCR and Western blotting demonstrated the involvement of the aforementioned signaling pathways in this process. RESULTS It was found that MSCs contributed significantly to decrease and increase of Ki-67 and Caspase-3, respectively. Also, MSCs dramatically reduced the length of telomere and telomerase activity and increased the β-Galactosidase activity in a significant manner. In addition, significant increase and decrease were also seen in BAX and BCL2 gene and protein expressions, respectively. CONCLUSION These findings revealed that close interaction between MSCs and neuroblastoma cells causes inhibition of the SH-SY5Y cell proliferation and promotes cell senescence via BAX and caspase-3 cascade pathways.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Hassanzadeh A, Altajer AH, Rahman HS, Saleh MM, Bokov DO, Abdelbasset WK, Marofi F, Zamani M, Yaghoubi Y, Yazdanifar M, Pathak Y, Chartrand MS, Jarahian M. Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy. Front Cell Dev Biol 2021; 9:686453. [PMID: 34322483 PMCID: PMC8311597 DOI: 10.3389/fcell.2021.686453] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University of Anbar, Ramadi, Iraq
| | - Dmitry O. Bokov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Adjunct Professor, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | | | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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Santos J, Heiniö C, Quixabeira D, Zafar S, Clubb J, Pakola S, Cervera-Carrascon V, Havunen R, Kanerva A, Hemminki A. Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers. Cells 2021; 10:cells10050978. [PMID: 33922052 PMCID: PMC8143525 DOI: 10.3390/cells10050978] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/10/2021] [Accepted: 04/19/2021] [Indexed: 01/29/2023] Open
Abstract
Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.
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Affiliation(s)
- Joao Santos
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- TILT Biotherapeutics Ltd., 00290 Helsinki, Finland
| | - Camilla Heiniö
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
| | - Dafne Quixabeira
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
| | - Sadia Zafar
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
| | - James Clubb
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- TILT Biotherapeutics Ltd., 00290 Helsinki, Finland
| | - Santeri Pakola
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
| | - Victor Cervera-Carrascon
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- TILT Biotherapeutics Ltd., 00290 Helsinki, Finland
| | - Riikka Havunen
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- TILT Biotherapeutics Ltd., 00290 Helsinki, Finland
| | - Anna Kanerva
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland
| | - Akseli Hemminki
- Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; (J.S.); (C.H.); (D.Q.); (S.Z.); (J.C.); (S.P.); (V.C.-C.); (R.H.); (A.K.)
- TILT Biotherapeutics Ltd., 00290 Helsinki, Finland
- Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland
- Correspondence:
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20
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Zhang T, Huang T, Su Y, Gao J. Mesenchymal Stem Cells‐Based Targeting Delivery System: Therapeutic Promises and Immunomodulation against Tumor. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Tianyuan Zhang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Ting Huang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Yuanqin Su
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Jianqing Gao
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Cancer Center of Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
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21
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Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy. Front Cell Dev Biol 2021; 9:654885. [PMID: 33869217 PMCID: PMC8044970 DOI: 10.3389/fcell.2021.654885] [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: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.
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Affiliation(s)
| | | | - Gerlinde R. Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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22
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Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21:158. [PMID: 33685452 PMCID: PMC7938588 DOI: 10.1186/s12935-021-01836-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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23
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Morales-Molina A, Gambera S, Leo A, García-Castro J. Combination immunotherapy using G-CSF and oncolytic virotherapy reduces tumor growth in osteosarcoma. J Immunother Cancer 2021; 9:e001703. [PMID: 33737338 PMCID: PMC7978281 DOI: 10.1136/jitc-2020-001703] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Osteosarcoma is the most common malignant solid tumor that affects bones, however, survival rates of patients with relapsed osteosarcoma have not improved in the last 30 years. Oncolytic virotherapy, which uses viruses designed to selectively replicate in cancer cells, has emerged as a promising treatment for solid tumors. Our group uses mesenchymal stem cells (MSCs) to transport oncolytic adenoviruses (OAds) to the tumor site, a therapeutic strategy called Celyvir. This treatment has been already applied in human patients, canine patients and different mouse models. In parallel, previous results have probed that administration of granulocyte-colony stimulating factor (G-CSF) increased immune infiltration in tumors. We then hypothesized that the mobilization of immune cells by G-CSF may increase the antitumor efficacy of Celyvir treatment by increasing the immune infiltration into the tumors. METHODS In this study, we use a murine version of Celyvir consisting in murine MSCs carrying the murine OAd dlE102-here called OAd-MSCs-in an immunocompetent model of osteosarcoma. We tested the antitumoral efficacy of the combination of OAd-MSCs plus G-CSF. RESULTS Our results show that treatment with OAd-MSCs or the union of OAd-MSCs with G-CSF (Combination) significantly reduced tumor growth of osteosarcoma in vivo. Moreover, treated tumors presented higher tumor infiltration of immune cells-especially tumor-infiltrating lymphocytes-and reduced T cell exhaustion, which seems to be enhanced in tumors treated with the Combination. The comparison of our results to those obtained from a cohort of pediatric osteosarcoma patients showed that the virotherapy induces immunological changes similar to those observed in patients with good prognosis. CONCLUSIONS The results open the possibility of using cellular virotherapy for the treatment of bone cancers. Indeed, its combination with G-CSF may be considered for the improvement of the therapy.
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Affiliation(s)
| | - Stefano Gambera
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain
| | - Angela Leo
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Firenze, Italy
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24
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The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery. J Pers Med 2021; 11:jpm11030161. [PMID: 33668854 PMCID: PMC7996318 DOI: 10.3390/jpm11030161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by means of supporting hematopoietic stem cell transplantation. Based on pre-clinical and clinical advances in neuroblastoma and other malignancies, we assess both the strong potential and the associated risks of using mesenchymal stromal cells in the therapy for neuroblastoma. Furthermore, we examine feasibility and safety aspects and discuss future directions for harnessing the advantageous properties of mesenchymal stromal cells for the advancement of therapy success.
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25
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Moreno R. Mesenchymal stem cells and oncolytic viruses: joining forces against cancer. J Immunother Cancer 2021; 9:e001684. [PMID: 33558278 PMCID: PMC7871674 DOI: 10.1136/jitc-2020-001684] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
The development of oncolytic viruses (OVs) has increased significantly in the past 20 years, with many candidates entering clinical trials and three of them receiving approval for some indications. Recently, OVs have also gathered interest as candidates to use in combination with immunotherapies for cancer due to their immunogenic properties, which include immunogenic cell death and the possibility to carry therapeutic transgenes in their genomes. OVs transform non-immunogenic 'cold' tumors into inflamed immunogenic 'hot' tumors, where immunotherapies show the highest efficacy. However, in monotherapy or in combination with immunotherapy, OVs face numerous challenges that limit their successful application, in particular upon systemic administration, such as liver sequestration, neutralizing interactions in blood, physical barriers to infection, and fast clearance by the immune system. In this regard, the use of mesenchymal stem cells (MSCs) as cells carrier for OV delivery addresses many of these obstacles acting as virus carriers and factories, expressing additional transgenes, and modulating the immune system. Here, I review the current progress of OVs-loaded MSCs in cancer, focusing on their interaction with the immune system, and discuss new strategies to improve their therapeutic efficacy.
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Affiliation(s)
- Rafael Moreno
- Virotherapy and immunotherapy group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain
- Cancer Virotherapy group, Oncobell Program, Institutd'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain
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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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Gómez A, Sardón D, Cejalvo T, Vázquez F, García-Castro J, Perisé-Barrios AJ. Biodistribution Analysis of Oncolytic Adenoviruses in Canine Patient Necropsy Samples Treated with Cellular Virotherapy. Mol Ther Oncolytics 2020; 18:525-534. [PMID: 32995478 PMCID: PMC7490470 DOI: 10.1016/j.omto.2020.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 08/10/2020] [Indexed: 11/17/2022] Open
Abstract
Oncolytic immunotherapy with competent viruses is an emerging approach in cancer treatment. The clinical safety of many types of oncolytic viruses (OVs) has been demonstrated. However, there is a lack of information about viral biodistribution in patients. The available data about oncolytic adenovirus biodistribution in human subjects treated intravenously consists of virus detection in body fluids, a few tumor biopsies, and a single report of patient necropsy samples. There is no information about adenoviral biodistribution in patients treated intravenously with cellular vehicles carrying an oncolytic adenovirus. We previously published reports regarding the efficacy and clinical safety of infusing mesenchymal stem cells (MSCs) infected with an OV in human and canine patients. In this study, we performed necropsies on 12 canine patients treated with dCelyvir, canine MSCs infected with ICOCAV17, a canine oncolytic adenovirus. The prevalence of microscopic lesions, especially chronic inflammatory responses in different organs, was higher than expected. Concomitantly, we found a positive immunoreaction to ICOCAV17 in analyzed samples. These findings support a possible role of the virus in development of histopathological alterations and ongoing systemic viral replication of ICOCAV17 in the period after therapy administration.
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Affiliation(s)
- Ana Gómez
- Veterinary Pathology Unit, Universidad Alfonso X el Sabio, 28691 Madrid, Spain
| | - David Sardón
- Veterinary Pathology Unit, Universidad Alfonso X el Sabio, 28691 Madrid, Spain
| | - Teresa Cejalvo
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Fernando Vázquez
- Veterinary Pathology Unit, Universidad Alfonso X el Sabio, 28691 Madrid, Spain
| | - Javier García-Castro
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
- Biomedical Research Unit, Universidad Alfonso X el Sabio, 28691 Madrid, Spain
| | - Ana Judith Perisé-Barrios
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
- Biomedical Research Unit, Universidad Alfonso X el Sabio, 28691 Madrid, Spain
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28
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Villa N, Rahman MM, Mamola J, D’Isabella J, Goras E, Kilbourne J, Lowe K, Daggett-Vondras J, Torres L, Christie J, Appel N, Cox AL, Kim JB, McFadden G. Autologous Transplantation Using Donor Leukocytes Loaded Ex Vivo with Oncolytic Myxoma Virus Can Eliminate Residual Multiple Myeloma. Mol Ther Oncolytics 2020; 18:171-188. [PMID: 32695875 PMCID: PMC7364119 DOI: 10.1016/j.omto.2020.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/19/2020] [Indexed: 02/08/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy of monoclonal plasma cells that remains incurable. Standard treatments for MM include myeloablative regimens and autologous cell transplantation for eligible patients. A major challenge of these treatments is the relapse of the disease due to residual MM in niches that become refractory to treatments. Therefore, novel therapies are needed in order to eliminate minimal residual disease (MRD). Recently, our laboratory reported that virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an allogeneic transplant mouse model. In this study, we demonstrate the capacity of donor autologous murine leukocytes, pre-armed with MYXV, to eliminate MRD in a BALB/c MM model. We report that MYXV-armed bone marrow (BM) carrier leukocytes are therapeutically superior to MYXV-armed peripheral blood mononuclear cells (PBMCs) or free virus. Importantly, when cured survivor mice were re-challenged with fresh myeloma cells, they developed immunity to the same MM that had comprised MRD. In vivo imaging demonstrated that autologous carrier cells armed with MYXV were very efficient at delivery of MYXV into the recipient tumor microenvironment. Finally, we demonstrate that treatment with MYXV activates the secretion of pro-immune molecules from the tumor bed. These results highlight the utility of exploiting autologous leukocytes to enhance tumor delivery of MYXV to treat MRD in vivo.
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Affiliation(s)
- Nancy.Y. Villa
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Masmudur M. Rahman
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Joseph. Mamola
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Julia D’Isabella
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Elizabeth Goras
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Jacquelyn Kilbourne
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Kenneth Lowe
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Juliane Daggett-Vondras
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Lino Torres
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - John Christie
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Nicole Appel
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Anna L. Cox
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
| | - Jae B. Kim
- PerkinElmer Inc., Waltham, MA 02451, USA
| | - Grant McFadden
- Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
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29
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Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1 + Subsets in Mouse Immunocompetent Models. Cancers (Basel) 2020; 12:cancers12071920. [PMID: 32708639 PMCID: PMC7409201 DOI: 10.3390/cancers12071920] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/09/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)-the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer.
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30
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Gan LL, Hii LW, Wong SF, Leong CO, Mai CW. Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion. Cancers (Basel) 2020; 12:1872. [PMID: 32664564 PMCID: PMC7408947 DOI: 10.3390/cancers12071872] [Citation(s) in RCA: 21] [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: 05/25/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer ranks high among the causes of cancer-related mortality. The prognosis of this grim condition has not improved significantly over the past 50 years, despite advancement in imaging techniques, cancer genetics and treatment modalities. Due to the relative difficulty in the early detection of pancreatic tumors, as low as 20% of patients are eligible for potentially curative surgery; moreover, chemotherapy and radiotherapy (RT) do not confer a great benefit in the overall survival of the patients. Currently, emerging developments in immunotherapy have yet to bring a significant clinical advantage among pancreatic cancer patients. In fact, pancreatic tumor-driven immune evasion possesses one of the greatest challenges leading to immunotherapeutic resistance. Most of the immune escape pathways are innate, while poor priming of hosts' immune response and immunoediting constitute the adaptive immunosuppressive machinery. In this review, we extensively discuss the pathway perturbations undermining the anti-tumor immunity specific to pancreatic cancer. We also explore feasible up-and-coming therapeutic strategies that may restore immunity and address therapeutic resistance, bringing hope to eliminate the status quo in pancreatic cancer prognosis.
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Affiliation(s)
- Li-Lian Gan
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
| | - Ling-Wei Hii
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Shew-Fung Wong
- School of Medicine, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Environmental and Population Health, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chee-Onn Leong
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
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31
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Zhang Y, Liu Z. Oncolytic Virotherapy for Malignant Tumor: Current Clinical Status. Curr Pharm Des 2020; 25:4251-4263. [PMID: 31682207 DOI: 10.2174/1381612825666191104090544] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
Abstract
Oncolytic viruses, as novel biological anti-tumor agents, provide anti-tumor therapeutic effects by different mechanisms including directly selective tumor cell lysis and secondary systemic anti-tumor immune responses. Some wide-type and genetically engineered oncolytic viruses have been applied in clinical trials. Among them, T-Vec has a significant therapeutic effect on melanoma patients and received the approval of the US Food and Drug Administration (FDA) as the first oncolytic virus to treat cancer in the US. However, the mechanisms of virus interaction with tumor and immune systems have not been clearly elucidated and there are still no "gold standards" for instructions of virotherapy in clinical trials. This Review collected the recent clinical trials data from 2005 to summarize the basic oncolytic viruses biology, describe the application in recent clinical trials, and discuss the challenges in the application of oncolytic viruses in clinical trials.
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Affiliation(s)
- Yuhui Zhang
- Department of Spine Surgery, Renji Hospital, Medical School, Shanghai Jiaotong University, Shanghai, China
| | - Zhuoming Liu
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States
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Rodríguez-Milla MÁ, Morales-Molina A, Perisé-Barrios AJ, Cejalvo T, García-Castro J. AKT and JUN are differentially activated in mesenchymal stem cells after infection with human and canine oncolytic adenoviruses. Cancer Gene Ther 2020; 28:64-73. [PMID: 32457488 DOI: 10.1038/s41417-020-0184-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023]
Abstract
There is increasing evidence about the use of oncolytic adenoviruses (Ads) as promising immunotherapy agents. We have previously demonstrated the clinical efficiency of mesenchymal stem cells (MSCs) infected with oncolytic Ads as an antitumoral immunotherapy (called Celyvir) in human and canine patients, using ICOVIR-5 or ICOCAV17 as human and canine oncolytic Ads, respectively. Considering the better clinical outcomes of canine patients, in this study we searched for differences in cellular responses of human and canine MSCs to Ad infection that may help understand the mechanisms leading to higher antitumor immune response. We found that infection of human and canine MSCs with ICOVIR-5 or ICOCAV17 did not activate the NF-κB pathway or the interferon regulatory factors IRF3 and IRF7. However, we observed differences in the profile of cytokines secretion, as infection of canine MSCs with ICOCAV17 resulted in lower secretion of several cytokines. Moreover, we showed that infection of human MSCs with ICOVIR-5 increased the phosphorylation of a number of proteins, including AKT and c-JUN. Finally, we demonstrated that differences in regulation of AKT and c-JUN in human and canine MSCs by ICOVIR-5 or ICOCAV17 are intrinsic to each virus. Our findings suggest that ICOCAV17 induces a more limited host response in canine MSCs, which may be related to a better clinical outcome. This result opens the possibility to develop new human oncolytic Ads with these specific properties. In addition, this improvement could be imitated by selecting specific human MSC on the basis of a limited host response after Ad infection.
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Affiliation(s)
| | | | - Ana Judith Perisé-Barrios
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220, Madrid, Spain.,Biomedical Research Unit, Universidad Alfonso X el Sabio, 28691, Madrid, Spain
| | - Teresa Cejalvo
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220, Madrid, Spain
| | - Javier García-Castro
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220, Madrid, Spain.
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Franco-Luzón L, García-Mulero S, Sanz-Pamplona R, Melen G, Ruano D, Lassaletta Á, Madero L, González-Murillo Á, Ramírez M. Genetic and Immune Changes Associated with Disease Progression under the Pressure of Oncolytic Therapy in A Neuroblastoma Outlier Patient. Cancers (Basel) 2020; 12:cancers12051104. [PMID: 32354143 PMCID: PMC7281487 DOI: 10.3390/cancers12051104] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/25/2020] [Accepted: 04/26/2020] [Indexed: 12/19/2022] Open
Abstract
Little is known about the effect of oncolytic adenovirotherapy on pediatric tumors. Here we present the clinical case of a refractory neuroblastoma that responded positively to Celyvir (ICOVIR-5 oncolytic adenovirus delivered by autologous mesenchymal stem cells) for several months. We analyzed samples during tumor evolution in order to identify molecular and mutational features that could explain the interactions between treatment and tumor and how the balance between both of them evolved. We identified a higher adaptive immune infiltration during stabilized disease compared to progression, and also a higher mutational rate and T-cell receptor (TCR) diversity during disease progression. Our results indicate an initial active role of the immune system controlling tumor growth during Celyvir therapy. The tumor eventually escaped from the control exerted by virotherapy through acquisition of resistance by the tumor microenvironment that exhausted the initial T cell response.
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Affiliation(s)
- Lidia Franco-Luzón
- Children Oncohematology Foundation, 28079 Madrid, Spain; (L.F.-L.); (L.M.)
| | - Sandra García-Mulero
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain;
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Rebeca Sanz-Pamplona
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Gustavo Melen
- Biomedical Research Foundation, Niño Jesús Children Hospital, 28009 Madrid, Spain; (G.M.); (Á.G.-M.)
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
| | - David Ruano
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
| | - Álvaro Lassaletta
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
| | - Luís Madero
- Children Oncohematology Foundation, 28079 Madrid, Spain; (L.F.-L.); (L.M.)
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
- Oncohematology Unit, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain
| | - África González-Murillo
- Biomedical Research Foundation, Niño Jesús Children Hospital, 28009 Madrid, Spain; (G.M.); (Á.G.-M.)
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
| | - Manuel Ramírez
- Biomedical Research Foundation, Niño Jesús Children Hospital, 28009 Madrid, Spain; (G.M.); (Á.G.-M.)
- La Princesa Institute of Health Research, 28006 Madrid, Spain; (D.R.); (Á.L.)
- Correspondence: ; Tel.: +34-9150-35938
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Sharif S, Ghahremani MH, Soleimani M. Differentiation Induction and Proliferation Inhibition by A Cell-Free Approach for Delivery of Exogenous miRNAs to Neuroblastoma Cells Using Mesenchymal Stem Cells. CELL JOURNAL 2020; 22:556-564. [PMID: 32347050 PMCID: PMC7211274 DOI: 10.22074/cellj.2021.6928] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/30/2019] [Indexed: 11/28/2022]
Abstract
Objective Neuroblastoma (NB) is one of the frequently observed malignant solid tumors of childhood and infancy,
accounting for 15% of pediatric cancer deaths. Recently, the approach of differentiation therapy has shown considerable
promise in effective treatment of NB patients. MiR-124 belongs to the nervous system-specific miRNAs that is increased
during neuronal differentiation and may be one of the potential therapeutic targets for the treatment of NB. However,
despite its well-established therapeutic potential, its efficient delivery to the targeted tumor cells is a challenging task.
Mesenchymal stem cells (MSCs) are multipotent adult progenitor cells that have antitumor properties, and they can
migrate to cancer cells and tumors. This study aimed to assess whether human adipose tissue-derived MSCs (hAD-
MSCs) have the potential to deliver exogenous miRNAs to NB cells to induce differentiation and decrease proliferation
of cancer cells.
Materials and Methods In this experimental study, hAD-MSCs were isolated, cultured, and differentiated. The M17
human NB cell line were also cultured. A specific type of miRNAs, i.e., miR-124 was successfully delivered to M17 NB
cells with the aid of hAD-MSCs using the direct or indirect (exosome-based) contacts.
Results It was shown that indirect delivery of miR-124 considerably decreased the proliferation of NB cells and
induced their differentiation.
Conclusion The results suggest the use of delivered exogenous miRNAs by the derived exosomes from hAD-MSCs
as a novel cell-free stem cell-based therapy for NB cancer.
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Affiliation(s)
- Samaneh Sharif
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic Address: .,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Ghahremani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Haematology, Tarbiat Modares University, Tehran, Iran
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Babaei A, Bannazadeh Baghi H, Nezhadi A, Jamalpoor Z. In Vitro Anti-cancer Activity of Adipose-Derived Mesenchymal Stem Cells Increased after Infection with Oncolytic Reovirus. Adv Pharm Bull 2020; 11:361-370. [PMID: 33880359 PMCID: PMC8046384 DOI: 10.34172/apb.2021.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/19/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Purpose: Reovirus type 3 Dearing (ReoT3D), a wild type oncolytic virus (OV) from the Reoviridae family, kills KRAS mutant cancer cells. However, the use of OVs has faced with some limitations such as immune responses, and delivery of OVs to the tumor sites in systemic therapy. To solve this, and also to increase the anti-cancer effects of these OVs, mesenchymal stem cells (MSCs) might be used as an effective vehicle for OVs delivery. In this study, we examined the anti-cancer effects of human adipose derived-MSCs (AD-MSCs) as a vehicle of ReoT3D against human glioblastoma cells. Methods: Here, AD-MSCs were characterized and toxicity of ReoT3D on them was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Then, capability of AD-MSCs for virus production was assessed by real-time polymerase chain reaction (PCR), and different in vitro anti-cancer experiments were applied for our anti-cancer purposes. Results: Our results from toxicity assay revealed that the isolated and provoked AD-MSCs were resistant to nontoxic concentration multiplicity of infection (MOI) >1 pfu/cells of ReoT3D. In addition, the results indicated that AD-MSCs were susceptible for virus life cycle complementation and were capable for production of virus progenies. Furthermore, our results showed that AD-MSCs had oncolysis effects and increased the anti-cancer effects of ReoT3D. Conclusion: AD-MSCs as a susceptible host for oncolytic reovirus could increase the anti-cancer activity of this OV against glioblastoma multiforme (GBM) cell line.
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Affiliation(s)
- Abouzar Babaei
- Trauma Research Center, Aja University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Akram Nezhadi
- Neuroscience Research Center, Aja University of Medical Sciences, Tehran, Iran
| | - Zahra Jamalpoor
- Trauma Research Center, Aja University of Medical Sciences, Tehran, Iran
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Hadryś A, Sochanik A, McFadden G, Jazowiecka-Rakus J. Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses. Eur J Pharmacol 2020; 874:172991. [PMID: 32044323 DOI: 10.1016/j.ejphar.2020.172991] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/09/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022]
Abstract
Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms.
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Affiliation(s)
- Agata Hadryś
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; Institute of Chemistry, University of Silesia, Poland.
| | - Aleksander Sochanik
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.
| | - Grant McFadden
- Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Hmadcha A, Martin-Montalvo A, Gauthier BR, Soria B, Capilla-Gonzalez V. Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy. Front Bioeng Biotechnol 2020; 8:43. [PMID: 32117924 PMCID: PMC7013101 DOI: 10.3389/fbioe.2020.00043] [Citation(s) in RCA: 232] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 01/21/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are among the most frequently used cell type for regenerative medicine. A large number of studies have shown the beneficial effects of MSC-based therapies to treat different pathologies, including neurological disorders, cardiac ischemia, diabetes, and bone and cartilage diseases. However, the therapeutic potential of MSCs in cancer is still controversial. While some studies indicate that MSCs may contribute to cancer pathogenesis, emerging data reported the suppressive effects of MSCs on cancer cells. Because of this reality, a sustained effort to understand when MSCs promote or suppress tumor development is needed before planning a MSC-based therapy for cancer. Herein, we provide an overview on the therapeutic application of MSCs for regenerative medicine and the processes that orchestrates tissue repair, with a special emphasis placed on cancer, including central nervous system tumors. Furthermore, we will discuss the current evidence regarding the double-edged sword of MSCs in oncological treatment and the latest advances in MSC-based anti-cancer agent delivery systems.
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Affiliation(s)
- Abdelkrim Hmadcha
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Pablo de Olavide University, University of Seville, CSIC, Seville, Spain.,Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain
| | - Alejandro Martin-Montalvo
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Pablo de Olavide University, University of Seville, CSIC, Seville, Spain
| | - Benoit R Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Pablo de Olavide University, University of Seville, CSIC, Seville, Spain.,Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain
| | - Bernat Soria
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.,School of Medicine, Miguel Hernández University, Alicante, Spain.,Pablo de Olavide University, Seville, Spain
| | - Vivian Capilla-Gonzalez
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Pablo de Olavide University, University of Seville, CSIC, Seville, Spain
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38
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Franco-Luzón L, González-Murillo Á, Alcántara-Sánchez C, García-García L, Tabasi M, Huertas AL, Chesler L, Ramírez M. Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma. Oncotarget 2020; 11:347-361. [PMID: 32064039 PMCID: PMC6996901 DOI: 10.18632/oncotarget.27401] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/21/2019] [Indexed: 12/25/2022] Open
Abstract
Celyvir (autologous mesenchymal cells -MSCs- that carry an oncolytic adenovirus) is a new therapeutic strategy for metastatic tumors developed by our research group over the last decade. There are limitations for studying the immune effects of human oncolytic adenoviruses in murine models since these viruses do not replicate naturally in these animals. The use of xenografts in immunodeficient mice prevent assessing important clinical aspects of this therapy such as the antiadenoviral immune response or the possible intratumoral immune changes, both of tumor infiltrating leukocytes and of the microenvironment. In our strategy, the presence of MSCs in the medicinal product adds an extra level of complexity. We present here a murine model that overcomes many of these limitations. We found that carrier cells outcompeted intravenous administration of naked particles in delivering the oncolytic virus into the tumor masses. The protection that MSCs could provide to the oncolytic adenovirus did not preclude the development of an antiadenoviral immune response. However, the presence of circulating antiadenoviral antibodies did not prevent changes detected at the tumor masses: increased infiltration and changes in the quality of immune cells per unit of tumor volume, and a less protumoral and more inflammatory profile of the tumor microenvironment. We believe that the model described here will enable the study of crucial events related to the immune responses affecting both the medicinal product and the tumor.
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Affiliation(s)
| | - África González-Murillo
- Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | | | - Lorena García-García
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Maryam Tabasi
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Ana Luis Huertas
- Servicio de Cirugía, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Louis Chesler
- Paediatric Solid Tumour Biology and Therapeutics Team, Division of Clinical Studies and Cancer Therapeutics Division, The Institute of Cancer Research, Sutton, Surrey, UK
| | - Manuel Ramírez
- Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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Ruano D, López-Martín JA, Moreno L, Lassaletta Á, Bautista F, Andión M, Hernández C, González-Murillo Á, Melen G, Alemany R, Madero L, García-Castro J, Ramírez M. First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors. Mol Ther 2020; 28:1033-1042. [PMID: 32053771 DOI: 10.1016/j.ymthe.2020.01.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.
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Affiliation(s)
- David Ruano
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | - José A López-Martín
- Servicio de Oncología Médica, Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Lucas Moreno
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | - Álvaro Lassaletta
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | | | - Maitane Andión
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | - Carmen Hernández
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | | | - Gustavo Melen
- Fundación de Investigación Biomédica, Hospital Universitario Niño Jesús, Madrid, Spain
| | - Ramón Alemany
- Institut Català d'Oncologia-IDIBELL, Barcelona, Spain
| | - Luis Madero
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain
| | | | - Manuel Ramírez
- Servicio de Oncología, Hospital Universitario Niño Jesús, Madrid, Spain.
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40
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Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy. Sci Rep 2020; 10:425. [PMID: 31949228 PMCID: PMC6965634 DOI: 10.1038/s41598-019-57240-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 12/21/2019] [Indexed: 11/28/2022] Open
Abstract
Mesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. Considering the fact that it is still currently a controversial debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.
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41
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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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42
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Zendedel E, Atkin SL, Sahebkar A. Use of stem cells as carriers of oncolytic viruses for cancer treatment. J Cell Physiol 2019; 234:14906-14913. [PMID: 30770550 DOI: 10.1002/jcp.28320] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 01/19/2019] [Accepted: 01/24/2019] [Indexed: 01/24/2023]
Abstract
Therapeutic application of stem cells and oncolytic viruses in cancer treatment has rapidly increased in the last decade. Oncolytic viruses are considered as a new class of anticancer agents because of their ability to selectively infect and destroy cancer cells. Furthermore, regarding the specific migratory capacity of stem cells, they can be used as carriers or vectors targeting metastatic cancer. Promising results have been reported regarding the use of stem cells and oncolytic viruses as a therapeutic approach for the treatment of metastatic cancer. The present review aimed to determine the approaches involved in the use of the tumor-homing capacity of stem cells for cancer treatment.
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Affiliation(s)
- Elham Zendedel
- Department of Biology, Faculty of Sciences, Islamic Azad University-Mashhad Branch, Mashhad, Iran
| | | | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Na Y, Nam JP, Hong J, Oh E, Shin HC, Kim HS, Kim SW, Yun CO. Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration. J Control Release 2019; 305:75-88. [PMID: 31071373 DOI: 10.1016/j.jconrel.2019.04.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 04/22/2019] [Accepted: 04/28/2019] [Indexed: 12/19/2022]
Abstract
Oncolytic adenovirus (oAd)-mediated gene therapy is a promising approach for cancer treatment because of its cancer cell-restricted replication and therapeutic gene expression. However, systemic administration of oAd is severely restricted by their immunogenic nature and poor tumor homing ability, thus oAd cannot be utilized to treat disseminated metastases. In this study, human bone marrow-derived mesenchymal stromal cell (hMSCs) was used as a viral replication-permissive carrier for oAd with an aim to improve the systemic delivery of the virus to tumor tissues. To overcome the poor delivery of oAd into hMSCs, a relaxin (RLX)-expressing oncolytic Ad (oAd/RLX), which degrades dense tumor extracellular matrix of highly desmoplastic pancreatic cancer, was complexed with biodegradable polymer (poly (ethyleneimine)-conjugated poly(CBA-DAH); PCDP), generating oAd/RLX-PCDP complex. oAd/RLX-PCDP complex enhanced the internalization of oAd into hMSC, leading to superior viral production and release from hMSCs, along with high RLX expression. Furthermore, systemic administration of oAd/RLX-PCDP-treated hMSCs elicited more potent antitumor effect compared to naked oAd/RLX or oAd/RLX-treated hMSC in pancreatic tumor model. This potent antitumor effect of systemically administered oAd/RLX-PCDP-treated hMSCs was achieved by superior viral replication in tumor tissues than any other treatment group. In conclusion, these results demonstrate that hMSCs are effective carriers for the systemic delivery of oAd to tumor sites and treatment of pancreatic cancer.
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Affiliation(s)
- Youjin Na
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Joung-Pyo Nam
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - JinWoo Hong
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | - Eonju Oh
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | | | | | - Sung Wan Kim
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
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Fleifel D, Rahmoon MA, AlOkda A, Nasr M, Elserafy M, El-Khamisy SF. Recent advances in stem cells therapy: A focus on cancer, Parkinson's and Alzheimer's. J Genet Eng Biotechnol 2018; 16:427-432. [PMID: 30733756 PMCID: PMC6354001 DOI: 10.1016/j.jgeb.2018.09.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 08/29/2018] [Accepted: 09/09/2018] [Indexed: 02/07/2023]
Abstract
Stem cells serve as potential therapeutics due to their high proliferative capacity, low immunogenic reactivity and their differentiating capabilities. Several pre-clinical and early-stage clinical studies are carried out to treat genetic diseases, cancers and neurodegenerative disorders with promising preliminary results. However, there are still many challenges that scientists are trying to overcome such as the unclear expression profile of stem cells in vivo, the homing of stem cells to the site of injury and their potential immune-reactivity. Prospective research lies in gene editing of autologous stem cells in vitro and safe injection of these modified cells back into patients. Here, we review the clinical trials executed using stem cell therapy in an attempt to cure challenging diseases like cancer, Parkinson's and Alzheimer's diseases.
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Affiliation(s)
- Dalia Fleifel
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
| | - Mai Atef Rahmoon
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
| | - Abdelrahman AlOkda
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
| | - Mostafa Nasr
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
| | - Menattallah Elserafy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
| | - Sherif F. El-Khamisy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 6th of October City, Giza 12578, Egypt
- Krebs Institute, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, S10 2TN Sheffield, UK
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LaRocca CJ, Warner SG. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. Clin Transl Med 2018; 7:35. [PMID: 30426287 PMCID: PMC6234197 DOI: 10.1186/s40169-018-0214-5] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022] Open
Abstract
Advances in the understanding of cancer immunotherapy and the development of multiple checkpoint inhibitors have dramatically changed the current landscape of cancer treatment. Recent large-scale phase III trials (e.g. PHOCUS, OPTiM) are establishing use of oncolytic viruses as another tool in the cancer therapeutics armamentarium. These viruses do not simply lyse cells to achieve their cancer-killing effects, but also cause dramatic changes in the tumor immune microenvironment. This review will highlight the major vector platforms that are currently in development (including adenoviruses, reoviruses, vaccinia viruses, herpesviruses, and coxsackieviruses) and how they are combined with checkpoint inhibitors. These vectors employ a variety of engineered capsid modifications to enhance infectivity, genome deletions or promoter elements to confer selective replication, and encode a variety of transgenes to enhance anti-tumor or immunogenic effects. Pre-clinical and clinical data have shown that oncolytic vectors can induce anti-tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8+ T cells) into the local tumor microenvironment. This "priming" by the viral infection can change a 'cold' tumor microenvironment into a 'hot' one with the influx of a multitude of immune cells and cytokines. This alteration sets the stage for subsequent checkpoint inhibitor delivery, as they are most effective in an environment with a large lymphocytic infiltrate. There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey-265), and the initial results are encouraging. It is clear that oncolytic viruses and checkpoint inhibitors will continue to evolve together as a combination therapy for multiple types of cancers.
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Affiliation(s)
- Christopher J LaRocca
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA
| | - Susanne G Warner
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA.
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46
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LaRocca CJ, Warner SG. A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer. Biomedicines 2018; 6:biomedicines6040104. [PMID: 30400571 PMCID: PMC6316500 DOI: 10.3390/biomedicines6040104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D's ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer.
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Affiliation(s)
| | - Susanne G Warner
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.
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Moreno R, Fajardo CA, Farrera-Sal M, Perisé-Barrios AJ, Morales-Molina A, Al-Zaher AA, García-Castro J, Alemany R. Enhanced Antitumor Efficacy of Oncolytic Adenovirus-loaded Menstrual Blood-derived Mesenchymal Stem Cells in Combination with Peripheral Blood Mononuclear Cells. Mol Cancer Ther 2018; 18:127-138. [PMID: 30322950 DOI: 10.1158/1535-7163.mct-18-0431] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/16/2018] [Accepted: 10/10/2018] [Indexed: 11/16/2022]
Abstract
Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)-loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow-mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood-derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy.
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Affiliation(s)
- Rafael Moreno
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncología-IDIBELL, Barcelona, Spain.
| | - Carlos Alberto Fajardo
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncología-IDIBELL, Barcelona, Spain
| | - Marti Farrera-Sal
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncología-IDIBELL, Barcelona, Spain
- VCN Biosciences S.L., Grifols Corporate Offices, Sant Cugat del Vallès, Spain
| | | | - Alvaro Morales-Molina
- Cellular Biotechnology Unit, Institute of Health Carlos III (ISCIII), Majadahonda, Madrid, Spain
| | - Ahmed Abdullah Al-Zaher
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncología-IDIBELL, Barcelona, Spain
| | - Javier García-Castro
- Cellular Biotechnology Unit, Institute of Health Carlos III (ISCIII), Majadahonda, Madrid, Spain
| | - Ramon Alemany
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncología-IDIBELL, Barcelona, Spain
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Morales-Molina Á, Gambera S, Cejalvo T, Moreno R, Rodríguez-Milla MÁ, Perisé-Barrios AJ, García-Castro J. Antitumor virotherapy using syngeneic or allogeneic mesenchymal stem cell carriers induces systemic immune response and intratumoral leukocyte infiltration in mice. Cancer Immunol Immunother 2018; 67:1589-1602. [PMID: 30066102 PMCID: PMC11028294 DOI: 10.1007/s00262-018-2220-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 07/27/2018] [Indexed: 12/29/2022]
Abstract
Oncolytic virotherapy uses oncolytic viruses that selectively replicate in cancer cells. The use of cellular vehicles with migration ability to tumors has been considered to increase their delivery to target sites. Following this approach, the antitumor efficacy of the treatment Celyvir (mesenchymal stem cells infected with the oncolytic adenovirus ICOVIR-5) has been demonstrated in patients with neuroblastoma. However, the better efficacy of syngeneic or allogeneic mesenchymal stem cells as cell carriers and the specific role of the immune system in this therapy are still unknown. In this study we use our virotherapy Celyvir with syngeneic and allogeneic mouse mesenchymal stem cells to determine their antitumor efficacy in a C57BL/6 murine adenocarcinoma model. Adoptive transfer of splenocytes from treated mice to new tumor-bearing mice followed by a secondary adoptive transfer to a third group was performed. Similar reduction of tumor growth and systemic activation of the innate and adaptive immune system was observed in groups treated with syngeneic or allogeneic mesenchymal stem cells loaded with ICOVIR-5. Moreover, a different pattern of infiltration was observed by immunofluorescence in Celyvir-treated groups. While non-treated tumors presented higher density of infiltrating immune cells in the periphery of the tumor, both syngeneic and allogeneic Celyvir-treated groups presented higher infiltration of CD45+ cells in the core of the tumor. Therefore, these results suggest that syngeneic and allogeneic Celyvir induce systemic activation of the immune system, similar antitumor effect and a higher intratumoral infiltration of leukocytes.
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Affiliation(s)
- Álvaro Morales-Molina
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain
| | - Stefano Gambera
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain
| | - Teresa Cejalvo
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain
| | - Rafael Moreno
- Virotherapy and Gene therapy Group, ProCure Program, Translational Research Laboratory, Instituto Catalan de Oncologia-IDIBELL, Barcelona, Spain
| | - Miguel Ángel Rodríguez-Milla
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain
| | - Ana Judith Perisé-Barrios
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain
| | - Javier García-Castro
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, lab. 51-00-031, Ctra Majadahonda-Pozuelo, Km 2, Majadahonda, 28220, Madrid, Spain.
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Cejalvo T, Perisé-Barrios AJ, del Portillo I, Laborda E, Rodriguez-Milla MA, Cubillo I, Vázquez F, Sardón D, Ramirez M, Alemany R, del Castillo N, García-Castro J. Remission of Spontaneous Canine Tumors after Systemic Cellular Viroimmunotherapy. Cancer Res 2018; 78:4891-4901. [DOI: 10.1158/0008-5472.can-17-3754] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 04/17/2018] [Accepted: 07/05/2018] [Indexed: 11/16/2022]
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50
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Rincón E, Cejalvo T, Kanojia D, Alfranca A, Rodríguez-Milla MÁ, Gil Hoyos RA, Han Y, Zhang L, Alemany R, Lesniak MS, García-Castro J. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model. Oncotarget 2018; 8:45415-45431. [PMID: 28525366 PMCID: PMC5542197 DOI: 10.18632/oncotarget.17557] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 04/18/2017] [Indexed: 12/28/2022] Open
Abstract
Oncolytic virotherapy represents a promising alternative for cancer treatment; however, viral delivery to the tumor represents a major challenge. Mesenchymal stem cells (MSCs) chemotax to tumors, and can serve as a viral delivery tool. Previously, we demonstrated antitumor therapeutic efficacy for mesenchymal stem cells (MSCs) infected with the oncolytic human adenovirus ICOVIR5 (Celyvir) for treatment of neuroblastoma patients. Given the lack of suitable immunocompetent preclinical models, the mechanism underlying Celyvir antitumor activity remains unknown. In this study, we used the syngeneic murine CMT64 cell line as a human adenovirus-semi-permissive tumor model and demonstrate the homing capacity of mouse Celyvir (mCelyvir) to CMT64 tumors. We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t. ICOVIR5 alone. Interestingly, the superior therapeutic effect of the combined therapy was associated with a higher tumor infiltration of CD8+ and CD4+ T cells. Our findings suggest that the use of MSCs as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, not only by driving the adenovirus to tumors, but also through their potential to recruit T cells.
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Affiliation(s)
- Esther Rincón
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain.,The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Teresa Cejalvo
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain
| | - Deepak Kanojia
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Arantzazu Alfranca
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain
| | | | | | - Yu Han
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Lingjiao Zhang
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Ramón Alemany
- Institut Català d´Oncologia, IDIBELL, Barcelona, Spain
| | - Maciej S Lesniak
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
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