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Sakunchotpanit G, Patil MK, Venkatesh K, Rohan TZ, Cheng D, Nambudiri VE. Treatment of malignant melanoma with coxsackievirus A21 (V937): An emerging oncolytic virotherapy. Exp Dermatol 2024; 33:e15169. [PMID: 39207089 DOI: 10.1111/exd.15169] [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: 05/08/2024] [Revised: 08/06/2024] [Accepted: 08/17/2024] [Indexed: 09/04/2024]
Abstract
Despite rising melanoma incidence in recent decades, there is a trend towards overall decreased mortality, reflecting multiple factors including improved treatment options for metastatic disease. While local treatments are the mainstay for early-stage melanoma, metastatic disease necessitates systemic treatment, with oncolytic virotherapy emerging as a promising option. For this review, articles were retrieved from PubMed from 1964 through 2024. We conducted title, abstract and full-text screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify articles describing the use of coxsackievirus A21 (V937), either as monotherapy or as part of combination therapy for malignant melanoma. Fifteen articles met inclusion criteria, offering preclinical and clinical data on V937's efficacy in reducing tumour burden. In addition to reporting manageable safety profiles, clinical trial data examining intratumoral V937 combination therapy with pembrolizumab and ipilimumab also endorsed favourable objective response rates compared to immune checkpoint inhibitor monotherapy (47% vs. 38% and 21% vs. 10%, respectively). In contrast, intravenous V937 monotherapy failed to yield additional benefit in a cohort of patients with Stage IIIC/IV melanoma (n = 3) despite achieving detectable levels in tumour tissue (1 × 109 TCID50). Although small subsets of patients experienced severe adverse effects and study design limitations imposed constraints on collected data, evidence for the efficacy of V937 remains encouraging. With few clinical trials evaluating V937 in melanoma, additional data is required before routine usage in standard treatment for metastatic lesions.
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Affiliation(s)
- Goranit Sakunchotpanit
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Mihir K Patil
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Carle Illinois College of Medicine, Urbana, Illinois, USA
| | - Kaushik Venkatesh
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas Z Rohan
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Debby Cheng
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Vinod E Nambudiri
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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2
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Karbalaee R, Mehdizadeh S, Ghaleh HEG, Izadi M, Kondori BJ, Dorostkar R, Hosseini SM. The Effects of Mesenchymal Stem Cells Loaded with Oncolytic Coxsackievirus A21 on Mouse Models of Colorectal Cancer. Curr Cancer Drug Targets 2024; 24:967-974. [PMID: 38310465 DOI: 10.2174/0115680096273465231201115839] [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: 07/21/2023] [Revised: 10/19/2023] [Accepted: 11/02/2023] [Indexed: 02/05/2024]
Abstract
BACKGROUND Cancer is a major cause of death worldwide. Colorectal cancer is the second most common type. Additional treatments like chemotherapy and radiation therapy may be recommended. Developing new techniques is vital due to drug resistance and a lack of targeted therapies. OBJECTIVE In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic Coxsackievirus A21 (CVA21) on a mouse model of CRC were investigated. METHODS The therapeutic potency of MSCs loaded with oncolytic CVA21 were evaluated in an experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide (NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-β) in the splenocyte supernatant were all used to evaluate the impact of MSCs loaded with CVA21. RESULTS The results of this study showed that the treatment of a mouse model of colorectal cancer with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH. Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion of IL-4, IL-10, and TGF-β. CONCLUSION The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing level of nitric oxide.
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Affiliation(s)
- Reza Karbalaee
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Saber Mehdizadeh
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Morteza Izadi
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Bahman Jalali Kondori
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
- Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ruhollah Dorostkar
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Morteza Hosseini
- Medicine, Quran and Hadith Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Peribañez-Dominguez S, Parra-Guillen ZP, Freshwater T, Troconiz IF. A physiologically based pharmacokinetic model for V937 oncolytic virus in mice. Front Pharmacol 2023; 14:1211452. [PMID: 37771727 PMCID: PMC10524596 DOI: 10.3389/fphar.2023.1211452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Results: Viral levels showed a drop from 108 to 105 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration. Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.
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Affiliation(s)
- Sara Peribañez-Dominguez
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Zinnia P. Parra-Guillen
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Tomoko Freshwater
- Quantitative Pharmacology and Pharmacometrics Immune/Oncology (QP2-I/O) Merck & Co., Inc., Rahway, NJ, United States
| | - Iñaki F. Troconiz
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- Institute of Data Science and Artificial Intelligence (DATAI), University of Navarra, Pamplona, Spain
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Wu YY, Sun TK, Chen MS, Munir M, Liu HJ. Oncolytic viruses-modulated immunogenic cell death, apoptosis and autophagy linking to virotherapy and cancer immune response. Front Cell Infect Microbiol 2023; 13:1142172. [PMID: 37009515 PMCID: PMC10050605 DOI: 10.3389/fcimb.2023.1142172] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/28/2023] [Indexed: 03/17/2023] Open
Abstract
Recent reports have revealed that oncolytic viruses (OVs) play a significant role in cancer therapy. The infection of OVs such as oncolytic vaccinia virus (OVV), vesicular stomatitis virus (VSV), parvovirus, mammalian reovirus (MRV), human adenovirus, Newcastle disease virus (NDV), herpes simplex virus (HSV), avian reovirus (ARV), Orf virus (ORFV), inactivated Sendai virus (ISV), enterovirus, and coxsackievirus offer unique opportunities in immunotherapy through diverse and dynamic pathways. This mini-review focuses on the mechanisms of OVs-mediated virotherapy and their effects on immunogenic cell death (ICD), apoptosis, autophagy and regulation of the immune system.
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Affiliation(s)
- Yi-Ying Wu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Te-Kai Sun
- Tsairder Boitechnology Co. Ltd., Taichung, Taiwan
| | - Ming-Shan Chen
- Department of Anesthesiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Muhammad Munir
- Department of Biomedical and Life Sciences, Lancaster University, Lancashire, United Kingdom
| | - Hung-Jen Liu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Ph.D Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- *Correspondence: Hung-Jen Liu,
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Silk AW, O’Day SJ, Kaufman HL, Bryan J, Norrell JT, Imbergamo C, Portal D, Zambrano-Acosta E, Palmeri M, Fein S, Wu C, Guerreiro L, Medina D, Bommareddy PK, Zloza A, Fox BA, Ballesteros-Merino C, Ren Y, Shafren D, Grose M, Vieth JA, Mehnert JM. A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study. Cancer Immunol Immunother 2022; 72:1405-1415. [DOI: 10.1007/s00262-022-03314-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022]
Abstract
Abstract
Background
CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB–IV melanoma.
Methods
Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety.
Results
Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8− T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179).
Conclusions
These findings suggest responses to this combination may be seen even in patients without a typical “immune-active” microenvironment.
Trial registration number
NCT02565992.
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Role of HMGB1 in Cutaneous Melanoma: State of the Art. Int J Mol Sci 2022; 23:ijms23169327. [PMID: 36012593 PMCID: PMC9409290 DOI: 10.3390/ijms23169327] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
High-mobility Group Box 1 (HMGB1) is a nuclear protein that plays a key role in acute and chronic inflammation. It has already been studied in several diseases, among them melanoma. Indeed, HMGB1 is closely associated with cell survival and proliferation and may be directly involved in tumor cell metastasis development thanks to its ability to promote cell migration. This research aims to assess the role of this molecule in the pathogenesis of human melanoma and its potential therapeutic role. The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years. The results showed that HMGB1 plays a crucial role in the pathogenesis of skin cancer, prognosis, and therapeutical response to therapy. Traditional therapies target this molecule indirectly, but future perspectives could include the development of new target therapy against HMGB1, thus adding a new approach to the therapy, which has often shown primary and secondary resistance. This could add a new therapy arm which has to be prolonged and specific for each patient.
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Ziogas DC, Martinos A, Petsiou DP, Anastasopoulou A, Gogas H. Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers. Cancers (Basel) 2022; 14:2873. [PMID: 35740539 PMCID: PMC9221332 DOI: 10.3390/cancers14122873] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.
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Affiliation(s)
| | | | | | | | - Helen Gogas
- First Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (D.C.Z.); (A.M.); (D.-P.P.); (A.A.)
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8
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Wang L, Chen Y, Liu X, Li Z, Dai X. The Application of CRISPR/Cas9 Technology for Cancer Immunotherapy: Current Status and Problems. Front Oncol 2022; 11:704999. [PMID: 35111663 PMCID: PMC8801488 DOI: 10.3389/fonc.2021.704999] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 12/27/2021] [Indexed: 12/19/2022] Open
Abstract
Cancer is one of the main causes of disease-related deaths in the world. Although cancer treatment strategies have been improved in recent years, the survival time of cancer patients is still far from satisfied. Cancer immunotherapy, such as Oncolytic virotherapy, Immune checkpoints inhibition, Chimeric antigen receptor T (CAR-T) cell therapy, Chimeric antigen receptor natural killer (CAR-NK) cell therapy and macrophages genomic modification, has emerged as an effective therapeutic strategy for different kinds of cancer. However, many patients do not respond to the cancer immunotherapy which warrants further investigation to optimize this strategy. The clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9), as a versatile genome engineering tool, has become popular in the biology research field and it was also applied to optimize tumor immunotherapy. Moreover, CRISPR-based high-throughput screening can be used in the study of immunomodulatory drug resistance mechanism. In this review, we summarized the development as well as the application of CRISPR/Cas9 technology in the cancer immunotherapy and discussed the potential problems that may be caused by this combination.
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Affiliation(s)
- Luyao Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
| | - Yurong Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
| | - Xinrui Liu
- Neurosurgery Department, First Hospital, Jilin University, Changchun, China
| | - Ziyi Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
- *Correspondence: Xiangpeng Dai,
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Mukesh RK, Kalam AA, Nag J, Jaikumar VS, Kunnakkadan U, Kumar NA, Suma SM, Rajavelu A, Johnson JB. Chandipura virus induces cell death in cancer cell lines of human origin and promotes tumor regression in vivo. MOLECULAR THERAPY-ONCOLYTICS 2021; 23:254-265. [PMID: 34761105 PMCID: PMC8554107 DOI: 10.1016/j.omto.2021.09.009] [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] [Received: 04/23/2021] [Revised: 09/20/2021] [Accepted: 09/29/2021] [Indexed: 11/25/2022]
Abstract
Chandipura virus (CHPV) is an emerging human pathogen of great clinical significance. In this study, we have investigated the susceptibility pattern of both normal and cancer cell lines of human origin to wild-type (wt) CHPV in order to explore the possibility of developing CHPV as an oncolytic vector (OV). Marked cytopathic effect along with enhanced virus output was observed in cancer cell lines (HeLa, A549, U-138, PC-3, and HepG2) in comparison to normal human adult dermal fibroblast (HADF) cells. At an MOI of 0.1, cancer cell lines were differentially susceptible to CHPV, with cells like HeLa and U-138 having pronounced cell death, while the PC-3 were comparatively resistant. All cell lines used in the study except U-138 restricted CHPV infection to varying degrees with IFN-β pre-treatment and supplementation of interferon (IFN) could neither activate the IFN signaling pathway in U-138 cells. Finally, U-138 tumor xenografts established in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice showed significant delay in tumor growth in the CHPV-challenged animals. Thus, targeted cytopathic effect in cancer cells at a very low dose with restricted replication in normal cells offers a rationale to exploit CHPV as an oncolytic vector in the future.
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Affiliation(s)
- Reshma Koolaparambil Mukesh
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.,Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Azeem Abdul Kalam
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Joydeep Nag
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.,Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Vishnu Sunil Jaikumar
- Animal Research Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Umerali Kunnakkadan
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.,Department of Biotechnology, University of Kerala, Thiruvananthapuram 695581, Kerala, India
| | - Nisha Asok Kumar
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.,Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | | | - Arumugam Rajavelu
- Pathogen Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - John Bernet Johnson
- Pathogen Biology, Virology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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11
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Burnett WJ, Burnett DM, Parkman G, Ramstead A, Contreras N, Gravley W, Holmen SL, Williams MA, VanBrocklin MW. Prior Exposure to Coxsackievirus A21 Does Not Mitigate Oncolytic Therapeutic Efficacy. Cancers (Basel) 2021; 13:4462. [PMID: 34503272 PMCID: PMC8431599 DOI: 10.3390/cancers13174462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 11/16/2022] Open
Abstract
Oncolytic viruses (OVs) are being developed as a type of immunotherapy and have demonstrated durable tumor responses and clinical efficacy. One such OV, Coxsackievirus A21 (CVA21), exhibited therapeutic efficacy in early phase clinical trials, demonstrating the ability to infect and kill cancer cells and stimulate anti-tumor immune responses. However, one of the major concerns in using this common cold virus as a therapeutic is the potential for innate and adaptive immune responses to mitigate the benefits of viral infection, particularly in individuals that have been exposed to coxsackievirus prior to treatment. In this study, we assess melanoma responses to CVA21 in the absence or presence of prior exposure to the virus. Melanomas were transplanted into naïve or CVA21-immunized C57BL6 mice and the mice were treated with intratumoral (IT) CVA21. We find that prior exposure to CVA21 does not dramatically affect tumor responses, nor does it alter overall survival. Our results suggest that prior exposure to coxsackievirus is not a critical determinant of patient selection for IT CVA21 interventions.
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Affiliation(s)
- William J. Burnett
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (W.J.B.); (D.M.B.); (G.P.)
| | - David M. Burnett
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (W.J.B.); (D.M.B.); (G.P.)
| | - Gennie Parkman
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (W.J.B.); (D.M.B.); (G.P.)
| | - Andrew Ramstead
- Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (A.R.); (N.C.); (M.A.W.)
| | - Nico Contreras
- Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (A.R.); (N.C.); (M.A.W.)
| | - William Gravley
- School of Medicine, University of Nevada Las Vegas, Las Vegas, NV 89154, USA;
| | - Sheri L. Holmen
- Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA;
| | - Matthew A. Williams
- Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (A.R.); (N.C.); (M.A.W.)
| | - Matthew W. VanBrocklin
- Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA;
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12
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Parra-Guillen ZP, Freshwater T, Cao Y, Mayawala K, Zalba S, Garrido MJ, de Alwis D, Troconiz IF. Mechanistic Modeling of a Novel Oncolytic Virus, V937, to Describe Viral Kinetic and Dynamic Processes Following Intratumoral and Intravenous Administration. Front Pharmacol 2021; 12:705443. [PMID: 34366859 PMCID: PMC8343024 DOI: 10.3389/fphar.2021.705443] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/07/2021] [Indexed: 12/28/2022] Open
Abstract
V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t1/2 = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.
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Affiliation(s)
- Zinnia P Parra-Guillen
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | | | - Youfang Cao
- Merck & Co., Inc., Kenilworth, NJ, United States
| | | | - Sara Zalba
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Maria J Garrido
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | | | - Iñaki F Troconiz
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
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13
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Geisler A, Hazini A, Heimann L, Kurreck J, Fechner H. Coxsackievirus B3-Its Potential as an Oncolytic Virus. Viruses 2021; 13:v13050718. [PMID: 33919076 PMCID: PMC8143167 DOI: 10.3390/v13050718] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
Oncolytic virotherapy represents one of the most advanced strategies to treat otherwise untreatable types of cancer. Despite encouraging developments in recent years, the limited fraction of patients responding to therapy has demonstrated the need to search for new suitable viruses. Coxsackievirus B3 (CVB3) is a promising novel candidate with particularly valuable features. Its entry receptor, the coxsackievirus and adenovirus receptor (CAR), and heparan sulfate, which is used for cellular entry by some CVB3 variants, are highly expressed on various cancer types. Consequently, CVB3 has broad anti-tumor activity, as shown in various xenograft and syngeneic mouse tumor models. In addition to direct tumor cell killing the virus induces a strong immune response against the tumor, which contributes to a substantial increase in the efficiency of the treatment. The toxicity of oncolytic CVB3 in healthy tissues is variable and depends on the virus strain. It can be abrogated by genetic engineering the virus with target sites of microRNAs. In this review, we present an overview of the current status of the development of CVB3 as an oncolytic virus and outline which steps still need to be accomplished to develop CVB3 as a therapeutic agent for clinical use in cancer treatment.
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Affiliation(s)
- Anja Geisler
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Ahmet Hazini
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;
| | - Lisanne Heimann
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Jens Kurreck
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Henry Fechner
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
- Correspondence: ; Tel.: +49-30-31-47-21-81
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14
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Liu Y, Li K, Zhu WB, Zhang H, Huang WT, Liu XC, Lin Y, Cai J, Yan GM, Qiu JG, Peng L, Liang JK, Hu C. Suppression of CCDC6 sensitizes tumor to oncolytic virus M1. Neoplasia 2020; 23:158-168. [PMID: 33338804 PMCID: PMC7749300 DOI: 10.1016/j.neo.2020.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 11/16/2022] Open
Abstract
Oncolytic virus is an effective therapeutic strategy for cancer treatment, which exploits natural or manipulated viruses to selectively target and kill cancer cells. However, the innate antiviral system of cancer cells may resistant to the treatment of oncolytic virus. M1 virus is a newly identified oncolytic virus belonging to alphavirus species, but the molecular mechanisms underlying its anticancer activity are largely unknown. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. RNA seq analysis was used to analyze the gene alternation after M1 virus infection. Small interfering RNAs transfection for gene knockdown was used for gene functional tests. Caspase-3/7 activity was detected by Caspase-Glo Assay Systems. A mice model of orthotopic bladder tumor was established to determine the oncolytic effectiveness of the M1 virus. The expression of cleaved-Caspase 3 as well as Ki-67 in tumor cells were detected by immunohistochemical analysis. To further define the molecular factors involved in M1 virus-mediated biological function, we knocked down genes related to alphavirus’ activity and found that CCDC6 plays an important role in the oncolytic activity of M1 virus. Moreover, knocked down of CCDC6 augments the reproduction of M1 virus and resulted in endoplasmic reticulum (ER) stress-induced cell apoptosis in vitro as well as in vivo orthotopic bladder cancer model. Our research provides a rational new target for developing new compounds to promote the efficacy of oncolytic virus therapy.
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Affiliation(s)
- Ying Liu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Guangzhou, China
| | - Ke Li
- Department of Urology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wen-Bo Zhu
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China
| | - Hao Zhang
- Department of Urology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wen-Tao Huang
- Department of Urology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xin-Cheng Liu
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China
| | - Yuan Lin
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China
| | - Jing Cai
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China
| | - Guang-Mei Yan
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jian-Guang Qiu
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Peng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jian-Kai Liang
- Department of Pharmacology, Sun Yat-sen University, Guangzhou, China.
| | - Cheng Hu
- Department of Urology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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15
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Hwang JK, Hong J, Yun CO. Oncolytic Viruses and Immune Checkpoint Inhibitors: Preclinical Developments to Clinical Trials. Int J Mol Sci 2020; 21:E8627. [PMID: 33207653 PMCID: PMC7697902 DOI: 10.3390/ijms21228627] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/30/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Immuno-oncology (IO) has been an active area of oncology research. Following US FDA approval of the first immune checkpoint inhibitor (ICI), ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody), in 2011, and of the first oncolytic virus, Imlygic (talimogene laherparepvec), in 2015, there has been renewed interest in IO. In the past decade, ICIs have changed the treatment paradigm for many cancers by enabling better therapeutic control, resuming immune surveillance, suppressing tumor immunosuppression, and restoring antitumor immune function. However, ICI therapies are effective only in a small subset of patients and show limited therapeutic potential due to their inability to demonstrate efficacy in 'cold' or unresponsive tumor microenvironments (TMEs). Relatedly, oncolytic viruses (OVs) have been shown to induce antitumor immune responses, augment the efficacy of existing cancer treatments, and reform unresponsive TME to turn 'cold' tumors 'hot,' increasing their susceptibility to checkpoint blockade immunotherapies. For this reason, OVs serve as ideal complements to ICIs, and multiple preclinical studies and clinical trials are demonstrating their combined therapeutic efficacy. This review will discuss the merits and limitations of OVs and ICIs as monotherapy then progress onto the preclinical rationale and the results of clinical trials of key combination therapies.
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Affiliation(s)
- June Kyu Hwang
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea; (J.K.H.); (J.H.)
| | - JinWoo Hong
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea; (J.K.H.); (J.H.)
- GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea; (J.K.H.); (J.H.)
- GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea
- Institute of Nano Science and Technology, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea
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16
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Hromic-Jahjefendic A, Lundstrom K. Viral Vector-Based Melanoma Gene Therapy. Biomedicines 2020; 8:E60. [PMID: 32187995 PMCID: PMC7148454 DOI: 10.3390/biomedicines8030060] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/06/2023] Open
Abstract
Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in diverse preclinical and clinical studies for the treatment of various diseases, including colon, head-and-neck, prostate and breast cancer as well as squamous cell carcinoma and glioma. The majority of studies have focused on immunotherapy and several drugs based on viral vectors have been approved. However, gene therapy for malignant melanoma based on viral vectors has not been utilized to its full potential yet. This review represents a summary of the achievements of preclinical and clinical studies using viral vectors, with the focus on malignant melanoma.
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Affiliation(s)
- Altijana Hromic-Jahjefendic
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
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17
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Abstract
Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications. Implications for Practice This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies. This review highlights recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on talimogene laherparepvec in the treatment of advanced melanoma as a model for future solid tumor indications.
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Affiliation(s)
- Omid Hamid
- The Angeles Clinic and Research InstituteLos AngelesCaliforniaUSA
| | | | - Igor Puzanov
- Roswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
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18
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Zainutdinov SS, Kochneva GV, Netesov SV, Chumakov PM, Matveeva OV. Directed evolution as a tool for the selection of oncolytic RNA viruses with desired phenotypes. Oncolytic Virother 2019; 8:9-26. [PMID: 31372363 PMCID: PMC6636189 DOI: 10.2147/ov.s176523] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 06/07/2019] [Indexed: 12/23/2022] Open
Abstract
Viruses have some characteristics in common with cell-based life. They can evolve and adapt to environmental conditions. Directed evolution can be used by researchers to produce viral strains with desirable phenotypes. Through bioselection, improved strains of oncolytic viruses can be obtained that have better safety profiles, increased specificity for malignant cells, and more efficient spread among tumor cells. It is also possible to select strains capable of killing a broader spectrum of cancer cell variants, so as to achieve a higher frequency of therapeutic responses. This review describes and analyses virus adaptation studies performed with members of four RNA virus families that are used for viral oncolysis: reoviruses, paramyxoviruses, enteroviruses, and rhabdoviruses.
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Affiliation(s)
- Sergei S Zainutdinov
- State Research Center of Virology and Biotechnology “Vector”
, Koltsovo630559, Russia
| | - Galina V Kochneva
- State Research Center of Virology and Biotechnology “Vector”
, Koltsovo630559, Russia
| | - Sergei V Netesov
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk630090, Russia
| | - Peter M Chumakov
- Engelhardt Institute of Molecular Biology
, Moscow119991, Russia
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products
, Moscow108819, Russia
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19
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Müller LME, Holmes M, Michael JL, Scott GB, West EJ, Scott KJ, Parrish C, Hall K, Stäble S, Jennings VA, Cullen M, McConnell S, Langton C, Tidswell EL, Shafren D, Samson A, Harrington KJ, Pandha H, Ralph C, Kelly RJ, Cook G, Melcher AA, Errington-Mais F. Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21. J Immunother Cancer 2019; 7:164. [PMID: 31262361 PMCID: PMC6604201 DOI: 10.1186/s40425-019-0632-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 06/06/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. METHODS This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. RESULTS An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. CONCLUSION This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
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Affiliation(s)
- Louise M. E. Müller
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Matthew Holmes
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Joanne L. Michael
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Gina B. Scott
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Emma J. West
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Karen J. Scott
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | | | - Kathryn Hall
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Sina Stäble
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Victoria A. Jennings
- Translational Immunotherapy Team, The Institute of Cancer Research and Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre, London, UK
| | - Matthew Cullen
- Haematological Malignancy Diagnostics Service, St. James’s University Hospital, Leeds, UK
| | - Stewart McConnell
- Department of Haematology, St. James’s University Hospital, Leeds, UK
| | - Catherine Langton
- Department of Haematology, St. James’s University Hospital, Leeds, UK
| | - Emma L. Tidswell
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Darren Shafren
- School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, Australia
| | - Adel Samson
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Kevin J. Harrington
- Translational Immunotherapy Team, The Institute of Cancer Research and Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre, London, UK
| | - Hardev Pandha
- Surrey Cancer Research Institute, Leggett Building, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Christy Ralph
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
| | - Richard J. Kelly
- Department of Haematology, St. James’s University Hospital, Leeds, UK
| | - Gordon Cook
- Section of Experimental Haematology, LIMR, University of Leeds, St. James’s University Hospital, Leeds, UK
| | - Alan A. Melcher
- Translational Immunotherapy Team, The Institute of Cancer Research and Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre, London, UK
| | - Fiona Errington-Mais
- Section of Infection and Immunity, Leeds Institute of Medical Research (LIMR), University of Leeds, St. James’s University Hospital, Level 5, Wellcome Trust Brenner Building (WTBB), Leeds, LS9 7TF UK
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20
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McCarthy C, Jayawardena N, Burga LN, Bostina M. Developing Picornaviruses for Cancer Therapy. Cancers (Basel) 2019; 11:E685. [PMID: 31100962 PMCID: PMC6562951 DOI: 10.3390/cancers11050685] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/02/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022] Open
Abstract
Oncolytic viruses (OVs) form a group of novel anticancer therapeutic agents which selectively infect and lyse cancer cells. Members of several viral families, including Picornaviridae, have been shown to have anticancer activity. Picornaviruses are small icosahedral non-enveloped, positive-sense, single-stranded RNA viruses infecting a wide range of hosts. They possess several advantages for development for cancer therapy: Their genomes do not integrate into host chromosomes, do not encode oncogenes, and are easily manipulated as cDNA. This review focuses on the picornaviruses investigated for anticancer potential and the mechanisms that underpin this specificity.
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Affiliation(s)
- Cormac McCarthy
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Nadishka Jayawardena
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Laura N Burga
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Mihnea Bostina
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
- Otago Micro and Nano Imaging, University of Otago, Dunedin 9016, New Zealand.
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21
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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: 83] [Impact Index Per Article: 11.9] [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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The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers (Basel) 2018; 10:cancers10100356. [PMID: 30261620 PMCID: PMC6210336 DOI: 10.3390/cancers10100356] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev—C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.
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Annels NE, Arif M, Simpson GR, Denyer M, Moller-Levet C, Mansfield D, Butler R, Shafren D, Au G, Knowles M, Harrington K, Vile R, Melcher A, Pandha H. Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus. Mol Ther Oncolytics 2018; 9:1-12. [PMID: 29989024 PMCID: PMC6035483 DOI: 10.1016/j.omto.2018.02.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.
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Affiliation(s)
- Nicola E. Annels
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | - Mehreen Arif
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | - Guy R. Simpson
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | - Mick Denyer
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | - Carla Moller-Levet
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | | | - Rachel Butler
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
| | - Darren Shafren
- Viralytics Limited, Suite 305, Level 3, 66 Hunter Street, Sydney, NSW 2000, Australia
| | - Gough Au
- Viralytics Limited, Suite 305, Level 3, 66 Hunter Street, Sydney, NSW 2000, Australia
| | - Margaret Knowles
- Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | | | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
| | - Alan Melcher
- The Institute of Cancer Research, London SM2 5PT, UK
| | - Hardev Pandha
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK
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24
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Fountzilas C, Patel S, Mahalingam D. Review: Oncolytic virotherapy, updates and future directions. Oncotarget 2017; 8:102617-102639. [PMID: 29254276 PMCID: PMC5731986 DOI: 10.18632/oncotarget.18309] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/03/2017] [Indexed: 12/14/2022] Open
Abstract
Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma. Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects. Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral-induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition.
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Affiliation(s)
- Christos Fountzilas
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sukeshi Patel
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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25
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Simon EJ, Howells MA, Stuart JD, Boehme KW. Serotype-Specific Killing of Large Cell Carcinoma Cells by Reovirus. Viruses 2017; 9:v9060140. [PMID: 28587298 PMCID: PMC5490817 DOI: 10.3390/v9060140] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 05/30/2017] [Accepted: 06/01/2017] [Indexed: 12/30/2022] Open
Abstract
Reovirus is under development as a therapeutic for numerous types of cancer. In contrast to other oncolytic viruses, the safety and efficacy of reovirus have not been improved through genetic manipulation. Here, we tested the oncolytic capacity of recombinant strains (rs) of prototype reovirus laboratory strains T1L and T3D (rsT1L and rsT3D, respectively) in a panel of non-small cell lung cancer (NSCLC) cell lines. We found that rsT1L was markedly more cytolytic than rsT3D in the large cell carcinoma cell lines tested, whereas killing of adenocarcinoma cell lines was comparable between rsT1L and rsT3D. Importantly, non-recombinant T1L and T3D phenocopied the kinetics and magnitude of cell death induced by recombinant strains. We identified gene segments L2, L3, and M1 as viral determinants of strain-specific differences cell killing of the large cell carcinoma cell lines. Together, these results indicate that recombinant reoviruses recapitulate the cell killing properties of non-recombinant, tissue culture-passaged strains. These studies provide a baseline for the use of reverse genetics with the specific objective of engineering more effective reovirus oncolytics. This work raises the possibility that type 1 reoviruses may have the capacity to serve as more effective oncolytics than type 3 reoviruses in some tumor types.
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Affiliation(s)
- Emily J Simon
- Department of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Response, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Morgan A Howells
- Department of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Response, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Johnasha D Stuart
- Department of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Response, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Karl W Boehme
- Department of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Response, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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26
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Russell SJ, Peng KW. Oncolytic Virotherapy: A Contest between Apples and Oranges. Mol Ther 2017; 25:1107-1116. [PMID: 28392162 DOI: 10.1016/j.ymthe.2017.03.026] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 03/16/2017] [Accepted: 03/17/2017] [Indexed: 02/06/2023] Open
Abstract
Viruses can be engineered or adapted for selective propagation in neoplastic tissues and further modified for therapeutic transgene expression to enhance their antitumor potency and druggability. Oncolytic viruses (OVs) can be administered locally or intravenously and spread to a variable degree at sites of tumor growth. OV-infected tumor cells die in situ, releasing viral and tumor antigens that are phagocytosed by macrophages, transported to regional lymph nodes, and presented to antigen-reactive T cells, which proliferate before dispersing to kill uninfected tumor cells at distant sites. Several OVs are showing clinical promise, and one of them, talimogene laherparepvec (T-VEC), was recently granted marketing approval for intratumoral therapy of nonresectable metastatic melanoma. T-VEC also appears to substantially enhance clinical responsiveness to checkpoint inhibitor antibody therapy. Here, we examine the T-VEC paradigm and review some of the approaches currently being pursued to develop the next generation of OVs for both local and systemic administration, as well as for use in combination with other immunomodulatory agents.
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Affiliation(s)
- Stephen J Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
| | - Kah-Whye Peng
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
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27
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Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma. Oncolytic Virother 2017; 6:11-18. [PMID: 28224120 PMCID: PMC5308590 DOI: 10.2147/ov.s100072] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development.
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Affiliation(s)
| | - Irbaz Bin Riaz
- Department of Internal Medicine, University of Arizona, Tucson
| | | | - Mitesh J Borad
- Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ; Department of Molecular Medicine, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
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28
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Yuan M, Webb E, Lemoine NR, Wang Y. CRISPR-Cas9 as a Powerful Tool for Efficient Creation of Oncolytic Viruses. Viruses 2016; 8:72. [PMID: 26959050 PMCID: PMC4810262 DOI: 10.3390/v8030072] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 02/10/2016] [Accepted: 02/10/2016] [Indexed: 01/19/2023] Open
Abstract
The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology.
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Affiliation(s)
- Ming Yuan
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Eika Webb
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Nicholas Robert Lemoine
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou 450052, China.
| | - Yaohe Wang
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou 450052, China.
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29
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Pol J, Buqué A, Aranda F, Bloy N, Cremer I, Eggermont A, Erbs P, Fucikova J, Galon J, Limacher JM, Preville X, Sautès-Fridman C, Spisek R, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch-Oncolytic viruses and cancer therapy. Oncoimmunology 2016; 5:e1117740. [PMID: 27057469 PMCID: PMC4801444 DOI: 10.1080/2162402x.2015.1117740] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/03/2015] [Indexed: 02/06/2023] Open
Abstract
Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.
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Affiliation(s)
- Jonathan Pol
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Aitziber Buqué
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Fernando Aranda
- Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Norma Bloy
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Isabelle Cremer
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Center de Recherche des Cordeliers, Paris, France
| | | | | | - Jitka Fucikova
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jérôme Galon
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers, Paris, France
| | | | | | - Catherine Sautès-Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Center de Recherche des Cordeliers, Paris, France
| | - Radek Spisek
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, U1015, CICBT507, Villejuif, France
| | - Guido Kroemer
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden
| | - Lorenzo Galluzzi
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
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30
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Fonteneau JF, Achard C, Zaupa C, Foloppe J, Erbs P. Oncolytic immunotherapy: The new clinical outbreak. Oncoimmunology 2015; 5:e1066961. [PMID: 26942085 DOI: 10.1080/2162402x.2015.1066961] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 06/22/2015] [Indexed: 02/08/2023] Open
Affiliation(s)
| | - Carole Achard
- INSERM UMR892, CNRS UMR6299, Université de Nantes , Nantes, France
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Tsang JJ, Atkins HL. The ex vivo purge of cancer cells using oncolytic viruses: recent advances and clinical implications. Oncolytic Virother 2015; 4:13-23. [PMID: 27512666 PMCID: PMC4918373 DOI: 10.2147/ov.s45525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Hematological malignancies are treated with intensive high-dose chemotherapy, with or without radiation. This is followed by hematopoietic stem cell (HSC) transplantation (HSCT) to rescue or reconstitute hematopoiesis damaged by the anticancer therapy. Autologous HSC grafts may contain cancer cells and purging could further improve treatment outcomes. Similarly, allogeneic HSCT may be improved by selectively purging alloreactive effector cells from the graft rather than wholesale immune cell depletion. Viral agents that selectively replicate in specific cell populations are being studied in experimental models of cancer and immunological diseases and have potential applications in the context of HSC graft engineering. This review describes preclinical studies involving oncolytic virus strains of adenovirus, herpes simplex virus type 1, myxoma virus, and reovirus as ex vivo purging agents for HSC grafts, as well as in vitro and in vivo experimental studies using oncolytic coxsackievirus, measles virus, parvovirus, vaccinia virus, and vesicular stomatitis virus to eradicate hematopoietic malignancies. Alternative ex vivo oncolytic virus strategies are also outlined that aim to reduce the risk of relapse following autologous HSCT and mitigate morbidity and mortality due to graft-versus-host disease in allogeneic HSCT.
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Affiliation(s)
- Jovian J Tsang
- Department of Biochemistry, University of Ottawa, ON, Canada; Cancer Therapeutics, Ottawa Hospital Research Institute, ON, Canada
| | - Harold L Atkins
- Cancer Therapeutics, Ottawa Hospital Research Institute, ON, Canada; Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, ON, Canada
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32
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Pol J, Bloy N, Obrist F, Eggermont A, Galon J, Cremer I, Erbs P, Limacher JM, Preville X, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch:: Oncolytic viruses for cancer therapy. Oncoimmunology 2014; 3:e28694. [PMID: 25097804 PMCID: PMC4091053 DOI: 10.4161/onci.28694] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 03/27/2014] [Indexed: 12/11/2022] Open
Abstract
Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.
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Affiliation(s)
- Jonathan Pol
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | - Norma Bloy
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | - Florine Obrist
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | | | - Jérôme Galon
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, UMRS1138; Paris, France ; Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers; Paris, France
| | - Isabelle Cremer
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, UMRS1138; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | | | | | | | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
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33
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Bradley S, Jakes AD, Harrington K, Pandha H, Melcher A, Errington-Mais F. Applications of coxsackievirus A21 in oncology. Oncolytic Virother 2014; 3:47-55. [PMID: 27512662 PMCID: PMC4918364 DOI: 10.2147/ov.s56322] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The clinical management of cancer continues to be dominated by macroscopic surgical resection, radiotherapy, and cytotoxic drugs. The major challenge facing oncology is to achieve more selective, less toxic and effective methods of targeting disseminated tumors, a challenge oncolytic virotherapy may be well-placed to meet. Characterization of coxsackievirus A21 (CVA21) receptor-based mechanism of virus internalization and lysis in the last decade has suggested promise for CVA21 as a virotherapy against malignancies which overexpress those receptors. Preclinical studies have demonstrated proof of principle, and with the results of early clinical trials awaited, CVA21 may be one of the few viruses to demonstrate benefit for patients. This review outlines the potential of CVA21 as an oncolytic agent, describing the therapeutic development of CVA21 in preclinical studies and early stage clinical trials. Preclinical evidence supports the potential use of CVA21 across a range of malignancies. Malignant melanoma is the most intensively studied cancer, and may represent a “test case” for future development of the virus. Although there are theoretical barriers to the clinical utility of oncolytic viruses like CVA21, whether these will block the efficacy of the virus in clinical practice remains to be established, and is a question which can only be answered by appropriate trials. As these data become available, the rapid journey of CVA21 from animal studies to clinical trials may offer a model for the translation of other oncolytic virotherapies from laboratory to clinic.
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Affiliation(s)
- Stephen Bradley
- Leeds Institute of Cancer and Pathology, Cancer Research UK and Experimental Cancer Medicine Centre, St James' University Hospital, Leeds, UK
| | - Adam D Jakes
- Leeds Institute of Cancer and Pathology, Cancer Research UK and Experimental Cancer Medicine Centre, St James' University Hospital, Leeds, UK
| | - Kevin Harrington
- Division of Cancer Biology, The Institute of Cancer Research, London, UK
| | - Hardev Pandha
- Oncology Department, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Alan Melcher
- Leeds Institute of Cancer and Pathology, Cancer Research UK and Experimental Cancer Medicine Centre, St James' University Hospital, Leeds, UK
| | - Fiona Errington-Mais
- Leeds Institute of Cancer and Pathology, Cancer Research UK and Experimental Cancer Medicine Centre, St James' University Hospital, Leeds, UK
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Characteristics of oncolytic vesicular stomatitis virus displaying tumor-targeting ligands. J Virol 2013; 87:13543-55. [PMID: 24089573 DOI: 10.1128/jvi.02240-13] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We sought proof of principle that tumor-targeting ligands can be displayed on the surface of vesicular stomatitis virus (VSV) by engineering its glycoprotein. Here, we successfully rescued VSVs displaying tumor vasculature-targeting ligands. By using a rational approach, we investigated various feasible insertion sites on the G protein of VSV (VSV-G) for display of tumor vasculature-targeting ligands, cyclic RGD (cRGD) and echistatin. We found seven sites on VSV-G that tolerated insertion of the 9-residue cRGD peptide, two of which could tolerate insertion of the 49-amino acid echistatin domain. All of the ligand-displaying viruses replicated as well as the parental virus. In vitro studies demonstrated that the VSV-echistatin viruses specifically bound to targeted integrins. Since the low-density lipoprotein receptor (LDLR) was recently identified as a major receptor for VSV, we investigated the entry of ligand-displaying viruses after masking LDLR. The experiment showed that the modified viruses can enter the cell independently of LDLR, whereas entry of unmodified virus is significantly blocked by a specific monoclonal antibody against LDLR. Both parental and ligand-displaying viruses displayed equal oncolytic efficacies in a syngeneic mouse myeloma model. We further demonstrated that single-chain antibody fragments against tumor-specific antigens can be inserted at the N terminus of the G protein and that corresponding replication-competent VSVs can be rescued efficiently. Overall, we demonstrated that functional tumor-targeting ligands can be displayed on replication-competent VSVs without perturbing viral growth and oncolytic efficacy. This study provides a rational foundation for the future development of fully retargeted oncolytic VSVs.
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Dey M, Auffinger B, Lesniak MS, Ahmed AU. Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making? Future Virol 2013; 8:675-693. [PMID: 24910708 DOI: 10.2217/fvl.13.47] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells. Glioblastoma multiforme, the most common adult primary brain tumor, has a disasterous history. It is one of the most deadly cancers known to humankind. Over the last century our understanding of this disease has grown exponentially. However, the median survival of patients suffering from this disease has only been extended by a few months. Even with the best, most aggressive modern therapeutic approaches available, malignant gliomas are still virtually 100% fatal. Motivated by the desperate need to find effective treatment strategies, more investments have been applied to oncolytic virotherapy preclinical and clinical studies. In this review we will discuss the antiglioma oncolytic virotherapy research field. We will survey its history and the principles laid down to serve as basis for preclinical works. We will also debate the variety of viral vectors used, their clinical applications, the lessons learned from clinical trials and possible future directions.
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Affiliation(s)
- Mahua Dey
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Brenda Auffinger
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Maciej S Lesniak
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Atique U Ahmed
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
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Abstract
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
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Myeloma xenograft destruction by a nonviral vector delivering oncolytic infectious nucleic acid. Mol Ther 2011; 19:1041-7. [PMID: 21505425 DOI: 10.1038/mt.2011.68] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The feasibility of using a nonviral vector formulation to initiate an oncolytic viral infection has not been previously demonstrated. We therefore sought to determine whether infectious nucleic acid (INA) could be used in place of virus particles to initiate an oncolytic picornavirus infection in vivo. Infectious RNA encoding coxsackievirus A21 (CVA21) was transcribed from plasmid DNA using T7 polymerase. Within 48 hours of injecting this RNA into KAS6/1 myeloma xenografts, high titers of infectious CVA21 virions were detected in the bloodstream. Tumors regressed rapidly thereafter and mice developed signs of myositis. At euthanasia, CVA21 was recovered from regressing tumors and from skeletal muscles. Treatment outcomes were comparable following intratumoral injection of naked RNA or fully infectious CVA21 virus. Dose-response studies showed that an effective oncolytic infection could be established by intratumoral injection of 1 µg of infectious RNA. The oncolytic infection could also be initiated by intravenous injection of infectious RNA. Our study demonstrates that INA is a highly promising alternative drug formulation for oncolytic virotherapy.
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Oncolysis of malignant human melanoma tumors by Coxsackieviruses A13, A15 and A18. Virol J 2011; 8:22. [PMID: 21241513 PMCID: PMC3033357 DOI: 10.1186/1743-422x-8-22] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 01/18/2011] [Indexed: 11/10/2022] Open
Abstract
Many RNA viruses are displaying great promise in the field of oncolytic virotherapy. Previously, we reported that the picornavirus Coxsackievirus A21 (CVA21) possessed potent oncolytic activity against cultured malignant melanoma cells and melanoma xenografts in mice. In the present study, we demonstrate that three additional Group A Coxsackieviruses; Coxsackievirus A13 (CVA13), Coxsackievirus A15 (CVA15) and Coxsackievirus A18 (CVA18), also have similar oncolytic activity against malignant melanoma. Each of the viruses grew quickly to high titers in cancer cells expressing ICAM-1 and intratumoral injection of preformed subcutaneous SK-Mel-28 xenografts in mice with CVA13, CVA15 and CVA18 resulted in significant tumor volume reduction.As preexisting immunity could potentially hinder oncolytic virotherapy, sera from stage IV melanoma patients and normal controls were tested for levels of protective antibody against the panel of oncolytic Coxsackieviruses. Serum neutralization assays revealed that 3 of 21 subjects possessed low levels of anti-CVA21 antibodies, while protective antibodies for CVA13, CVA15 and CVA18 were not detected in any sample. Serum from individuals who were seropositive for CVA21 failed to exhibit cross-neutralization of CVA13, CVA15 and CVA18. From these studies it can be concluded that the administration of CVA13, CVA15 or CVA18 could be employed as a potential multivalent oncolytic therapy against malignant melanoma.
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Venkataraman S, Reddy SP, Loo J, Idamakanti N, Hallenbeck PL, Reddy VS. Structure of Seneca Valley Virus-001: an oncolytic picornavirus representing a new genus. Structure 2008; 16:1555-61. [PMID: 18940610 PMCID: PMC2572565 DOI: 10.1016/j.str.2008.07.013] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 07/08/2008] [Accepted: 07/08/2008] [Indexed: 11/28/2022]
Abstract
The crystal structure of Seneca Valley Virus-001 (SVV-001), the representative member of a new genus, Senecavirus, is reported at 2.3A resolution. SVV-001 is the first naturally occurring nonpathogenic picornavirus shown to mediate selective cytotoxicity towards tumor cells with neuroendocrine cancer features. The nonsegmented (+) ssRNA genome of SVV-001 shares closest sequence similarity with the genomes of the members of Cardiovirus. The overall tertiary structure of VP1-VP4 subunits is conserved with the exception of loops, especially those of VP1 that show large deviations relative to the members of the cardioviruses. The surface loops of VP1 and VP2 are predicted to mediate cell tropism of SVV-001. In addition, the organization of the packaged nucleic acid density indicates that certain regions of VP2 and VP4 interact closely with the packaged nucleic acid.
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Affiliation(s)
- Sangita Venkataraman
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
| | | | - Jackie Loo
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
| | | | | | - Vijay S. Reddy
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
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Russell SJ, Peng KW. Viruses as anticancer drugs. Trends Pharmacol Sci 2007; 28:326-33. [PMID: 17573126 PMCID: PMC3125087 DOI: 10.1016/j.tips.2007.05.005] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Revised: 04/11/2007] [Accepted: 05/25/2007] [Indexed: 01/14/2023]
Abstract
Oncolytic viruses are being developed as anticancer drugs. They propagate selectively in tumor tissue and destroy it without causing excessive damage to normal non-cancerous tissues. When used as drugs, they must meet stringent criteria for safety and efficacy and be amenable to pharmacological study in human subjects. Specificity for neoplastic tissue is the key to safety, and this goal can be achieved through a variety of ingenious virus-engineering strategies. Antiviral immunity remains a significant barrier to the clinical efficacy of oncolytic viruses but this is being addressed by using novel immune-evasive delivery strategies and immunosuppressive drugs. Noninvasive pharmacokinetic monitoring is facilitated by engineering marker genes into the viral genome. Clinical data on the pharmacokinetics of oncolytic viruses will be the key to accelerating their development and approval as effective anticancer drugs. This review introduces concepts relevant to the use of viruses as anticancer drugs, emphasizing targeting mechanisms as well as safety and efficacy issues that are currently limiting their clinical success.
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Affiliation(s)
- Stephen J Russell
- Molecular Medicine Program, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
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Vähä-Koskela MJ, Heikkilä JE, Hinkkanen AE. Oncolytic viruses in cancer therapy. Cancer Lett 2007; 254:178-216. [PMID: 17383089 PMCID: PMC7126325 DOI: 10.1016/j.canlet.2007.02.002] [Citation(s) in RCA: 226] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2006] [Revised: 02/01/2007] [Accepted: 02/05/2007] [Indexed: 12/26/2022]
Abstract
Oncolytic virotherapy is a promising form of gene therapy for cancer, employing nature’s own agents to find and destroy malignant cells. The purpose of this review is to provide an introduction to this very topical field of research and to point out some of the current observations, insights and ideas circulating in the literature. We have strived to acknowledge as many different oncolytic viruses as possible to give a broader picture of targeting cancer using viruses. Some of the newest additions to the panel of oncolytic viruses include the avian adenovirus, foamy virus, myxoma virus, yaba-like disease virus, echovirus type 1, bovine herpesvirus 4, Saimiri virus, feline panleukopenia virus, Sendai virus and the non-human coronaviruses. Although promising, virotherapy still faces many obstacles that need to be addressed, including the emergence of virus-resistant tumor cells.
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Affiliation(s)
- Markus J.V. Vähä-Koskela
- Åbo Akademi University, Department of Biochemistry and Pharmacy and Turku Immunology Centre, Turku, Finland
- Turku Graduate School of Biomedical Sciences, Turku, Finland
- Corresponding author. Address: Åbo Akademi University, Department of Biochemistry and Pharmacy and Turku Immunology Centre, Turku, Finland. Tel.: +358 2 215 4018; fax: +358 2 215 4745.
| | - Jari E. Heikkilä
- Åbo Akademi University, Department of Biochemistry and Pharmacy and Turku Immunology Centre, Turku, Finland
| | - Ari E. Hinkkanen
- Åbo Akademi University, Department of Biochemistry and Pharmacy and Turku Immunology Centre, Turku, Finland
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