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Schoeps B, Lauer UM, Elbers K. Deciphering permissivity of human tumor ecosystems to oncolytic viruses. Oncogene 2025; 44:1069-1077. [PMID: 40148688 PMCID: PMC11996678 DOI: 10.1038/s41388-025-03357-5] [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: 11/27/2024] [Revised: 02/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Effective cancer therapy involves initiation of a tumor-specific immune response. Consequently, the interest in oncolytic viruses (OV) capable of triggering immunogenic cell death has sparked in recent years. However, the common use of pre-clinical models that fail to mirror patient tumor ecosystems (TES) hinders clinical translation. Here, we provide a condensed view on the intricate interplay between several aspects of TES and OV action and discuss these considerations in the view of recently developed pre-clinical human model systems. Given the urgent demand for innovative cancer treatments, the purpose of this review is to highlight the so-far overlooked complex impact of the tumor microenvironment (TME) on OV permissivity, with the intent to provide a foundation for future, more effective pre-clinical studies.
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Affiliation(s)
| | - Ulrich M Lauer
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, Tübingen, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Tübingen, Germany
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2
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Uno K, Kubota E, Mori Y, Nishigaki R, Kojima Y, Kanno T, Sasaki M, Fukusada S, Sugimura N, Tanaka M, Ozeki K, Shimura T, Johnston RN, Kataoka H. Mesenchymal stem cell-derived small extracellular vesicles as a delivery vehicle of oncolytic reovirus. Life Sci 2025; 368:123489. [PMID: 39987955 DOI: 10.1016/j.lfs.2025.123489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 02/10/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
AIM The oncolytic reovirus has demonstrated efficacy against various cancer types in preclinical and clinical studies. However, its anti-tumor activity is limited. This study aimed to develop a novel drug delivery system (DDS) using small extracellular vesicles (sEVs) derived from human adipose-derived mesenchymal stem cells to enhance the therapeutic potential of reovirus. MATERIALS AND METHODS sEVs, which offer distinct advantages over traditional systems such as nanoparticles due to their natural biocompatibility, low immunogenicity, ability to cross biological barriers, and cell-derived targeting properties, were engineered to encapsulate reovirus particles (sEVs-reo). The anti-tumor activity of sEVs-reo was evaluated using colorectal cancer cell lines HCT116 and SW480. Additionally, resistance to neutralizing antibodies, internalization by cancer cells, and efficacy against junctional adhesion molecule-A(JAM-A)-knockout colon cancer cells resistant to reovirus, generated via CRISPR/Cas9, were assessed. KEY FINDINGS sEVs-reo encapsulated reovirus particles effectively, and at a concentration of 0.5 μg/ml, reduced viable tumor cells by 60.3 % in HCT116 and 42.5 % in SW480. Remarkably, sEVs-reo exhibited significant efficacy even in the presence of neutralizing antibodies, including anti-σ1 antibodies and serum from reovirus-infected mice. sEVs-reo were rapidly internalized by cancer cells within 4 h while exhibiting reduced immunogenicity relative to reovirus, and demonstrated significant anti-tumor activity against JAM-A-deficient colon cancer cells. SIGNIFICANCE This study demonstrates that sEVs-reo can address key challenges associated with oncolytic virotherapy. These findings support potential of sEVs as a novel and effective DDS for reovirus in colon cancer treatment, while offering a versatile platform to enhance the efficacy of other oncolytic viruses.
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Affiliation(s)
- Konomu Uno
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
| | - Yoshinori Mori
- Department of Gastroenterology, Nagoya City University West Medical Center, Kita-ku, Nagoya 462-8508, Japan
| | - Ruriko Nishigaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Yuki Kojima
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Takuya Kanno
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Makiko Sasaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Shigeki Fukusada
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Naomi Sugimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Mamoru Tanaka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Keiji Ozeki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
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Tang S, Yong L, Cui Y, Li H, Bischof E, Cai F. Harnessing Oncolytic Viruses for Targeted Therapy in Triple-Negative Breast Cancer. Int J Med Sci 2025; 22:2186-2207. [PMID: 40303488 PMCID: PMC12035831 DOI: 10.7150/ijms.105683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/19/2025] [Indexed: 05/02/2025] Open
Abstract
Breast cancer is the most prevalent malignant tumor among women, with triple-negative breast cancer (TNBC) being one of the most aggressive forms due to its high invasiveness and metastatic potential. Traditional treatments such as endocrine therapy and anti-HER2-targeted therapy are largely ineffective for TNBC, and while chemotherapy shows some promise, resistance remains a significant hurdle. Recently, there has been increasing interest in biological therapies, especially oncolytic viruses (OVs). OVs promote anti-tumor effects by selectively killing tumor cells and stimulating immune responses, and have achieved notable breakthroughs in breast cancer treatment. OVs have demonstrated effectiveness comparable to surgery, radiotherapy, or chemotherapy in selected cancers, but data are sparse in the context of TNBC. This review provides an overview of recent progress in the application of OVs as a tool for precision TNBC treatment.
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Affiliation(s)
- Shasha Tang
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
| | - Liyun Yong
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
| | - Yong Cui
- Department of General Surgery, People's Hospital of Otog Qianqi, Sharita Tara East Street, Aolezhaoqi Town, Otog Qianqi 016200, China
| | - Haibin Li
- Department of General Surgery, People's Hospital of Otog Qianqi, Sharita Tara East Street, Aolezhaoqi Town, Otog Qianqi 016200, China
| | - Evelyne Bischof
- Department of Medical Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Fengfeng Cai
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
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Yari A, Hosseini SY, Asiyabi S, Hajiahmadi N, Farahmand M, Bamdad T. Oncolytic reovirus enhances the effect of CEA immunotherapy when combined with PD1-PDL1 inhibitor in a colorectal cancer model. Immunotherapy 2025; 17:425-435. [PMID: 40353308 DOI: 10.1080/1750743x.2025.2501926] [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: 12/02/2024] [Accepted: 05/01/2025] [Indexed: 05/14/2025] Open
Abstract
AIM The effectiveness of immunotherapy with tumor associated antigen vaccines can be enhanced by combining oncolytic viruses with immune checkpoint inhibitors. This study evaluates the efficacy of oncolytic reovirus in combination with an adenovector expressing carcinoembryonic antigen (Ad-CEA) and a programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor in a mouse model. METHODS Mice bearing CEA-expressing CT26 tumor cells were immunized with Ad-CEA along with a PD-1/PD-L1 inhibitor. Subsequently, three doses of reovirus were injected into the tumors. Tumor size, histopathological examination, CD8 and FOXP3 expression, the cytotoxicity of spleen T cell lymphocytes, and the secretion of Interferon-γ (IFN-γ) and Tumor necrosis factor- α (TNF-α) were examined. RESULTS The triple therapy used in this study resulted in the lowest tumor growth and the highest level of cytotoxic immunity. The Foxp3 levels in the tumor microenvironment and TNF-α secretion decreased compared to other control groups. Additionally, this group exhibited the lowest number of mitotic figures and the highest amount of tumor-infiltrating lymphocytes. CONCLUSION The combination of tumor vaccines with oncolytic viruses significantly improves treatment efficacy. Furthermore, inhibiting the PD-1/PD-L1 interaction during vaccination and also with virotherapy enhances immunovirotherapy by reducing immunosuppressive effects and stimulating the immune system, leading to improved therapeutic outcomes.
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Affiliation(s)
- Atefeh Yari
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Sanaz Asiyabi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nazila Hajiahmadi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Farahmand
- Research Center for Emergency and Disaster Resilience, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
| | - Taravat Bamdad
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Yamada Y, Wang YC, Liu HP, Gerongano GR, Tseng CY, Liu SC, Liao GR, Chang CC, Liao JW, Wang ML, Chang YY, Lin FY, Hsu WL. Development of attenuated Orf virus as a safe oncolytic viral vector for nasopharyngeal carcinoma treatment. Virol J 2025; 22:50. [PMID: 40001231 PMCID: PMC11863438 DOI: 10.1186/s12985-025-02672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Orf virus (ORFV) is gaining attention as a promising viral vector for cancer therapy because of its unique properties. Recent studies have shown that ORFV could be effective against various cancers, particularly nasopharyngeal carcinoma. This research explores the ability of wild-type ORFV and recombinant ORFVs, which lack specific virulence factors, to kill NPC cells and modulate the immune response. METHODS Two NPC cell lines, HK1 (from Hong Kong) and TW02 (from Taiwan), were infected with wild-type ORFV and two recombinant ORFVs lacking either vascular endothelial growth factor (VEGF) or chemokine binding protein (CBP) virulence factors. The oncolytic effects were evaluated by assessing cell death pathways, particularly pyroptosis, which was monitored through the cleavage of gasdermin E (GSDME). The activation of survival pathways, such as focal adhesion kinase (FAK) and AKT, was also analyzed. In addition, the influence of ORFV infection on natural killer (NK) cell recruitment and cytotoxicity was investigated. In vivo experiments were conducted in a xenograft mouse model in which HK1 tumors were used to evaluate the antitumor activity of wild-type ORFV and two deletion-mutant ORFVs. RESULTS Wild-type ORFV effectively killed NPC cells, especially HK1 cells. The recombinant ORFVs, despite being attenuated by the loss of VEGF or CBP, retained the ability to infect and cause NPC cell death, with the CBP-deleted virus showing notable effectiveness in HK1 cells. Early ORFV infection led to pyroptosis via GSDME cleavage, causing cell detachment and a reduction in FAK and AKT activation. ORFV also enhanced NK cell recruitment and boosted NK cell-mediated cytotoxicity in infected NPC cells. In the HK1 xenograft model, CBP-deleted ORFV significantly inhibited tumor growth. CONCLUSION ORFV, particularly the wild-type and CBP-deleted variants, has significant potential as an oncolytic viral vector for NPC therapy. It induces cell death via pyroptosis and enhances immune-mediated tumor cell destruction through NK cells. The attenuated CBP-deleted ORFV offers a safer and effective option for cancer treatment, making it a promising candidate for future therapeutic applications.
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Affiliation(s)
- Yumiko Yamada
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Chih Wang
- Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Hao-Ping Liu
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Greg Ryan Gerongano
- Department of Pathology, Corazon Locsin Montelibano Memorial Regional Hospital, Bacolod City, Philippines
| | - Ching-Yu Tseng
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Shu-Chen Liu
- Department Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
| | - Guan-Ru Liao
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chao-Chin Chang
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Mei-Lin Wang
- Department of Microbiology and Immunology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yuan-Yen Chang
- Department of Microbiology and Immunology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Fong-Yuan Lin
- Department of Animal Healthcare, Hungkuang University, Taichung, Taiwan
| | - Wei-Li Hsu
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
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Peter M, Mundt B, Menze A, Woller N, Volk V, Ernst AM, Öhler LA, Talbot SR, Wedemeyer H, Falk C, Feuerhake F, Wirth TC, Kühnel F. Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors. EMBO Mol Med 2025; 17:265-300. [PMID: 39789356 PMCID: PMC11821991 DOI: 10.1038/s44321-024-00187-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 01/12/2025] Open
Abstract
Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggests the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.
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Affiliation(s)
- Malin Peter
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bettina Mundt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arne Menze
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Norman Woller
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Valery Volk
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Amanda M Ernst
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Leon A Öhler
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steven R Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, 30625, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Christine Falk
- Institute of Transplantation Immunology, Hannover Medical School, Hannover, Germany
| | | | - Thomas C Wirth
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian Kühnel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
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Yang Y, Hu Y, Yang Y, Liu Q, Zheng P, Yang Z, Duan B, He J, Li W, Li D, Zheng X, Wang M, Fu Y, Long Q, Ma Y. Tumor Vaccine Exploiting Membranes with Influenza Virus-Induced Immunogenic Cell Death to Decorate Polylactic Coglycolic Acid Nanoparticles. ACS NANO 2025; 19:3115-3134. [PMID: 39806805 DOI: 10.1021/acsnano.4c00654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.
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Affiliation(s)
- Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yongmao Hu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Yunnan University, Kunming 650091, China
| | - Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Qingwen Liu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Peng Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Zhongqian Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Biao Duan
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Jinrong He
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Weiran Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Duo Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Department of Acute Infectious Diseases Control and Prevention, Yunnan Provincial Center for Disease Control and Prevention, Kunming 650000, China
| | - Xiao Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Mengzhen Wang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yuting Fu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Qiong Long
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yanbing Ma
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- State Key Laboratory of Respiratory Health and Multimorbidity, Kunming 650031, China
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8
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Rajwani J, Vishnevskiy D, Turk M, Naumenko V, Gafuik C, Kim DS, Mah LK, Snelling S, Gonzales GA, Xue J, Chanda A, Potts KG, Todesco HM, Lau KCK, Hildebrand KM, Chan JA, Liao S, Monument MJ, Hyrcza M, Bose P, Jenne CN, Canton J, Zemp FJ, Mahoney DJ. VSV ∆M51 drives CD8 + T cell-mediated tumour regression through infection of both cancer and non-cancer cells. Nat Commun 2024; 15:9933. [PMID: 39548070 PMCID: PMC11567966 DOI: 10.1038/s41467-024-54111-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/02/2024] [Indexed: 11/17/2024] Open
Abstract
Oncolytic viruses (OV) are designed to selectively infect and kill cancer cells, while simultaneously eliciting antitumour immunity. The mechanism is expected to originate from infected cancer cells. However, recent reports of tumour regression unaccompanied by cancer cell infection suggest a more complex mechanism of action. Here, we engineered vesicular stomatitis virus (VSV)ΔM51-sensitive and VSVΔM51-resistant tumour lines to elucidate the role of OV-infected cancer and non-cancer cells. We found that, while cancer cell infections elicit oncolysis and antitumour immunity as expected, infection of non-cancer cells alone can also contribute to tumour regression. This effect is partly attributed to the systemic production of cytokines that promote dendritic cell (DC) activation, migration and antigen cross-presentation, leading to magnified antitumour CD8+ T cell activation and tumour regression. Such OV-induced antitumour immunity is complementary to PD-1 blockade. Overall, our results reveal mechanistic insights into OV-induced antitumour immunity that can be leveraged to improve OV-based therapeutics.
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Affiliation(s)
- Jahanara Rajwani
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Daniil Vishnevskiy
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Madison Turk
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Victor Naumenko
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Chris Gafuik
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Dae-Sun Kim
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Laura K Mah
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Shannon Snelling
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Gerone A Gonzales
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Faculty of Veterinary Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Jingna Xue
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Ayan Chanda
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Kyle G Potts
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Hayley M Todesco
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Keith C K Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Karys M Hildebrand
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Surgery, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- McCaig Bone and Joint Institute, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Jennifer A Chan
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Pathology and Laboratory Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Shan Liao
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Michael J Monument
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Surgery, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- McCaig Bone and Joint Institute, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Martin Hyrcza
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Pathology and Laboratory Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Pinaki Bose
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Oncology; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Craig N Jenne
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Johnathan Canton
- The Calvin, Joan and Phoebe Snyder Institute for Chronic Disease; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Faculty of Veterinary Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Franz J Zemp
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Douglas J Mahoney
- Arnie Charbonneau Cancer Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada.
- Alberta Children's Hospital Research Institute; University of Calgary, Calgary, AB, T2N 4N1, Canada.
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada.
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine; University of Calgary, Calgary, AB, T2N 4N1, Canada.
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9
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Nelson A, McMullen N, Gebremeskel S, De Antueno R, Mackenzie D, Duncan R, Johnston B. Fusogenic vesicular stomatitis virus combined with natural killer T cell immunotherapy controls metastatic breast cancer. Breast Cancer Res 2024; 26:78. [PMID: 38750591 PMCID: PMC11094881 DOI: 10.1186/s13058-024-01818-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/30/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Metastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models. METHODS Using primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells. RESULTS Treatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge. CONCLUSION Combining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer.
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Affiliation(s)
- Adam Nelson
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, B3H 4R2, Halifax, NS, Canada
| | - Nichole McMullen
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
| | - Simon Gebremeskel
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, B3H 4R2, Halifax, NS, Canada
| | - Roberto De Antueno
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
| | - Duncan Mackenzie
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
| | - Roy Duncan
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, B3H 4R2, Halifax, NS, Canada
- Department of Biochemistry and Molecular Biology, Dalhousie University, B3H 4R2, Halifax, NS, Canada
- Department of Pediatrics, Dalhousie University, B3H 4R2, Halifax, NS, Canada
| | - Brent Johnston
- Department of Microbiology and Immunology, Dalhousie University, B3H 4R2, Halifax, NS, Canada.
- Beatrice Hunter Cancer Research Institute, B3H 4R2, Halifax, NS, Canada.
- Department of Pathology, Dalhousie University, B3H 4R2, Halifax, NS, Canada.
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10
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Lim Y, Park J, Lim JE, Park M, Koh SK, Lee M, Kim SK, Lee SH, Song KH, Park DG, Kim HY, Jeong BC, Cho D. Evaluating a combination treatment of NK cells and reovirus against bladder cancer cells using an in vitro assay to simulate intravesical therapy. Sci Rep 2024; 14:7390. [PMID: 38548803 PMCID: PMC10979019 DOI: 10.1038/s41598-024-56297-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/05/2024] [Indexed: 04/01/2024] Open
Abstract
Intravesical treatment using either reovirus or natural killer (NK) cells serves as an efficient strategy for the treatment of bladder cancer cells (BCCs); however, corresponding monotherapies have often shown modest cytotoxicity. The potential of a locoregional combination using high-dose reovirus and NK cell therapy in an intravesical approach has not yet been studied. In this study, we evaluated the effectiveness of reoviruses and expanded NK cells (eNK) as potential strategies for the treatment of bladder cancer. The anti-tumor effects of mono-treatment with reovirus type 3 Dearing strain (RC402 and RP116) and in combination with interleukin (IL)-18/-21-pretreated eNK cells were investigated on BCC lines (5637, HT-1376, and 253J-BV) using intravesical therapy to simulate in vitro model. RP116 and IL-18/-21-pretreated eNK cells exhibited effective cytotoxicity against grade 1 carcinoma (5637 cells) when used alone, but not against HT-1376 (grade 2 carcinoma) and 253J-BV cells (derived from a metastatic site). Notably, combining RP116 with IL-18/-21-pretreated eNK cells displayed effective cytotoxicity against both HT-1376 and 253J-BV cells. Our findings underscore the potential of a combination therapy using reoviruses and NK cells as a promising strategy for treating bladder cancer.
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Affiliation(s)
- Yuree Lim
- Department of Biopharmaceutical Convergence, Sungkyunkwan University (SKKU), Suwon, Korea
| | - Jeehun Park
- Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Joung Eun Lim
- Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Minji Park
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Seung Kwon Koh
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Mijeong Lee
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Sang-Ki Kim
- Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | | | - Dong Guk Park
- ViroCure Inc., Seoul, Republic of Korea
- Department of Surgery, School of Medicine, Dankook University, Cheonan, South Korea
| | - Hyun-Young Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Byong Chang Jeong
- Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
| | - Duck Cho
- Department of Biopharmaceutical Convergence, Sungkyunkwan University (SKKU), Suwon, Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea.
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11
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Hu M, Liao X, Tao Y, Chen Y. Advances in oncolytic herpes simplex virus and adenovirus therapy for recurrent glioma. Front Immunol 2023; 14:1285113. [PMID: 38022620 PMCID: PMC10652401 DOI: 10.3389/fimmu.2023.1285113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Recurrent glioma treatment is challenging due to molecular heterogeneity and treatment resistance commonly observed in these tumors. Researchers are actively pursuing new therapeutic strategies. Oncolytic viruses have emerged as a promising option. Oncolytic viruses selectively replicate within tumor cells, destroying them and stimulating the immune system for an enhanced anticancer response. Among Oncolytic viruses investigated for recurrent gliomas, oncolytic herpes simplex virus and oncolytic adenovirus show notable potential. Genetic modifications play a crucial role in optimizing their therapeutic efficacy. Different generations of replicative conditioned oncolytic human adenovirus and oncolytic HSV have been developed, incorporating specific modifications to enhance tumor selectivity, replication efficiency, and immune activation. This review article summarizes these genetic modifications, offering insights into the underlying mechanisms of Oncolytic viruses' therapy. It also aims to identify strategies for further enhancing the therapeutic benefits of Oncolytic viruses. However, it is important to acknowledge that additional research and clinical trials are necessary to establish the safety, efficacy, and optimal utilization of Oncolytic viruses in treating recurrent glioblastoma.
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Affiliation(s)
- Mingming Hu
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - XuLiang Liao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Tao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yaohui Chen
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
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12
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Sugimura N, Kubota E, Mori Y, Aoyama M, Tanaka M, Shimura T, Tanida S, Johnston RN, Kataoka H. Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer. Cancer Immunol Immunother 2023; 72:3593-3608. [PMID: 37526659 PMCID: PMC10992117 DOI: 10.1007/s00262-023-03509-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023]
Abstract
Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy.
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Affiliation(s)
- Naomi Sugimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan.
| | - Yoshinori Mori
- Department of Gastroenterology, Nagoya City University West Medical Center, Kita-Ku, Nagoya, 462-8508, Japan
| | - Mineyoshi Aoyama
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Mizuho-Ku, Nagoya, 467-8603, Japan
| | - Mamoru Tanaka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Satoshi Tanida
- Department of Gastroenterology, Gamagori Municipal Hospital, Hirata-Cho, Gamagori, 443-8501, Japan
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan
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13
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Xie R, Huang H, Chen T, Huang X, Chen C. Effectiveness and safety of pelareorep plus chemotherapy versus chemotherapy alone for advanced solid tumors: a meta-analysis. Front Pharmacol 2023; 14:1228225. [PMID: 37829303 PMCID: PMC10566296 DOI: 10.3389/fphar.2023.1228225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/11/2023] [Indexed: 10/14/2023] Open
Abstract
Background: Pelareorep is an oncolytic virus that causes oncolytic effects in many solid tumors, and it has shown therapeutic benefits. However, few studies have compared pelareorep combined with chemotherapy to traditional chemotherapy alone in advanced solid tumors. Consequently, we intended to evaluate the effectiveness and safety of pelareorep plus chemotherapy in this paper. Methods: We searched four databases including PubMed, Embase, Cochrane Library and Web of Science comprehensively for studies comparing pelareorep combined with chemotherapy to chemotherapy alone in the treatment of advanced solid tumors. The outcomes measures were 1-year overall survival (OS), 2-year OS, 4-month progression-free survival (PFS), 1-year PFS, objective response rate (ORR), any-grade adverse events (any-grade AEs), and severe AEs (grade ≥ 3). Results: There were five studies involving 492 patients included in the study. Combination therapy did not significantly improve clinical outcomes in terms of 1-year OS [RR = 1.02, 95%CI = (0.82-1.25)], 2-year OS [RR = 1.00, 95%CI = (0.67-1.49)], 4-month PFS [RR = 1.00, 95%CI = (0.67-1.49)], 1-year PFS [RR = 0.79, 95%CI = (0.44-1.42)], and ORR [OR = 0.79, 95%CI = (0.49-1.27)] compared to chemotherapy alone, and the subgroup analysis of 2-year OS, 1-year PFS, and ORR based on countries and tumor sites showed similar results. In all grades, the incidence of AEs was greater with combination therapy, including fever [RR = 3.10, 95%CI = (1.48-6.52)], nausea [RR = 1.19, 95%CI = (1.02-1.38)], diarrhea [RR = 1.87, 95%CI = (1.39-2.52)], chills [RR = 4.14, 95%CI = (2.30-7.43)], headache [RR = 1.46, 95%CI = (1.02-2.09)], vomiting [RR = 1.38, 95%CI = (1.06-1.80)] and flu-like symptoms [RR = 4.18, 95%CI = (2.19-7.98)]. However, severe adverse events did not differ significantly between the two arms. Conclusion: Pelareorep addition to traditional chemotherapy did not lead to significant improvements in OS, PFS, or ORR in advanced solid tumor patients, but it did partially increase AEs in all grades, with no discernible differences in serious AEs. Therefore, the combination treatment is not recommended in patients with advanced solid tumors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400841, identifier CRD42023400841.
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Affiliation(s)
- Renxian Xie
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Hongxin Huang
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Tong Chen
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Xuehan Huang
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Chuangzhen Chen
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
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14
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Jiang Y, Zhang H, Wang J, Chen J, Guo Z, Liu Y, Hua H. Exploiting RIG-I-like receptor pathway for cancer immunotherapy. J Hematol Oncol 2023; 16:8. [PMID: 36755342 PMCID: PMC9906624 DOI: 10.1186/s13045-023-01405-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize "immune-cold" tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.
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Affiliation(s)
- Yangfu Jiang
- Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Hongying Zhang
- Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiao Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jinzhu Chen
- Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zeyu Guo
- Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongliang Liu
- Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui Hua
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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15
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Zhang Y, Gabere M, Taylor MA, Simoes CC, Dumbauld C, Barro O, Tesfay MZ, Graham AL, Ferdous KU, Savenka AV, Chamcheu JC, Washam CL, Alkam D, Gies A, Byrum SD, Conti M, Post SR, Kelly T, Borad MJ, Cannon MJ, Basnakian A, Nagalo BM. Repurposing live attenuated trivalent MMR vaccine as cost-effective cancer immunotherapy. Front Oncol 2022; 12:1042250. [PMID: 36457491 PMCID: PMC9706410 DOI: 10.3389/fonc.2022.1042250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/12/2022] [Indexed: 09/10/2024] Open
Abstract
It has long been known that oncolytic viruses wield their therapeutic capability by priming an inflammatory state within the tumor and activating the tumor immune microenvironment, resulting in a multifaceted antitumor immune response. Vaccine-derived viruses, such as measles and mumps, have demonstrated promising potential for treating human cancer in animal models and clinical trials. However, the extensive cost of manufacturing current oncolytic viral products makes them far out of reach for most patients. Here by analyzing the impact of intratumoral (IT) administrations of the trivalent live attenuated measles, mumps, and rubella viruses (MMR) vaccine, we unveil the cellular and molecular basis of MMR-induced anti-cancer activity. Strikingly, we found that IT delivery of low doses of MMR correlates with tumor control and improved survival in murine hepatocellular cancer and colorectal cancer models via increased tumor infiltration of CD8+ granzyme B+ T-cells and decreased macrophages. Moreover, our data indicate that MMR activates key cellular effectors of the host's innate and adaptive antitumor immunity, culminating in an immunologically coordinated cancer cell death. These findings warrant further work on the potential for MMR to be repurposed as safe and cost-effective cancer immunotherapy to impact cancer patients globally.
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Affiliation(s)
- Yuguo Zhang
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Musa Gabere
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Mika A. Taylor
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Camila C. Simoes
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Chelsae Dumbauld
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Oumar Barro
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Mulu Z. Tesfay
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Alicia L. Graham
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Khandoker Usran Ferdous
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Alena V. Savenka
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Jean Christopher Chamcheu
- School of Basic Pharmaceutical and Toxicological Science, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, United States
| | - Charity L. Washam
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Duah Alkam
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Allen Gies
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Stephanie D. Byrum
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Matteo Conti
- Public Health Department, AUSL Imola, Imola, Italy
| | - Steven R. Post
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Thomas Kelly
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Mitesh J. Borad
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Martin J. Cannon
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Alexei Basnakian
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Bolni M. Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
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16
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Groeneveldt C, Kinderman P, van Stigt Thans JJC, Labrie C, Griffioen L, Sluijter M, van den Wollenberg DJM, Hoeben RC, den Haan JMM, van der Burg SH, van Hall T, van Montfoort N. Preinduced reovirus-specific T-cell immunity enhances the anticancer efficacy of reovirus therapy. J Immunother Cancer 2022; 10:jitc-2021-004464. [PMID: 35853671 PMCID: PMC9301813 DOI: 10.1136/jitc-2021-004464] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Many solid tumors do not respond to immunotherapy due to their immunologically cold tumor microenvironment (TME). We and others found that oncolytic viruses (OVs), including reovirus type 3 Dearing, can enhance the efficacy of immunotherapy by recruiting CD8+ T cells to the TME. A significant part of the incoming CD8+ T cells is directed toward reovirus itself, which may be detrimental to the efficacy of OVs. However, here we aim to exploit these incoming virus-specific T cells as anticancer effector cells. METHODS We performed an in-depth characterization of the reovirus-induced T-cell response in immune-competent mice bearing pancreatic KPC3 tumors. The immunodominant CD8+ T-cell epitope of reovirus was identified using epitope prediction algorithms and peptide arrays, and the quantity and quality of reovirus-specific T cells after reovirus administration were assessed using high-dimensional flow cytometry. A synthetic long peptide (SLP)-based vaccination strategy was designed to enhance the intratumoral frequency of reovirus-specific CD8+ T cells. RESULTS Reovirus administration did not induce tumor-specific T cells but rather induced high frequencies of reovirus-specific CD8+ T cells directed to the immunodominant epitope. Priming of reovirus-specific T cells required a low-frequent population of cross-presenting dendritic cells which was absent in Batf3-/- mice. While intratumoral and intravenous reovirus administration induced equal systemic frequencies of reovirus-specific T cells, reovirus-specific T cells were highly enriched in the TME exclusively after intratumoral administration. Here, they displayed characteristics of potent effector cells with high expression of KLRG1, suggesting they may be responsive against local reovirus-infected cells. To exploit these reovirus-specific T cells as anticancer effector cells, we designed an SLP-based vaccination strategy to induce a strong T-cell response before virotherapy. These high frequencies of circulating reovirus-specific T cells were reactivated on intratumoral reovirus administration and significantly delayed tumor growth. CONCLUSIONS These findings provide proof of concept that OV-specific T cells, despite not being tumor-specific, can be exploited as potent effector cells for anticancer treatment when primed before virotherapy. This is an attractive strategy for low-immunogenic tumors lacking tumor-specific T cells.
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Affiliation(s)
- Christianne Groeneveldt
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Priscilla Kinderman
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Camilla Labrie
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Lisa Griffioen
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Marjolein Sluijter
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Rob C Hoeben
- Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Joke M M den Haan
- Molecular Cell Biology and Immunlogy, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands
| | - Sjoerd H van der Burg
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Thorbald van Hall
- Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Nadine van Montfoort
- Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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17
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Brown M. Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity. Cancer Treat Res 2022; 183:91-129. [PMID: 35551657 DOI: 10.1007/978-3-030-96376-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. Such context is determined in large part by sensing of pathogen specific and damage associated features by pathogen recognition receptors (PRRs). PRR activation induces the delivery of T cell priming cues (e.g. chemokines, co-stimulatory ligands, and cytokines) from antigen presenting cells, playing a decisive role in the cancer immunity cycle. Indeed, endogenous PRR activation within the tumor microenvironment (TME) has been shown to generate spontaneous antitumor T cell immunity, e.g., cGAS-STING mediated activation of antigen presenting cells after release of DNA from dying tumor cells. Thus, instigating intratumor PRR activation, particularly with the goal of generating Th1-promoting inflammation that stokes endogenous priming of antitumor CD8+ T cells, is a growing area of clinical investigation. This approach is analogous to in situ vaccination, ultimately providing a personalized antitumor response against relevant tumor associated antigens. Here I discuss clinical stage intratumor modalities that function via activation of PRRs. These approaches are being tested in various solid tumor contexts including melanoma, colorectal cancer, glioblastoma, head and neck squamous cell carcinoma, bladder cancer, and pancreatic cancer. Their mechanism (s) of action relative to other immunotherapy approaches (e.g., antigen-defined cancer vaccines, CAR T cells, dendritic cell vaccines, and immune checkpoint blockade), as well as their potential to complement these approaches are also discussed. Examples to be reviewed include TLR agonists, STING agonists, RIG-I agonists, and attenuated or engineered viruses and bacterium. I also review common key requirements for effective in situ immune activation, discuss differences between various strategies inclusive of mechanisms that may ultimately limit or preclude antitumor efficacy, and provide a summary of relevant clinical data.
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Affiliation(s)
- Michael Brown
- Department of Neurosurgery, Duke University, Durham, NC, USA.
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18
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Mardi A, Shirokova AV, Mohammed RN, Keshavarz A, Zekiy AO, Thangavelu L, Mohamad TAM, Marofi F, Shomali N, Zamani A, Akbari M. Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction. Cancer Cell Int 2022; 22:168. [PMID: 35488303 PMCID: PMC9052538 DOI: 10.1186/s12935-022-02585-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a promising and rapidly expanding therapeutic option for a wide range of human malignancies. Despite the ongoing progress of CAR T-cell therapy in hematologic malignancies, the application of this therapeutic strategy in solid tumors has encountered several challenges due to antigen heterogeneity, suboptimal CAR T-cell trafficking, and the immunosuppressive features of the tumor microenvironment (TME). Oncolytic virotherapy is a novel cancer therapy that employs competent or genetically modified oncolytic viruses (OVs) to preferentially proliferate in tumor cells. OVs in combination with CAR T-cells are promising candidates for overcoming the current drawbacks of CAR T-cell application in tumors through triggering immunogenic cell death (ICD) in cancer cells. ICD is a type of cellular death in which danger-associated molecular patterns (DAMPs) and tumor-specific antigens are released, leading to the stimulation of potent anti-cancer immunity. In the present review, we discuss the biological causes of ICD, different types of ICD, and the synergistic combination of OVs and CAR T-cells to reach potent tumor-specific immunity.
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Affiliation(s)
- Amirhossein Mardi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anastasia V Shirokova
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Science, Cihan University of Sulaimaniya, Suleimanyah, Kurdistan region, Iraq.,College of. Veterinary Medicine, University of Sulaimani, Suleimanyah, Iraq
| | - Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Talar Ahmad Merza Mohamad
- Department of Pharmacology and Toxicology, Clinical Pharmacy, Hawler Medical University, College of Pharmacy, Kurdistan Region-Erbil, Iraq
| | - Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Tian Y, Xie D, Yang L. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduct Target Ther 2022; 7:117. [PMID: 35387984 PMCID: PMC8987060 DOI: 10.1038/s41392-022-00951-x] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.
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Affiliation(s)
- Yaomei Tian
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
- College of Bioengineering, Sichuan University of Science & Engineering, No. 519, Huixing Road, 643000, Zigong, Sichuan, People's Republic of China
| | - Daoyuan Xie
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China.
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20
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Schuelke MR, Gundelach JH, Coffey M, West E, Scott K, Johnson DR, Samson A, Melcher A, Vile RG, Bram RJ. Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors. Neurooncol Adv 2022; 4:vdac085. [PMID: 35821679 PMCID: PMC9268737 DOI: 10.1093/noajnl/vdac085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Brain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses. Methods The trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter. Results Six patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients. Conclusions Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.
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Affiliation(s)
- Matthew R Schuelke
- Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Matt Coffey
- Oncolytics Biotech, Calgary, Alberta, Canada
| | - Emma West
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Karen Scott
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Derek R Johnson
- Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Adel Samson
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Alan Melcher
- The Institute of Cancer Research/Royal Marsden, National Institute for Health Research Biomedical Research Centre, London, UK
| | - Richard G Vile
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Richard J Bram
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
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21
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Feola S, Russo S, Ylösmäki E, Cerullo V. Oncolytic ImmunoViroTherapy: A long history of crosstalk between viruses and immune system for cancer treatment. Pharmacol Ther 2021; 236:108103. [PMID: 34954301 DOI: 10.1016/j.pharmthera.2021.108103] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/09/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022]
Abstract
Cancer Immunotherapy relies on harnessing a patient's immune system to fine-tune specific anti-tumor responses and ultimately eradicate cancer. Among diverse therapeutic approaches, oncolytic viruses (OVs) have emerged as a novel form of cancer immunotherapy. OVs are a naturally occurring or genetically modified class of viruses able to selectively kill cancer cells, leaving healthy cells unharmed; in the last two decades, the role of OVs has been redefined to act beyond their oncolytic activity. Indeed, the immunogenic cancer cell death mediated by OVs induces the release of tumor antigens that in turn induces anti-tumor immunity, allowing OVs to act as in situ therapeutic cancer vaccines. Additionally, OVs can be engineered for intratumoral delivery of immunostimulatory molecules such as tumor antigens or cytokines to further enhance anti-tumor response. Moreover, OVs can be used in combination with other cancer immunotherapeutic approaches such as Immune Checkpoint Inhibitors and CAR-T cells. The current review first defines the three main mechanisms of action (MOA) of OVs currently used in cancer therapy that are: i) Oncolysis, ii) OV-induced cancer-specific immune activation, and iii) Exploiting pre-existing anti-viral immunity to enhance cancer therapy. Secondly, we focus on how OVs can induce and/or improve anti-cancer immunity in a specific or unspecific fashion, highlighting the importance of these approaches. Finally, the last part of the review analyses OVs combined with other cancer immunotherapies, revising present and future clinical applications.
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Affiliation(s)
- S Feola
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - S Russo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - E Ylösmäki
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - V Cerullo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, S. Pansini 5, 80131 Naples, Italy.
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22
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A new insight into aggregation of oncolytic adenovirus Ad5-delta-24-RGD during CsCl gradient ultracentrifugation. Sci Rep 2021; 11:16088. [PMID: 34373477 PMCID: PMC8352973 DOI: 10.1038/s41598-021-94573-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
Two-cycle cesium chloride (2 × CsCl) gradient ultracentrifugation is a conventional approach for purifying recombinant adenoviruses (rAds) for research purposes (gene therapy, vaccines, and oncolytic vectors). However, rAds containing the RGD-4C peptide in the HI loop of the fiber knob domain tend to aggregate during 2 × CsCl gradient ultracentrifugation resulting in a low infectious titer yield or even purification failure. An iodixanol-based purification method preventing aggregation of the RGD4C-modified rAds has been proposed. However, the reason explaining aggregation of the RGD4C-modified rAds during 2 × CsCl but not iodixanol gradient ultracentrifugation has not been revealed. In the present study, we showed that rAds with the RGD-4C peptide in the HI loop but not at the C-terminus of the fiber knob domain were prone to aggregate during 2 × CsCl but not iodixanol gradient ultracentrifugation. The cysteine residues with free thiol groups after the RGD motif within the inserted RGD-4C peptide were responsible for formation of the interparticle disulfide bonds under atmospheric oxygen and aggregation of Ad5-delta-24-RGD4C-based rAds during 2 × CsCl gradient ultracentrifugation, which could be prevented using iodixanol gradient ultracentrifugation, most likely due to antioxidant properties of iodixanol. A cysteine-to-glycine substitution of the cysteine residues with free thiol groups (RGD-2C2G) prevented aggregation during 2 × CsCl gradient purification but in coxsackie and adenovirus receptor (CAR)-low/negative cancer cell lines of human and rodent origin, this reduced cytolytic efficacy to the levels observed for a fiber non-modified control vector. However, both Ad5-delta-24-RGD4C and Ad5-delta-24-RGD2C2G were equally effective in the murine immunocompetent CT-2A glioma model due to a primary role of antitumor immune responses in the therapeutic efficacy of oncolytic virotherapy.
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23
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Mozaffari Nejad AS, Noor T, Munim ZH, Alikhani MY, Ghaemi A. A bibliometric review of oncolytic virus research as a novel approach for cancer therapy. Virol J 2021; 18:98. [PMID: 33980264 PMCID: PMC8113799 DOI: 10.1186/s12985-021-01571-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Background In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research. Methods A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software. Results In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters. Conclusion The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.
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Affiliation(s)
| | - Tehjeeb Noor
- Faculty of Medicine, University of Bergen, Horten, Norway
| | - Ziaul Haque Munim
- Faculty of Technology, Natural and Maritime Sciences, University of South-Eastern Norway, Horten, Norway
| | - Mohammad Yousef Alikhani
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Amir Ghaemi
- Department of Influenza and Other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran.
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24
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Annels NE, Simpson GR, Denyer M, Arif M, Coffey M, Melcher A, Harrington K, Vile R, Pandha H. Oncolytic Reovirus-Mediated Recruitment of Early Innate Immune Responses Reverses Immunotherapy Resistance in Prostate Tumors. Mol Ther Oncolytics 2021; 20:434-446. [PMID: 33665363 PMCID: PMC7900644 DOI: 10.1016/j.omto.2020.09.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023] Open
Abstract
Prostate cancers are considered "cold" tumors characterized by minimal T cell infiltrates, absence of a type I interferon (IFN) signature, and the presence of immunosuppressive cells. This non-inflamed phenotype is likely responsible for the lack of sensitivity of prostate cancer patients to immune checkpoint blockade (ICB) therapy. Oncolytic virus therapy can potentially overcome this resistance to immunotherapy in prostate cancers by transforming cold tumors into "hot," immune cell-infiltrated tumors. We investigated whether the combination of intratumoral oncolytic reovirus, followed by targeted blockade of Programmed cell death protein 1 (PD-1) checkpoint inhibition and/or the immunomodulatory CD73/Adenosine system can enhance anti-tumor immunity. Treatment of subcutaneous TRAMP-C2 prostate tumors with combined intratumoral reovirus and anti-PD-1 or anti-CD73 antibody significantly enhanced survival of mice compared with reovirus or either antibody therapy alone. Only combination therapy led to rejection of pre-established tumors and protection from tumor re-challenge. This therapeutic effect was dependent on CD4+ T cells and natural killer (NK) cells. NanoString immune profiling of tumors confirmed that reovirus increased tumor immune cell infiltration and revealed an upregulation of the immune-regulatory receptor, B- and T-lymphocyte attenuator (BTLA). This expression of BTLA on innate antigen-presenting cells (APCs) and its ligand, Herpesvirus entry mediator (HVEM), on T cells from reovirus-infected tumors was in keeping with a role for the HVEM-BTLA pathway in promoting the potent anti-tumor memory response observed.
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Affiliation(s)
- Nicola E. Annels
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG, UK
| | - Guy R. Simpson
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG, UK
| | - Mick Denyer
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG, UK
| | - Mehreen Arif
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG, UK
| | - Matt Coffey
- Oncolytics Biotech, Inc., 210, 1167 Kensington Crescent NW Calgary, AB T2N 1X7, Canada
| | - Alan Melcher
- Translational Immunotherapy Team, The Institute of Cancer Research, 237 Fulham Road, London SW6 6JB, UK
| | - Kevin Harrington
- Targeted Therapy Team, The Institute of Cancer Research, 237 Fulham Road, London SW6 6JB, UK
| | - Richard Vile
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Hardev Pandha
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG, UK
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25
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Müller LME, Migneco G, Scott GB, Down J, King S, Askar B, Jennings V, Oyajobi B, Scott K, West E, Ralph C, Samson A, Ilett EJ, Muthana M, Coffey M, Melcher A, Parrish C, Cook G, Lawson M, Errington-Mais F. Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche. J Immunother Cancer 2021; 9:e001803. [PMID: 33741729 PMCID: PMC7986878 DOI: 10.1136/jitc-2020-001803] [Citation(s) in RCA: 13] [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] [Accepted: 02/17/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Multiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported. METHODS This study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment. RESULTS Using the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes. CONCLUSION These data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.
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Affiliation(s)
- Louise M E Müller
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Gemma Migneco
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Gina B Scott
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Jenny Down
- Sheffield Myeloma Research Team, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Sancha King
- Sheffield Myeloma Research Team, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Basem Askar
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Victoria Jennings
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | - Babatunde Oyajobi
- Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Karen Scott
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Emma West
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Christy Ralph
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Adel Samson
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Elizabeth J Ilett
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Munitta Muthana
- Sheffield Myeloma Research Team, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Matt Coffey
- Oncolytics Biotech Inc, Calgary, Alberta, Canada
| | - Alan Melcher
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | | | - Gordon Cook
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Michelle Lawson
- Sheffield Myeloma Research Team, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Fiona Errington-Mais
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
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Viroimmunotherapy for breast cancer: promises, problems and future directions. Cancer Gene Ther 2020; 28:757-768. [PMID: 33268826 DOI: 10.1038/s41417-020-00265-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/26/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023]
Abstract
Virotherapy, a strategy to use live viruses as therapeutics, is a relatively novel field in the treatment of cancer. With the advancements in molecular biology and virology, there has been a huge increase in research on cancer virotherapy. For the treatment of cancer, viruses could be used either as vectors in gene therapy or as oncolytic agents. A variety of viruses have been studied for their potential usage in gene therapy or oncolytic therapy. In this review, we discuss virotherapy with a special focus on breast cancer. Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women worldwide. Current treatments are insufficient to cure metastatic breast cancer and are often associated with severe side effects that further deteriorates patients' quality of life. Therefore, novel therapeutic approaches such as virotherapy need to be developed for the treatment of breast cancer. Here we summarize the current treatments for breast cancer and the potential use of virotherapy in the treatment of the disease. Furthermore, we discuss the use of oncolytic viruses as immunotherapeutics and the rational combination of oncolytic viruses with other therapeutics for optimal treatment of breast cancer. Finally, we outline the progress made in virotherapy for breast cancer and the shortcomings that need to be addressed for this novel therapy to move to the clinic for better treatment of breast cancer.
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Müller L, Berkeley R, Barr T, Ilett E, Errington-Mais F. Past, Present and Future of Oncolytic Reovirus. Cancers (Basel) 2020; 12:E3219. [PMID: 33142841 PMCID: PMC7693452 DOI: 10.3390/cancers12113219] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a "one size fits all" approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.
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Groeneveldt C, Kinderman P, van den Wollenberg DJM, van den Oever RL, Middelburg J, Mustafa DAM, Hoeben RC, van der Burg SH, van Hall T, van Montfoort N. Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy. J Immunother Cancer 2020; 8:jitc-2020-001191. [PMID: 33082167 PMCID: PMC7577070 DOI: 10.1136/jitc-2020-001191] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 12/14/2022] Open
Abstract
Background T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors. Methods The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells. Results Replication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease. Conclusions Oncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors.
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Affiliation(s)
- Christianne Groeneveldt
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Priscilla Kinderman
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ruben L van den Oever
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jim Middelburg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Dana A M Mustafa
- Department of Pathology, Tumor Immuno-Pathology Laboratory, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Rob C Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sjoerd H van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Nadine van Montfoort
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
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Closely related reovirus lab strains induce opposite expression of RIG-I/IFN-dependent versus -independent host genes, via mechanisms of slow replication versus polymorphisms in dsRNA binding σ3 respectively. PLoS Pathog 2020; 16:e1008803. [PMID: 32956403 PMCID: PMC7529228 DOI: 10.1371/journal.ppat.1008803] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 10/01/2020] [Accepted: 07/13/2020] [Indexed: 12/28/2022] Open
Abstract
The Dearing isolate of Mammalian orthoreovirus (T3D) is a prominent model of virus-host relationships and a candidate oncolytic virotherapy. Closely related laboratory strains of T3D, originating from the same ancestral T3D isolate, were recently found to exhibit significantly different oncolytic properties. Specifically, the T3DPL strain had faster replication kinetics in a panel of cancer cells and improved tumor regression in an in vivo melanoma model, relative to T3DTD. In this study, we discover that T3DPL and T3DTD also differentially activate host signalling pathways and downstream gene transcription. At equivalent infectious dose, T3DTD induces higher IRF3 phosphorylation and expression of type I IFNs and IFN-stimulated genes (ISGs) than T3DPL. Using mono-reassortants with intermediate replication kinetics and pharmacological inhibitors of reovirus replication, IFN responses were found to inversely correlate with kinetics of virus replication. In other words, slow-replicating T3D strains induce more IFN signalling than fast-replicating T3D strains. Paradoxically, during co-infections by T3DPL and T3DTD, there was still high IRF3 phosphorylation indicating a phenodominant effect by the slow-replicating T3DTD. Using silencing and knock-out of RIG-I to impede IFN, we found that IFN induction does not affect the first round of reovirus replication but does prevent cell-cell spread in a paracrine fashion. Accordingly, during co-infections, T3DPL continues to replicate robustly despite activation of IFN by T3DTD. Using gene expression analysis, we discovered that reovirus can also induce a subset of genes in a RIG-I and IFN-independent manner; these genes were induced more by T3DPL than T3DTD. Polymorphisms in reovirus σ3 viral protein were found to control activation of RIG-I/ IFN-independent genes. Altogether, the study reveals that single amino acid polymorphisms in reovirus genomes can have large impact on host gene expression, by both changing replication kinetics and by modifying viral protein activity, such that two closely related T3D strains can induce opposite cytokine landscapes.
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Chaurasiya S, Fong Y, Warner SG. Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges. Cancers (Basel) 2020; 12:cancers12061699. [PMID: 32604787 PMCID: PMC7352900 DOI: 10.3390/cancers12061699] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/15/2022] Open
Abstract
The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use.
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31
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Marotel M, Hasim MS, Hagerman A, Ardolino M. The two-faces of NK cells in oncolytic virotherapy. Cytokine Growth Factor Rev 2020; 56:59-68. [PMID: 32586674 DOI: 10.1016/j.cytogfr.2020.06.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022]
Abstract
Oncolytic viruses (OVs) are immunotherapeutics capable of directly killing cancer cells and with potent immunostimulatory properties. OVs exert their antitumor effect, at least partially, by activating the antitumor immune response, of which NK cells are an important component. However, if on the one hand increasing evidence revealed that NK cells are important mediators of oncolytic virotherapy, on the other hand, NK cells have evolved to fight viral infections, and therefore they can have a detrimental effect for the efficacy of OVs. In this review, we will discuss the dichotomy between the antitumor and antiviral functions of NK cells related to oncolytic virotherapy. We will also review NK cell-based and OV-based therapies, engineered OVs aimed at enhancing immune stimulation, and combination therapies involving OVs and NK cells currently used in cancer immunotherapy.
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Affiliation(s)
- M Marotel
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - M S Hasim
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - A Hagerman
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada; University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Ottawa, Canada
| | - M Ardolino
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada; University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Ottawa, Canada.
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Chitosan-Based Delivery of Avian Reovirus Fusogenic Protein p10 Gene: In Vitro and In Vivo Studies towards a New Vaccine against Melanoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4045760. [PMID: 32626742 PMCID: PMC7306838 DOI: 10.1155/2020/4045760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 05/22/2020] [Indexed: 12/29/2022]
Abstract
Reovirus is known to have an anticancer effect in both the preclinical and clinical assays. Current evidence suggests that the reovirus-mediated impact on tumor growth depends on the activation of specific antitumor immune responses. A feasible explanation for the oncolytic effects and immune system activation is through the expression of the fusogenic reovirus protein. In this work, we evaluated the in vivo antitumor effects of the expression of fusogenic protein p10 of avian reovirus (ARV-p10). We used chitosan nanoparticles (CH-NPs) as a vehicle for the ARV-p10 DNA in murine B16 melanoma models both in vitro and in vivo. We confirmed that ARV-p10 delivery through a chitosan-based formulation (ARV-p10 CH-NPs) was capable of inducing cell fusion in cultured melanoma cells, showing a mild cytotoxic effect. Interestingly, intratumor injection of ARV-p10 CH-NPs delayed tumor growth, without changing lymphoid populations in the tumor tissue and spleen. The injection of chitosan nanoparticles (CH-NPs) also delayed tumor growth, suggesting the nanoparticle itself would attack tumor cells. In conclusion, we proved that in vitro ARV-p10 protein expression using CH-NPs in murine melanoma cells induces a cytotoxic effect associated with its cell fusion. Further studies are necessary for establishing a protocol for efficient in vivo DNA delivery of fusion proteins to produce an antitumoral effect.
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Flores EB, Aksoy BA, Bartee E. Initial dose of oncolytic myxoma virus programs durable antitumor immunity independent of in vivo viral replication. J Immunother Cancer 2020; 8:e000804. [PMID: 32581062 PMCID: PMC7319776 DOI: 10.1136/jitc-2020-000804] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Oncolytic therapy uses live-replicating viruses to improve the immunological status of treated tumors. Critically, while these viruses are known to self-amplify in vivo, clinical oncolytic therapies still appear to display a strong dose dependence and the mechanisms mediating this dose dependence are not well understood. METHODS To explore this apparent contradiction, we investigated how the initial dose of oncolytic myxoma virus affected the subsequent ability of treatment to alter the immunological status of tumors as well as synergize with programmed cell death protein 1 (PD1) blockade. RESULTS Our results indicate that, due to viral self-amplification in vivo, the overall load of myxoma virus rapidly normalizes within treated tumors despite up to 3-log differences in inoculating dose. Because of this, therapeutic efficacy in the absence of checkpoint blockade is largely dose independent. Despite this rapid normalization, however, treatment with high or low doses of myxoma virus induces distinct immunological changes within treated tumors. Critically, these changes appear to be durably programmed based on the initial oncolytic dose with low-dose treatment failing to induce immunological improvements despite rapidly achieving equivalent viral burdens. Finally, due to the distinct immunological profiles induced by high and low myxoma virus doses, oncolytic efficacy resulting from combination with PD1 blockade therapy displays a strong dose dependence. CONCLUSIONS Taken together, these data suggest that the ability of oncolytic myxoma virus to immunologically reprogram treated tumors is dependent on initial viral dose. Additionally, this work could provide a possible mechanistic explanation for clinical results observed with other oncolytic viruses.
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Affiliation(s)
- Erica B Flores
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Bulent A Aksoy
- College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Eric Bartee
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Cai L, Liu Z. Novel recombinant coxsackievirus B3 with genetically inserted basic peptide elicits robust antitumor activity against lung cancer. Cancer Med 2020; 9:5210-5220. [PMID: 32459400 PMCID: PMC7367620 DOI: 10.1002/cam4.3143] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 04/01/2020] [Accepted: 04/24/2020] [Indexed: 12/19/2022] Open
Abstract
Cancer therapy that utilizes oncolytic virus may offer an exciting alternative, and coxsackievirus B3 (CVB3) is a potent oncolytic virus. This study was to assess the oncolytic activities of novel recombinant CVB3 with genetically inserted basic peptides in lung cancer. Recombinant CVB3 was produced in Vero cells, with or without genetically inserted basic peptides. In vitro and in vivo experiments with nude mouse models bearing human lung carcinoma xenografts were performed to examine the antitumor activities. Cytokines and immune responses to the recombinant CVB3 were determined in cynomolgus monkeys. Recombinant CVB3 with genetically inserted basic peptides was associated with significantly higher pH values within tumors. Mice treated with recombinant CVB3 showed significantly less tumor progression, and recombinant CVB3 with genetically inserted basic peptides appeared to enhance tumor suppression. Recombinant CVB3 was associated with significantly less proliferation of various lung cancer cells without affecting proliferation of normal lung fibroblasts. The cytokine profiles of the cynomolgus monkeys were comparable among control group (normal saline solution) and those given recombinant CVB3 with or without fused basic peptides, with no induction of excessive cytokine or immune responses. In conclusions, recombinant CVB3, especially those with fused basic peptides, possess strong antitumor activities without eliciting excessive immune responses.
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Affiliation(s)
- Ligang Cai
- Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhiyi Liu
- Wuhan Boweid Biotechnology Co., Ltd., Wuhan, Hubei, China
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Oncolytic immunotherapy and bortezomib synergy improves survival of refractory multiple myeloma in a preclinical model. Blood Adv 2020; 3:797-812. [PMID: 30850386 DOI: 10.1182/bloodadvances.2018025593] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P < .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.
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Groeneveldt C, van Hall T, van der Burg SH, Ten Dijke P, van Montfoort N. Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses. Trends Immunol 2020; 41:406-420. [PMID: 32223932 DOI: 10.1016/j.it.2020.03.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022]
Abstract
In cancer immunotherapy, a patient's own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-β (TGF-β)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-β signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade.
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Affiliation(s)
- Christianne Groeneveldt
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Sjoerd H van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands
| | - Nadine van Montfoort
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
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Leung EY, Ennis DP, Kennedy PR, Hansell C, Dowson S, Farquharson M, Spiliopoulou P, Nautiyal J, McNamara S, Carlin LM, Fisher K, Davis DM, Graham G, McNeish IA. NK Cells Augment Oncolytic Adenovirus Cytotoxicity in Ovarian Cancer. Mol Ther Oncolytics 2020; 16:289-301. [PMID: 32195317 PMCID: PMC7068056 DOI: 10.1016/j.omto.2020.02.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 02/10/2020] [Indexed: 12/20/2022] Open
Abstract
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses-the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)-to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
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Affiliation(s)
- Elaine Y.L. Leung
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Darren P. Ennis
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Ovarian Cancer Action Research Centre and Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK
| | - Philippa R. Kennedy
- Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK
| | - Christopher Hansell
- Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Suzanne Dowson
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Pavlina Spiliopoulou
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Ovarian Cancer Action Research Centre and Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK
| | - Jaya Nautiyal
- Ovarian Cancer Action Research Centre and Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK
| | - Sophie McNamara
- Ovarian Cancer Action Research Centre and Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK
| | | | | | - Daniel M. Davis
- Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK
| | - Gerard Graham
- Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Iain A. McNeish
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Ovarian Cancer Action Research Centre and Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK
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Li Y, Shen Y, Zhao R, Samudio I, Jia W, Bai X, Liang T. Oncolytic virotherapy in hepato-bilio-pancreatic cancer: The key to breaking the log jam? Cancer Med 2020; 9:2943-2959. [PMID: 32130786 PMCID: PMC7196045 DOI: 10.1002/cam4.2949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Traditional therapies have limited efficacy in hepatocellular carcinoma, pancreatic cancer, and biliary tract cancer, especially for advanced and refractory cancers. Through a deeper understanding of antitumor immunity and the tumor microenvironment, novel immunotherapies are becoming available for cancer treatment. Oncolytic virus (OV) therapy is an emerging type of immunotherapy that has demonstrated effective antitumor efficacy in many preclinical studies and clinical studies. Thus, it may represent a potential feasible treatment for hard to treat gastrointestinal (GI) tumors. Here, we summarize the research progress of OV therapy for the treatment of hepato-bilio-pancreatic cancers. In general, most OV therapies exhibits potent, specific oncolysis both in cell lines in vitro and the animal models in vivo. Currently, several clinical trials have suggested that OV therapy may also be effective in patients with refractory hepato-bilio-pancreatic cancer. Multiple strategies such as introducing immunostimulatory genes, modifying virus capsid and combining various other therapeutic modalities have been shown enhanced specific oncolysis and synergistic anti-cancer immune stimulation. Combining OV with other antitumor therapies may become a more effective strategy than using virus alone. Nevertheless, more studies are needed to better understand the mechanisms underlying the therapeutic effects of OV, and to design appropriate dosing and combination strategies.
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Affiliation(s)
- Yuwei Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | | | | | - William Jia
- Virogin Biotech Canada Ltd, Vancouver, Canada
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
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Deng H, Liu H, de Silva T, Xue Y, Mohamud Y, Ng CS, Qu J, Zhang J, Jia WW, Lockwood WW, Luo H. Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma. MOLECULAR THERAPY-ONCOLYTICS 2019; 14:266-278. [PMID: 31463367 PMCID: PMC6709373 DOI: 10.1016/j.omto.2019.07.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 07/13/2019] [Indexed: 02/05/2023]
Abstract
KRAS mutant (KRASmut) lung adenocarcinoma is a refractory cancer without available targeted therapy. The current study explored the possibility to develop coxsackievirus type B3 (CVB3) as an oncolytic agent for the treatment of KRASmut lung adenocarcinoma. In cultured cells, we discovered that CVB3 selectively infects and lyses KRASmut lung adenocarcinoma cells (A549, H2030, and H23), while sparing normal lung epithelial cells (primary, BEAS2B, HPL1D, and 1HAEo) and EGFRmut lung adenocarcinoma cells (HCC4006, PC9, H3255, and H1975). Using stable cells expressing a single driver mutation of either KRASG12V or EGFRL858R in normal lung epithelial cells (HPL1D), we further showed that CVB3 specifically kills HPL1D-KRASG12V cells with minimal harm to HPL1D-EGFRL858R and control cells. Mechanistically, we demonstrated that aberrant activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and compromised type I interferon immune response in KRASmut lung adenocarcinoma cells serve as key factors contributing to the sensitivity to CVB3-induced cytotoxicity. Lastly, we conducted in vivo xenograft studies using two immunocompromised mouse models. Our results revealed that intratumoral injection of CVB3 results in a marked tumor regression of KRASmut lung adenocarcinoma in both non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma (NSG) and NOD-SCID xenograft models. Together, our findings suggest that CVB3 is an excellent candidate to be further developed as a targeted therapy for KRASmut lung adenocarcinoma.
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Affiliation(s)
- Haoyu Deng
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Huitao Liu
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Tanya de Silva
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
| | - YuanChao Xue
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Yasir Mohamud
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Chen Seng Ng
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
| | - Junyan Qu
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Centre for Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Jingchun Zhang
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - William W.G. Jia
- Department of Surgery, Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
| | - William W. Lockwood
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
- Corresponding author: William W. Lockwood, Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
| | - Honglin Luo
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Corresponding author: Honglin Luo, Centre for Heart Lung Innovation, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
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Schuelke MR, Wongthida P, Thompson J, Kottke T, Driscoll CB, Huff AL, Shim KG, Coffey M, Pulido J, Evgin L, Vile RG. Diverse immunotherapies can effectively treat syngeneic brainstem tumors in the absence of overt toxicity. J Immunother Cancer 2019; 7:188. [PMID: 31315671 PMCID: PMC6637625 DOI: 10.1186/s40425-019-0673-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 07/10/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Immunotherapy has shown remarkable clinical promise in the treatment of various types of cancers. However, clinical benefits derive from a highly inflammatory mechanism of action. This presents unique challenges for use in pediatric brainstem tumors including diffuse intrinsic pontine glioma (DIPG), since treatment-related inflammation could cause catastrophic toxicity. Therefore, the goal of this study was to investigate whether inflammatory, immune-based therapies are likely to be too dangerous to pursue for the treatment of pediatric brainstem tumors. METHODS To complement previous immunotherapy studies using patient-derived xenografts in immunodeficient mice, we developed fully immunocompetent models of immunotherapy using transplantable, syngeneic tumors. These four models - HSVtk/GCV suicide gene immunotherapy, oncolytic viroimmunotherapy, adoptive T cell transfer, and CAR T cell therapy - have been optimized to treat tumors outside of the CNS and induce a broad spectrum of inflammatory profiles, maximizing the chances of observing brainstem toxicity. RESULTS All four models achieved anti-tumor efficacy in the absence of toxicity, with the exception of recombinant vaccinia virus expressing GMCSF, which demonstrated inflammatory toxicity. Histology, imaging, and flow cytometry confirmed the presence of brainstem inflammation in all models. Where used, the addition of immune checkpoint blockade did not introduce toxicity. CONCLUSIONS It remains imperative to regard the brainstem with caution for immunotherapeutic intervention. Nonetheless, we show that further careful development of immunotherapies for pediatric brainstem tumors is warranted to harness the potential potency of anti-tumor immune responses, despite their possible toxicity within this anatomically sensitive location.
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Affiliation(s)
- Matthew R Schuelke
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA
- Medical Scientist Training Program, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Jill Thompson
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Timothy Kottke
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Amanda L Huff
- Virology and Gene Therapy Track, Mayo Clinic, Rochester, MN, 55905, USA
| | - Kevin G Shim
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA
- Medical Scientist Training Program, Mayo Clinic, Rochester, MN, 55905, USA
| | - Matt Coffey
- Oncolytics Biotech, Inc., Calgary, AB, T2N 1X7, Canada
| | - Jose Pulido
- Department of Ophthalmology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Laura Evgin
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Richard G Vile
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
- Leeds Cancer Research UK Clinical Centre, Faculty of Medicine and Health, St James' University Hospital, University of Leeds, West Yorkshire, UK.
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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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Jennings VA, Scott GB, Rose AMS, Scott KJ, Migneco G, Keller B, Reilly K, Donnelly O, Peach H, Dewar D, Harrington KJ, Pandha H, Samson A, Vile RG, Melcher AA, Errington-Mais F. Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. Mol Ther 2019; 27:1139-1152. [PMID: 31053413 PMCID: PMC6554638 DOI: 10.1016/j.ymthe.2019.04.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/08/2019] [Accepted: 04/08/2019] [Indexed: 02/09/2023] Open
Abstract
A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.
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Affiliation(s)
- Victoria A Jennings
- The Institute of Cancer Research, Division of Radiotherapy and Imaging, Chester Beatty Laboratories, London SW3 6JB, UK; Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Gina B Scott
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Ailsa M S Rose
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Karen J Scott
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Gemma Migneco
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Brian Keller
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Katrina Reilly
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Oliver Donnelly
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | - Howard Peach
- St James's University Hospital, Leeds LS9 7TF, UK
| | - Donald Dewar
- St James's University Hospital, Leeds LS9 7TF, UK
| | - Kevin J Harrington
- The Institute of Cancer Research, Division of Radiotherapy and Imaging, Chester Beatty Laboratories, London SW3 6JB, UK
| | - Hardev Pandha
- Leggett Building, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK
| | - Adel Samson
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
| | | | - Alan A Melcher
- The Institute of Cancer Research, Division of Radiotherapy and Imaging, Chester Beatty Laboratories, London SW3 6JB, UK.
| | - Fiona Errington-Mais
- Section of Infection and Immunity, Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK
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Davola ME, Mossman KL. Oncolytic viruses: how "lytic" must they be for therapeutic efficacy? Oncoimmunology 2019; 8:e1581528. [PMID: 31069150 PMCID: PMC6492965 DOI: 10.1080/2162402x.2019.1596006] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/22/2019] [Accepted: 03/07/2019] [Indexed: 12/21/2022] Open
Abstract
Oncolytic viruses (OVs) preferentially target and kill cancer cells without affecting healthy cells through a multi-modal mechanism of action. While historically the direct killing activity of OVs was considered the primary mode of action, initiation or augmentation of a host antitumor immune response is now considered an essential aspect of oncolytic virotherapy. To improve oncolytic virotherapy, many studies focus on increasing virus replication and spread. In this article, we open for discussion the traditional dogma that correlates replication with the efficacy of OVs, pointing out several examples that oppose this principle.
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Affiliation(s)
- Maria Eugenia Davola
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada
| | - Karen Louise Mossman
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada
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Cervera-Carrascon V, Havunen R, Hemminki A. Oncolytic adenoviruses: a game changer approach in the battle between cancer and the immune system. Expert Opin Biol Ther 2019; 19:443-455. [PMID: 30905206 DOI: 10.1080/14712598.2019.1595582] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Oncolytic adenoviruses are among the most studied oncolytic viruses because of their tumor selectivity, safety, and transgene-delivery capability. With a growing number of different immunotherapies against cancer, the extraordinary immunogenicity of the adenovirus has emerged as a differentiating strength. Enabling T-cell related therapies with oncolytic adenoviruses appears a promising approach due to its inherent ability to elicit responses from the adaptive immune compartment. AREAS COVERED These viruses have successfully enhanced both adoptive T-cell therapies and immune-checkpoint therapies. Oncolytic viruses induce several effects at the tumor and on the systemic level that help to circumvent current limitations of T-cells and related therapies, such as T-cell trafficking, tumor immune suppressivity and antigen spreading EXPERT OPINION Taking into account the multitude of possibilities of treating cancer with immunotherapies, learning to optimize the combinations and administration strategies of these drugs, could lead to durable responses in patients with currently incurable cancers.
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Affiliation(s)
- Victor Cervera-Carrascon
- a Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine , University of Helsinki , Helsinki , Finland.,b TILT Biotherapeutics Ltd , Helsinki , Finland
| | - Riikka Havunen
- a Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine , University of Helsinki , Helsinki , Finland.,b TILT Biotherapeutics Ltd , Helsinki , Finland
| | - Akseli Hemminki
- a Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine , University of Helsinki , Helsinki , Finland.,b TILT Biotherapeutics Ltd , Helsinki , Finland.,c Hospital Comprehensive Cancer Center , Helsinki University , Helsinki , Finland
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Martinez-Quintanilla J, Seah I, Chua M, Shah K. Oncolytic viruses: overcoming translational challenges. J Clin Invest 2019; 129:1407-1418. [PMID: 30829653 DOI: 10.1172/jci122287] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic virotherapy (OVT) is a promising approach in which WT or engineered viruses selectively replicate and destroy tumor cells while sparing normal ones. In the last two decades, different oncolytic viruses (OVs) have been modified and tested in a number of preclinical studies, some of which have led to clinical trials in cancer patients. These clinical trials have revealed several critical limitations with regard to viral delivery, spread, resistance, and antiviral immunity. Here, we focus on promising research strategies that have been developed to overcome the aforementioned obstacles. Such strategies include engineering OVs to target a broad spectrum of tumor cells while evading the immune system, developing unique delivery mechanisms, combining other immunotherapeutic agents with OVT, and using clinically translatable mouse tumor models to potentially translate OVT more readily into clinical settings.
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Affiliation(s)
| | - Ivan Seah
- Center for Stem Cell Therapeutics and Imaging and
| | - Melissa Chua
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
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Pol JG, Atherton MJ, Bridle BW, Stephenson KB, Le Boeuf F, Hummel JL, Martin CG, Pomoransky J, Breitbach CJ, Diallo JS, Stojdl DF, Bell JC, Wan Y, Lichty BD. Development and applications of oncolytic Maraba virus vaccines. Oncolytic Virother 2018; 7:117-128. [PMID: 30538968 PMCID: PMC6263248 DOI: 10.2147/ov.s154494] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oncolytic activity of the MG1 strain of the Maraba vesiculovirus has proven efficacy in numerous preclinical cancer models, and relied not only on a direct cytotoxicity but also on the induction of both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, we introduced the MG1 virus in a prime-boost cancer vaccine strategy. To this aim, a replication-incompetent adenoviral [Ad] vector together with the oncolytic MG1 have each been armed with a transgene expressing a same tumor antigen. Immune priming with the Ad vaccine subsequently boosted with the MG1 vaccine mounted tumor-specific responses of remarkable magnitude, which significantly prolonged survival in various murine cancer models. Based on these promising results, we validated the safety profile of the Ad:MG1 oncolytic vaccination strategy in nonhuman primates and initiated clinical investigations in cancer patients. Two clinical trials are currently under way (NCT02285816; NCT02879760). The present review will recapitulate the discoveries that led to the development of MG1 oncolytic vaccines from bench to bedside.
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Affiliation(s)
- Jonathan G Pol
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM), U1138, Paris, France
- Team 11 labelled Ligue Nationale contre le Cancer, Cordeliers Research Center, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Sorbonne Universités/Université Pierre et Marie Curie/Paris VI, Paris, France
| | - Matthew J Atherton
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada,
| | - Byram W Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | | | - Fabrice Le Boeuf
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Jeff L Hummel
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada,
- Clinical Trial Division, CANSWERS, Georgetown, ON, Canada
| | | | | | | | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - David F Stojdl
- Turnstone Biologics, Ottawa, ON, Canada,
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - John C Bell
- Turnstone Biologics, Ottawa, ON, Canada,
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Yonghong Wan
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada,
| | - Brian D Lichty
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada,
- Turnstone Biologics, Ottawa, ON, Canada,
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Bourhill T, Mori Y, Rancourt DE, Shmulevitz M, Johnston RN. Going (Reo)Viral: Factors Promoting Successful Reoviral Oncolytic Infection. Viruses 2018; 10:E421. [PMID: 30103501 PMCID: PMC6116061 DOI: 10.3390/v10080421] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 08/09/2018] [Accepted: 08/09/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses show intriguing potential as cancer therapeutic agents. These viruses are capable of selectively targeting and killing cancerous cells while leaving healthy cells largely unaffected. The use of oncolytic viruses for cancer treatments in selected circumstances has recently been approved by the Food and Drug Administration (FDA) of the US and work is progressing on engineering viral vectors for enhanced selectivity, efficacy and safety. However, a better fundamental understanding of tumour and viral biology is essential for the continued advancement of the oncolytic field. This knowledge will not only help to engineer more potent and effective viruses but may also contribute to the identification of biomarkers that can determine which patients will benefit most from this treatment. A mechanistic understanding of the overlapping activity of viral and standard chemotherapeutics will enable the development of better combinational approaches to improve patient outcomes. In this review, we will examine each of the factors that contribute to productive viral infections in cancerous cells versus healthy cells. Special attention will be paid to reovirus as it is a well-studied virus and the only wild-type virus to have received orphan drug designation by the FDA. Although considerable insight into reoviral biology exists, there remain numerous deficiencies in our understanding of the factors regulating its successful oncolytic infection. Here we will discuss what is known to regulate infection as well as speculate about potential new mechanisms that may enhance successful replication. A joint appreciation of both tumour and viral biology will drive innovation for the next generation of reoviral mediated oncolytic therapy.
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Affiliation(s)
- Tarryn Bourhill
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Yoshinori Mori
- Department of Gastroenterology, Nagoya City West Medical Center, Kita-Ku, Nagoya 467-8601, Japan.
| | - Derrick E Rancourt
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Maya Shmulevitz
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
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48
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Melcher A. Oncolytic Virotherapy: Single Cycle Cures or Repeat Treatments? (Repeat Dosing Is Crucial!). Mol Ther 2018; 26:1875-1876. [PMID: 30017879 PMCID: PMC6094867 DOI: 10.1016/j.ymthe.2018.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Affiliation(s)
- Alan Melcher
- Institute of Cancer Research, Department of Radiotherapy and Imaging, London, UK.
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Phillips MB, Stuart JD, Rodríguez Stewart RM, Berry JT, Mainou BA, Boehme KW. Current understanding of reovirus oncolysis mechanisms. Oncolytic Virother 2018; 7:53-63. [PMID: 29942799 PMCID: PMC6005300 DOI: 10.2147/ov.s143808] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mammalian orthoreovirus (reovirus) is under development as a cancer virotherapy. Clinical trials demonstrate that reovirus-based therapies are safe and tolerated in patients with a wide variety of cancers. Although reovirus monotherapy has proven largely ineffective, reovirus sensitizes cancer cells to existing chemotherapeutic agents and radiation. Clinical trials are underway to test the efficacy of reovirus in combination with chemotherapeutic and radiation regimens and to evaluate the effectiveness of reovirus in conjunction with immunotherapies. Central to the use of reovirus to treat cancer is its capacity to directly kill cancer cells and alter the cellular environment to augment other therapies. Apoptotic cell death is a prominent mechanism of reovirus cancer cell killing. However, reoviruses can also kill cancer cells through nonapoptotic mechanisms. Here, we describe mechanisms of reovirus cancer cell killing, highlight how reovirus is used in combination with existing cancer treatments, and discuss what is known as to how reovirus modulates cancer immunotherapy.
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Affiliation(s)
- Matthew B Phillips
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | - Johnasha D Stuart
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | | | | | | | - Karl W Boehme
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
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Mahalingam D, Goel S, Aparo S, Patel Arora S, Noronha N, Tran H, Chakrabarty R, Selvaggi G, Gutierrez A, Coffey M, Nawrocki ST, Nuovo G, Mita MM. A Phase II Study of Pelareorep (REOLYSIN ®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma. Cancers (Basel) 2018; 10:E160. [PMID: 29799479 PMCID: PMC6025223 DOI: 10.3390/cancers10060160] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/16/2018] [Accepted: 05/17/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.
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Affiliation(s)
- Devalingam Mahalingam
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
- Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
| | - Sanjay Goel
- Montefiore Medical Center, New York, NY 10467, USA.
| | | | - Sukeshi Patel Arora
- Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
| | | | - Hue Tran
- Oncolytics Biotech Inc., Calgary, AB T2N 1X7, Canada.
| | | | | | | | | | - Steffan T Nawrocki
- Department of Medicine, Division of Translational and Regenerative Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Gerard Nuovo
- Comprehensive Cancer Center, Ohio State University, Columbus, OH and Phylogeny, Inc., Powell, OH 43065, USA.
| | - Monica M Mita
- Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA.
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