|
1
|
Azmal M, Miah MM, Prima FS, Paul JK, Haque ASNB, Ghosh A. Advances and challenges in cancer immunotherapy: Strategies for personalized treatment. Semin Oncol 2025; 52:152345. [PMID: 40305928 DOI: 10.1016/j.seminoncol.2025.152345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 05/02/2025]
Abstract
Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.
Collapse
Affiliation(s)
- Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Md Munna Miah
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Fatema Sultana Prima
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Jibon Kumar Paul
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Anm Shah Newaz Been Haque
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Ajit Ghosh
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Bartee E. Killing cancer quickly: inducing hyper-acute rejection of patient tumors. Cell Res 2025:10.1038/s41422-025-01099-3. [PMID: 40074797 DOI: 10.1038/s41422-025-01099-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025] Open
Affiliation(s)
- Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Spirito F, Nocini R, Mori G, Albanese M, Georgakopoulou EA, Sivaramakrishnan G, Khalil B, Špiljak B, Surya V, Mishra D, Chaurasia A. The Potential of Oncolytic Virotherapy in the Treatment of Head and Neck Cancer: A Comprehensive Review. Int J Mol Sci 2024; 25:12990. [PMID: 39684701 DOI: 10.3390/ijms252312990] [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: 11/21/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Head and neck cancer (HNC) represents a challenging oncological entity with significant morbidity and mortality rates. Despite advances in conventional therapies, including surgery, chemotherapy, and radiation therapy, the overall survival rates for advanced HNC remain suboptimal. In recent years, the emerging field of oncolytic virotherapy has gained attention as a promising therapeutic approach for various malignancies, including HNC. This review provides a comprehensive overview of the current understanding of oncolytic viruses (Ovs) in the context of HNC treatment, including their mechanisms of action, preclinical and clinical studies, challenges, and future directions. Future oncolytic virotherapy focuses on improving delivery and specificity through nanoparticle carriers and genetic modifications to enhance tumor targeting and immune response. Combining different OVs and integrating them with immunotherapies, such as checkpoint inhibitors, could overcome tumor resistance and improve outcomes. Personalized approaches and rigorous clinical trials are key to ensuring the safety and effectiveness of virotherapy in treating HNC.
Collapse
Affiliation(s)
- Francesca Spirito
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Riccardo Nocini
- Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, University of Verona, 37134 Verona, Italy
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Massimo Albanese
- Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, University of Verona, 37134 Verona, Italy
| | - Eleni A Georgakopoulou
- Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Basel Khalil
- Department of Basic Sciences, Faculty of Dentistry, University of Damascus, Damascus 30621, Syria
| | - Bruno Špiljak
- Department of Oral Medicine, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Varun Surya
- Department of Oral Pathology and Microbiology, Centre for Dental Educationand Research, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Deepika Mishra
- Department of Oral Pathology and Microbiology, Centre for Dental Educationand Research, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Akhilanand Chaurasia
- Department of Oral Medicine and Radiology, King George's Medical University, Lucknow 226003, India
| |
Collapse
|
|
6
|
Khan M, Dong Y, Ullah R, Li M, Huang Q, Hu Y, Yang L, Luo Z. Recent Advances in Bacterium-Based Therapeutic Modalities for Melanoma Treatment. Adv Healthc Mater 2024; 13:e2401076. [PMID: 39375965 DOI: 10.1002/adhm.202401076] [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: 03/21/2024] [Revised: 07/16/2024] [Indexed: 10/09/2024]
Abstract
Melanoma is one of the most severe skin cancer indications with rapid progression and a high risk of metastasis. However, despite the accumulated advances in melanoma treatment including adjuvant radiation, chemotherapy, and immunotherapy, the overall melanoma treatment efficacy in the clinics is still not satisfactory. Interestingly, bacterial therapeutics have demonstrated unique properties for tumor-related therapeutic applications, such as tumor-targeted motility, tailorable cytotoxicity, and immunomodulatory capacity of the tumor microenvironment, which have emerged as a promising platform for melanoma therapy. Indeed, the recent advances in genetic engineering and nanotechnologies have boosted the application potential of bacterium-based therapeutics for treating melanoma by further enhancing their tumor-homing, cell-killing, drug delivery, and immunostimulatory capacities. This review provides a comprehensive summary of the state-of-the-art bacterium-based anti-melanoma modalities, which are categorized according to their unique functional merits, including tumor-specific cytotoxins, tumor-targeted drug delivery platforms, and immune-stimulatory agents. Furthermore, a perspective is provided discussing the potential challenges and breakthroughs in this area. The insights in this review may facilitate the development of more advanced bacterium-based therapeutic modalities for improved melanoma treatment efficacy.
Collapse
Affiliation(s)
- Mubassir Khan
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yilong Dong
- Ruian People's Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325016, P. R. China
| | - Razi Ullah
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Lab for Vascular Implants College of Bioengineering Chongqing University, Chongqing, 400030, P. R. China
| | - Menghuan Li
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Qiping Huang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yan Hu
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Li Yang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| |
Collapse
|
|
7
|
Stilpeanu RI, Secara BS, Cretu-Stancu M, Bucur O. Oncolytic Viruses as Reliable Adjuvants in CAR-T Cell Therapy for Solid Tumors. Int J Mol Sci 2024; 25:11127. [PMID: 39456909 PMCID: PMC11508774 DOI: 10.3390/ijms252011127] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/28/2024] Open
Abstract
Although impactful scientific advancements have recently been made in cancer therapy, there remains an opportunity for future improvements. Immunotherapy is perhaps one of the most cutting-edge categories of therapies demonstrating potential in the clinical setting. Genetically engineered T cells express chimeric antigen receptors (CARs), which can detect signals expressed by the molecules present on the surface of cancer cells, also called tumor-associated antigens (TAAs). Their effectiveness has been extensively demonstrated in hematological cancers; therefore, these results can establish the groundwork for their applications on a wide range of requirements. However, the application of CAR-T cell technology for solid tumors has several challenges, such as the existence of an immune-suppressing tumor microenvironment and/or inadequate tumor infiltration. Consequently, combining therapies such as CAR-T cell technology with other approaches has been proposed. The effectiveness of combining CAR-T cell with oncolytic virus therapy, with either genetically altered or naturally occurring viruses, to target tumor cells is currently under investigation, with several clinical trials being conducted. This narrative review summarizes the current advancements, opportunities, benefits, and limitations in using each therapy alone and their combination. The use of oncolytic viruses offers an opportunity to address the existing challenges of CAR-T cell therapy, which appear in the process of trying to overcome solid tumors, through the combination of their strengths. Additionally, utilizing oncolytic viruses allows researchers to modify the virus, thus enabling the targeted delivery of specific therapeutic agents within the tumor environment. This, in turn, can potentially enhance the cytotoxic effect and therapeutic potential of CAR-T cell technology on solid malignancies, with impactful results in the clinical setting.
Collapse
MESH Headings
- Humans
- Neoplasms/therapy
- Neoplasms/immunology
- Oncolytic Viruses/genetics
- Oncolytic Viruses/immunology
- Immunotherapy, Adoptive/methods
- Oncolytic Virotherapy/methods
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Animals
- Tumor Microenvironment/immunology
- T-Lymphocytes/immunology
- Combined Modality Therapy/methods
- Adjuvants, Immunologic
- Antigens, Neoplasm/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
Collapse
Affiliation(s)
- Ruxandra Ilinca Stilpeanu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (B.S.S.)
| | - Bianca Stefania Secara
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (B.S.S.)
| | | | - Octavian Bucur
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (B.S.S.)
- Genomics Research and Development Institute, 020021 Bucharest, Romania
- Viron Molecular Medicine Institute, Boston, MA 02108, USA
| |
Collapse
|
|
8
|
Glauß S, Neumeyer V, Hanesch L, Marek J, Hartmann N, Wiedemann GM, Altomonte J. A Novel Chimeric Oncolytic Virus Mediates a Multifaceted Cellular Immune Response in a Syngeneic B16 Melanoma Model. Cancers (Basel) 2024; 16:3405. [PMID: 39410025 PMCID: PMC11475060 DOI: 10.3390/cancers16193405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. METHODS AND RESULTS We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. CONCLUSIONS Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Jennifer Altomonte
- Department of Internal Medicine II, Rechts der Isar Hospital, Technical University of Munich, 81675 Munich, Germany; (S.G.); (V.N.); (L.H.); (J.M.); (N.H.); (G.M.W.)
| |
Collapse
|
|
9
|
Valenzuela-Cardenas M, Fisher C, Bartee MY, Bartee E. IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200866. [PMID: 39290317 PMCID: PMC11407086 DOI: 10.1016/j.omton.2024.200866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/23/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024]
Abstract
Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune-related toxicities, which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes, both augmenting antitumor immune responses and decreasing systemic toxicities. We have shown recently that a doubly recombinant oncolytic myxoma virus that secretes a soluble version of PD1 as well as an interleukin-12 (IL-12) fusion protein (vPD1/IL-12) can cause potent regression of disseminated cancers. Here we show that, despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL-12 still results in systemic, IL-12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor α with tumor necrosis factor receptor 2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL-12-mediated toxicities to be alleviated through the use of US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) blockers such as etanercept.
Collapse
Affiliation(s)
| | - Carrie Fisher
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Mee Y Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| |
Collapse
|
|
10
|
Gujar S, Pol JG, Kumar V, Lizarralde-Guerrero M, Konda P, Kroemer G, Bell JC. Tutorial: design, production and testing of oncolytic viruses for cancer immunotherapy. Nat Protoc 2024; 19:2540-2570. [PMID: 38769145 DOI: 10.1038/s41596-024-00985-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 02/12/2024] [Indexed: 05/22/2024]
Abstract
Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor immunity. Furthermore, OVs can be used in combination with established or upcoming immunotherapeutic agents, especially immune checkpoint inhibitors, to efficiently target a wide range of malignancies. The development of OV-based therapy involves three major steps before clinical evaluation: design, production and preclinical testing. OVs can be designed as natural or engineered strains and subsequently selected for their ability to kill a broad spectrum of cancer cells rather than normal, healthy cells. OV selection is further influenced by multiple factors, such as the availability of a specific viral platform, cancer cell permissivity, the need for genetic engineering to render the virus non-pathogenic and/or more effective and logistical considerations around the use of OVs within the laboratory or clinical setting. Selected OVs are then produced and tested for their anticancer potential by using syngeneic, xenograft or humanized preclinical models wherein immunocompromised and immunocompetent setups are used to elucidate their direct oncolytic ability as well as indirect immunotherapeutic potential in vivo. Finally, OVs demonstrating the desired anticancer potential progress toward translation in patients with cancer. This tutorial provides guidelines for the design, production and preclinical testing of OVs, emphasizing considerations specific to OV technology that determine their clinical utility as cancer immunotherapy agents.
Collapse
Affiliation(s)
- Shashi Gujar
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Jonathan G Pol
- INSERM, U1138, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Cité, Paris, France
- Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Vishnupriyan Kumar
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Manuela Lizarralde-Guerrero
- INSERM, U1138, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Cité, Paris, France
- Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Ecole Normale Supérieure de Lyon, Lyon, France
| | - Prathyusha Konda
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Guido Kroemer
- INSERM, U1138, Paris, France.
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
- Université Paris Cité, Paris, France.
- Sorbonne Université, Paris, France.
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France.
- Institut Universitaire de France, Paris, France.
- Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - John C Bell
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
- Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
| |
Collapse
|
|
11
|
Webb MJ, Sangsuwannukul T, van Vloten J, Evgin L, Kendall B, Tonne J, Thompson J, Metko M, Moore M, Chiriboga Yerovi MP, Olin M, Borgatti A, McNiven M, Monga SPS, Borad MJ, Melcher A, Roberts LR, Vile R. Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response. Nat Commun 2024; 15:5442. [PMID: 38937436 PMCID: PMC11211353 DOI: 10.1038/s41467-024-49286-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 05/29/2024] [Indexed: 06/29/2024] Open
Abstract
Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
Collapse
Affiliation(s)
- Mason J Webb
- Department of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Jacob van Vloten
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Laura Evgin
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z1L3, Canada
- Michael Smith Genome Sciences Department, BC Cancer Research Institute, Vancouver, BC, V5Z1L3, Canada
| | - Benjamin Kendall
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jason Tonne
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jill Thompson
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Muriel Metko
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Madelyn Moore
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA
| | | | - Michael Olin
- Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Antonella Borgatti
- Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN, 55108, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA
- Clinical Investigation Center, University of Minnesota, St. Paul, MN, 55108, USA
| | - Mark McNiven
- Mayo Center for Biomedical Discovery, Mayo Clinic, Rochester, MN, 55905, USA
| | - Satdarshan P S Monga
- Pittsburgh Liver Institute, University of Pittsburgh and UPMC, Pittsburgh, PA, 15261, USA
| | - Mitesh J Borad
- Department of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA
| | - Alan Melcher
- Division of Radiotherapy and Imaging, Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK
| | - Lewis R Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
- Joan Reece Department of Immuno-oncology, King's College London, London, UK.
| |
Collapse
|
|
12
|
Vile R, Webb M, van Vloten J, Evgin L, Sangsuwannukul T, Kendall B, Tonne J, Thompson J, Metko M, Moore M, Yerovi MC, McNiven M, Monga S, Borad M, Roberts L. Chimerization of the Anti-Viral CD8 + T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy. RESEARCH SQUARE 2023:rs.3.rs-3576281. [PMID: 38045348 PMCID: PMC10690324 DOI: 10.21203/rs.3.rs-3576281/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC. Since HCC standard of care atezolizumab/bevacizumab incorporates ICI, we tested the hypothesis that pro-inflammatory VSV-IFNß would recruit, prime, and activate anti-tumor T cells, whose activity anti-PD-L1 ICI would potentiate. However, in a partially anti-PD-L1-responsive model of HCC, addition of VSV-IFNß abolished anti-PD-L1 therapy. Cytometry by Time of Flight showed that VSV-IFNß expanded dominant anti-viral effector CD8 T cells with concomitant, relative disappearance of anti-tumor T cell populations which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, the potent anti-viral response became amalgamated with an anti-tumor T cell response generating highly significant cures compared to anti-PD-L1 ICI alone. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, by chimerizing anti-viral and anti-tumor T cell responses through encoding tumor antigens within the virus, oncolytic virotherapy can be purposed for very effective immune driven tumor clearance and can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
Collapse
|
|
13
|
Webb MJ, Kottke T, Kendall BL, Swanson J, Uzendu C, Tonne J, Thompson J, Metko M, Moore M, Borad M, Roberts L, Diaz RM, Olin M, Borgatti A, Vile R. Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses. Mol Ther Oncolytics 2023; 29:129-142. [PMID: 37313455 PMCID: PMC10258242 DOI: 10.1016/j.omto.2023.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/18/2023] [Indexed: 06/15/2023] Open
Abstract
In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.
Collapse
Affiliation(s)
- Mason J. Webb
- Division of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Timothy Kottke
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Jack Swanson
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Chisom Uzendu
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Jason Tonne
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Jill Thompson
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Muriel Metko
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Madelyn Moore
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Mitesh Borad
- Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Lewis Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Rosa M. Diaz
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Michael Olin
- Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Antonella Borgatti
- Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55108, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Clinical Investigation Center, University of Minnesota, St. Paul, MN 55108, USA
| | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| |
Collapse
|
|
14
|
Ottolino-Perry K, Mealiea D, Sellers C, Acuna SA, Angarita FA, Okamoto L, Scollard D, Ginj M, Reilly R, McCart JA. Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis. Mol Ther Oncolytics 2023; 29:44-58. [PMID: 37180034 PMCID: PMC10173076 DOI: 10.1016/j.omto.2023.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/05/2023] [Indexed: 05/15/2023] Open
Abstract
Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers.
Collapse
Affiliation(s)
- Kathryn Ottolino-Perry
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
| | - David Mealiea
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
| | - Clara Sellers
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
| | - Sergio A. Acuna
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
| | - Fernando A. Angarita
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
| | - Lili Okamoto
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
| | - Deborah Scollard
- STTARR, Radiation Medicine Program, Princess Margaret Hospital, UHN, 610 University Avenue, M5G 2C1 Toronto, ON, Canada
| | - Mihaela Ginj
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
| | - Raymond Reilly
- Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, M5S 3M2 Toronto, ON, Canada
| | - J. Andrea McCart
- Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8 Toronto, ON, Canada
- Department of Surgery, Mount Sinai Hospital and University of Toronto, 600 University Avenue, M5G 1X5 Toronto, ON, Canada
- Corresponding author: Dave Mealiea, Room 1225, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
| |
Collapse
|
|
15
|
Huang Z, Guo H, Lin L, Li S, Yang Y, Han Y, Huang W, Yang J. Application of oncolytic virus in tumor therapy. J Med Virol 2023; 95:e28729. [PMID: 37185868 DOI: 10.1002/jmv.28729] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 05/17/2023]
Abstract
Oncolytic viruses (OVs) can selectively kill tumor cells without affecting normal cells, as well as activate the innate and adaptive immune systems in patients. Thus, they have been considered as a promising measure for safe and effective cancer treatment. Recently, a few genetically engineered OVs have been developed to further improve the effect of tumor elimination by expressing specific immune regulatory factors and thus enhance the body's antitumor immunity. In addition, the combined therapies of OVs and other immunotherapies have been applied in clinical. Although there are many studies on this hot topic, a comprehensive review is missing on illustrating the mechanisms of tumor clearance by OVs and how to modify engineered OVs to further enhance their antitumor effects. In this study, we provided a review on the mechanisms of immune regulatory factors in OVs. In addition, we reviewed the combined therapies of OVs with other therapies including radiotherapy and CAR-T or TCR-T cell therapy. The review is useful in further generalize the usage of OV in cancer treatment.
Collapse
Affiliation(s)
- Zhijian Huang
- Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Hongen Guo
- Department of Dermatology, Dermatology Hospital of Fuzhou, Fujian, Fuzhou, China
| | - Lin Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Shixiong Li
- Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yong Yang
- Department of Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yuanyuan Han
- Center of Tree Shrew Germplasm Resources, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Weiwei Huang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jialiang Yang
- Geneis Beijing Co., Ltd, Beijing, China
- Academician Workstation, Changsha Medical University, Changsha, China
| |
Collapse
|
|
16
|
Lin ZZ, Hu MCT, Hsu C, Wu YM, Lu YS, Ho JAA, Yeh SH, Chen PJ, Cheng AL. Synergistic efficacy of telomerase-specific oncolytic adenoviral therapy and histone deacetylase inhibition in human hepatocellular carcinoma. Cancer Lett 2023; 556:216063. [PMID: 36669725 DOI: 10.1016/j.canlet.2023.216063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 12/08/2022] [Accepted: 01/10/2023] [Indexed: 01/20/2023]
Abstract
The telomerase-specific oncolytic adenovirus Telomelysin and the histone deacetylase inhibitor AR42 have demonstrated anticancer effects in preclinical models of human hepatocellular carcinoma (HCC). However, the clinical development of Telomelysin may be hindered by human antiviral immunity and tumor resistance. Combining oncolytic and epigenetic therapies is a viable approach for treating various cancers. This study investigated the potential synergism of Telomelysin and AR42 and the relevant underlying mechanisms. Telomelysin and AR42 exhibited synergistic antiproliferative effects in human HCC models in vitro and in vivo. Apoptosis induced by Telomelysin was significantly enhanced by AR42 in both PLC5 and Hep3B HCC cells. AR42 treatment unexpectedly attenuated the expression of the coxsackievirus and adenovirus receptor and the mRNA levels of human telomerase reverse transcriptase, which may be positively associated with the cytotoxicity of Telomelysin. Meanwhile, the cellular antiviral interferon response was not altered by AR42 treatment. Further, we found that Telomelysin enhanced Akt phosphorylation in HCC cells. AR42 reduced Telomelysin-induced phospho-Akt activation and enhanced Telomelysin-induced apoptosis. The correlation of Akt phosphorylation with drug-induced apoptosis was validated in HCC cells with upregulated or downregulated Akt signaling. Combination therapy with Telomelysin and AR42 demonstrated synergistic anti-HCC efficacy. Clinical trials investigating this new combination regimen are warranted.
Collapse
Affiliation(s)
- Zhong-Zhe Lin
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | | | - Chiun Hsu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yen-Shen Lu
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ja-An Annie Ho
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ann-Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
| |
Collapse
|
|
17
|
Yang K, Feng S, Luo Z. Oncolytic Adenovirus, a New Treatment Strategy for Prostate Cancer. Biomedicines 2022; 10:biomedicines10123262. [PMID: 36552019 PMCID: PMC9775875 DOI: 10.3390/biomedicines10123262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Prostate cancer is the most common cancer and one of the leading causes of cancer mortality in males. Androgen-deprivation therapy (ADT) is an effective strategy to inhibit tumour growth at early stages. However, 10~50% of cases are estimated to progress to metastatic castration-resistant prostate cancer (mCRPC) which currently lacks effective treatments. Clinically, salvage treatment measures, such as endocrine therapy and chemotherapy, are mostly used for advanced prostate cancer, but their clinical outcomes are not ideal. When the existing clinical therapeutic methods can no longer inhibit the development of advanced prostate cancer, human adenovirus (HAdV)-based gene therapy and viral therapy present promising effects. Pre-clinical studies have shown its powerful oncolytic effect, and clinical studies are ongoing to further verify its effect and safety in prostate cancer treatment. Targeting the prostate by HAdV alone or in combination with radiotherapy and chemotherapy sheds light on patients with castration-resistant and advanced prostate cancer. This review summarizes the advantages of oncolytic virus-mediated cancer therapy, strategies of HAdV modification, and existing preclinical and clinical investigations of HAdV-mediated gene therapy to further evaluate the potential of oncolytic adenovirus in prostate cancer treatment.
Collapse
Affiliation(s)
- Kaiyi Yang
- Department of Urology, Xiangya Hospital, Central South University, Changsha 410008, China
- Correspondence: (K.Y.); (Z.L.)
| | - Shenghui Feng
- Provincial Key Laboratory of Tumour Pathogens and Molecular Pathology, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhijun Luo
- Provincial Key Laboratory of Tumour Pathogens and Molecular Pathology, Queen Mary School, Nanchang University, Nanchang 330031, China
- Correspondence: (K.Y.); (Z.L.)
| |
Collapse
|
|
18
|
Wang G, Liu Y, Liu S, Lin Y, Hu C. Oncolyic Virotherapy for Prostate Cancer: Lighting a Fire in Winter. Int J Mol Sci 2022; 23:12647. [PMID: 36293504 PMCID: PMC9603894 DOI: 10.3390/ijms232012647] [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: 07/20/2022] [Revised: 09/30/2022] [Accepted: 10/07/2022] [Indexed: 11/11/2022] Open
Abstract
As the most common cancer of the genitourinary system, prostate cancer (PCa) is a global men's health problem whose treatments are an urgent research issue. Treatment options for PCa include active surveillance (AS), surgery, endocrine therapy, chemotherapy, radiation therapy, immunotherapy, etc. However, as the cancer progresses, the effectiveness of treatment options gradually decreases, especially in metastatic castration-resistant prostate cancer (mCRPC), for which there are fewer therapeutic options and which have a shorter survival period and worse prognosis. For this reason, oncolytic viral therapy (PV), with its exceptional properties of selective tumor killing, relatively good safety in humans, and potential for transgenic delivery, has attracted increasing attention as a new form of anti-tumor strategy for PCa. There is growing evidence that OV not only kills tumor cells directly by lysis but can also activate anticancer immunity by acting on the tumor microenvironment (TME), thereby preventing tumor growth. In fact, evidence of the efficacy of this strategy has been observed since the late 19th century. However, subsequently, interest waned. The renewed interest in this therapy was due to advances in biotechnological methods and innovations at the end of the 20th century, which was also the beginning of PCa therapy with OV. Moreover, in combination with chemotherapy, radiotherapy, gene therapy or immunotherapy, OV viruses can have a wide range of applications and can provide an effective therapeutic result in the treatment of PCa.
Collapse
Affiliation(s)
- Gongwei Wang
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ying Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Shuoru Liu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuan Lin
- Department of Pharmacology, Sun Yat-sen University, Guangzhou 528478, China
| | - Cheng Hu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| |
Collapse
|
|
19
|
Therapeutic Efficacy of Oncolytic Viruses in Fighting Cancer: Recent Advances and Perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3142306. [PMID: 35910836 PMCID: PMC9337963 DOI: 10.1155/2022/3142306] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/20/2022] [Accepted: 05/26/2022] [Indexed: 12/22/2022]
Abstract
Immunotherapy is at the cutting edge of modern cancer treatment. Innovative medicines have been developed with varying degrees of success that target all aspects of tumor biology: tumors, niches, and the immune system. Oncolytic viruses (OVs) are a novel and potentially immunotherapeutic approach for cancer treatment. OVs reproduce exclusively in cancer cells, causing the tumor mass to lyse. OVs can also activate the immune system in addition to their primary activity. Tumors create an immunosuppressive environment by suppressing the immune system’s ability to respond to tumor cells. By injecting OVs into the tumor, the immune system is stimulated, allowing it to generate a robust and long-lasting response against the tumor. The essential biological properties of oncolytic viruses, as well as the underlying mechanisms that enable their usage as prospective anticancer medicines, are outlined in this review. We also discuss the increased efficacy of virotherapy when combined with other cancer medications.
Collapse
|
|
20
|
Valenzuela-Cardenas M, Gowan C, Dryja P, Bartee MY, Bartee E. TNF blockade enhances the efficacy of myxoma virus-based oncolytic virotherapy. J Immunother Cancer 2022; 10:e004770. [PMID: 35577502 PMCID: PMC9114862 DOI: 10.1136/jitc-2022-004770] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Oncolytic virotherapy (OV) represents a method to treat a variety of solid tumors by inducing antitumor immune responses. While this therapy has been extremely efficacious in preclinical models, translating these successes into human patients has proven challenging. One of the major reasons for these failures is the existence of immune-regulatory mechanisms, which dampen the efficacy of virally induced antitumor immunity. Unfortunately, the full extent of these immune-regulatory pathways remains unclear. METHODS To address this issue, we generated a doubly recombinant, oncolytic myxoma virus which expresses both a soluble fragment of programmed cell death protein 1 (PD1) and an interleukin 12 (IL-12) fusion protein (vPD1/IL-12 (virus-expressing PD1 and IL-12)). We then tested the molecular impact and therapeutic efficacy of this construct in multiple models of disseminated disease to identify novel pathways, which are associated with poor therapeutic outcomes. RESULTS Our results demonstrate that vPD1/IL-12 causes robust inflammation during therapy including inducing high levels of tumor necrosis factor (TNF). Surprisingly, although expression of TNF has generally been assumed to be beneficial to OV, the presence of this TNF appears to inhibit therapeutic efficacy by reducing intratumoral T-cell viability. Likely because of this, disruption of the TNF pathway, either through genetic knockout or antibody-based blockade, significantly enhances the overall outcomes of vPD1/IL-12-based therapy that allows for the generation of complete cures in normally non-responsive models. CONCLUSIONS These data suggest that some aspects of OV-induced inflammation might represent a double-edged sword during therapy and that specific blockade of TNF might enhance the efficacy of these treatments.
Collapse
Affiliation(s)
- Miriam Valenzuela-Cardenas
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Cody Gowan
- Division of Nephrology and Hypertension, Mayo Clinical, Jacksonville, Florida, USA
| | - Parker Dryja
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Mee Y Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| |
Collapse
|
|
21
|
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.
Collapse
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.
| |
Collapse
|
|
22
|
Zarezadeh Mehrabadi A, Roozbahani F, Ranjbar R, Farzanehpour M, Shahriary A, Dorostkar R, Esmaeili Gouvarchin Ghaleh H. Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses. World J Surg Oncol 2022; 20:16. [PMID: 35027068 PMCID: PMC8756705 DOI: 10.1186/s12957-021-02486-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background Cancer is one of the critical issues of the global health system with a high mortality rate even with the available therapies, so using novel therapeutic approaches to reduce the mortality rate and increase the quality of life is sensed more than ever. Main body CAR-T cell therapy and oncolytic viruses are innovative cancer therapeutic approaches with fewer complications than common treatments such as chemotherapy and radiotherapy and significantly improve the quality of life. Oncolytic viruses can selectively proliferate in the cancer cells and destroy them. The specificity of oncolytic viruses potentially maintains the normal cells and tissues intact. T-cells are genetically manipulated and armed against the specific antigens of the tumor cells in CAR-T cell therapy. Eventually, they are returned to the body and act against the tumor cells. Nowadays, virology and oncology researchers intend to improve the efficacy of immunotherapy by utilizing CAR-T cells in combination with oncolytic viruses. Conclusion Using CAR-T cells along with oncolytic viruses can enhance the efficacy of CAR-T cell therapy in destroying the solid tumors, increasing the permeability of the tumor cells for T-cells, reducing the disturbing effects of the immune system, and increasing the success chance in the treatment of this hazardous disease. In recent years, significant progress has been achieved in using oncolytic viruses alone and in combination with other therapeutic approaches such as CAR-T cell therapy in pre-clinical and clinical investigations. This principle necessitates a deeper consideration of these treatment strategies. This review intends to curtly investigate each of these therapeutic methods, lonely and in combination form. We will also point to the pre-clinical and clinical studies about the use of CAR-T cell therapy combined with oncolytic viruses.
Collapse
Affiliation(s)
- Ali Zarezadeh Mehrabadi
- Immunology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdieh Farzanehpour
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Shahriary
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ruhollah Dorostkar
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
23
|
Chen XT, Dai SY, Zhan Y, Yang R, Chen DQ, Li Y, Zhou EQ, Dong R. Progress of oncolytic virotherapy for neuroblastoma. Front Pediatr 2022; 10:1055729. [PMID: 36467495 PMCID: PMC9716318 DOI: 10.3389/fped.2022.1055729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022] Open
Abstract
As a neuroendocrine tumor derived from the neural crest, neuroblastoma (NB) is the most common extracranial solid tumor in children. The prognosis in patients with low- and intermediate-risk NB is favorable while that in high-risk patients is often detrimental. However, the management of the considerably large proportion of high-risk patients remains challenging in clinical practice. Among various new approaches, oncolytic virus (OV) therapy offers great advantages in tumor treatment, especially for high-risk NB. Genetic modified OVs can target NB specifically without affecting normal tissue and avoid the widespread drug resistance issue in anticancer monotherapy. Meanwhile, its safety profile provides great potential in combination therapy with chemo-, radio-, and immunotherapy. The therapeutic efficacy of OV for NB is impressive from bench to bedside. The effectiveness and safety of OVs have been demonstrated and reported in studies on children with NB. Furthermore, clinical trials on some OVs (Celyvir, Pexa-Vec (JX-594) and Seneca Valley Virus (NTX-010)) have reported great results. This review summarizes the latest evidence in the therapeutic application of OVs in NB, including those generated in cell lines, animal models and clinical trials.
Collapse
Affiliation(s)
- Xiao-Tong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Shu-Yang Dai
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yong Zhan
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Ran Yang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - De-Qian Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yi Li
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - En-Qing Zhou
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| |
Collapse
|
|
24
|
Goradel NH, Alizadeh A, Hosseinzadeh S, Taghipour M, Ghesmati Z, Arashkia A, Negahdari B. Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses. Future Oncol 2021; 18:245-259. [PMID: 34821517 DOI: 10.2217/fon-2021-0802] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.
Collapse
Affiliation(s)
- Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezoo Alizadeh
- Department of Biochemistry & Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Shahnaz Hosseinzadeh
- Department of Microbiology & Immunology, Faculty of Medicine, Ardabil University of Medical Sciences, Iran
| | - Mitra Taghipour
- Department of Biotechnology, Faculty of Agriculture & Natural Resources, Imam Khomeini International University, Qazvin, Iran
| | - Zeinab Ghesmati
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Arashkia
- Department of Molecular Virology, Pasteur Institute of Iran, Tehran, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
25
|
The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13225687. [PMID: 34830842 PMCID: PMC8616105 DOI: 10.3390/cancers13225687] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/27/2021] [Accepted: 11/08/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Multiple myeloma is a type of blood cancer caused by the uncontrolled growth of antibody producing B cells (known as plasma cells) that reside in the bone marrow. It is classed as a largely incurable cancer as whilst patients respond well to initial chemotherapy treatments, unfortunately after periods of disease remission, relapse usually occurs with the emergence of chemotherapy resistance. Therefore, there is a need for new approaches that not only reduce tumour load but also prevent tumour relapse. Oncolytic viruses (OVs) (tumour killing viruses) are being explored as a therapy for various cancers, including multiple myeloma. This review discusses the use of OVs in myeloma in preclinical model systems and early phase clinical trials, and discusses some of the hurdles involved in the translation to myeloma patients. Abstract Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the bone marrow. Current anti-myeloma therapies (conventional chemotherapies, immunomodulatory drugs i.e., thalidomide and its’ analogues, proteasome inhibitors, monoclonal antibodies, and radiotherapy) initially substantially debulk tumour burden, but after a period of remission ‘plateau phase’ disease invariably relapses due to tumour recrudescence from foci of minimal residual disease (MRD) and accumulating drug resistance. Therefore, there is a compelling clinical need for the development of novel treatment regimens to target MRD and effectively eliminate all remaining tumour cells. This review will discuss the potential use of oncolytic virus (OV) therapies in the treatment of myeloma. Specifically, it will focus on preclinical studies using DNA viruses (adenovirus (Ad), vaccinia virus (VV), myxoma virus (MYXV), and herpes simplex virus (HSV)), RNA viruses (reovirus (reo), coxsackie virus, measles virus (MV) and bovine viral diarrhoea virus (BVDV), and vesicular stomatitis virus (VSV)), and on four types of viruses (VV, reo, MV-NIS and VSV-IFNβ-NIS) that have been assessed clinically in a small number of myeloma patients.
Collapse
|
|
26
|
The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors. NANOMATERIALS 2021; 11:nano11113018. [PMID: 34835785 PMCID: PMC8623458 DOI: 10.3390/nano11113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
Collapse
|
|
27
|
Miyajima N, Ragab Eissa I, Abdelmoneim M, Naoe Y, Ichinose T, Matsumura S, Bustos-Villalobos I, Mukoyama N, Morimoto D, Shibata M, Takeuchi D, Tsunoda N, Kikumori T, Tanaka M, Kodera Y, Kasuya H. S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model. NAGOYA JOURNAL OF MEDICAL SCIENCE 2021; 83:683-696. [PMID: 34916713 PMCID: PMC8648537 DOI: 10.18999/nagjms.83.4.683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/21/2021] [Indexed: 11/11/2022]
Abstract
Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8+ T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8+ T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.
Collapse
Affiliation(s)
- Noriyuki Miyajima
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
,Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Ibrahim Ragab Eissa
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
,Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Mohamed Abdelmoneim
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
,Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Yoshinori Naoe
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
| | - Toru Ichinose
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
| | - Shigeru Matsumura
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
| | - Itzel Bustos-Villalobos
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
| | - Nobuaki Mukoyama
- Department of Otolaryngology Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Daishi Morimoto
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Masahiro Shibata
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Dai Takeuchi
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Nobuyuki Tsunoda
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Toyone Kikumori
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | | | - Yasuhiro Kodera
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Hideki Kasuya
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya Japan
| |
Collapse
|
|
28
|
Alekseenko I, Kuzmich A, Kondratyeva L, Kondratieva S, Pleshkan V, Sverdlov E. Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement. Int J Mol Sci 2021; 22:ijms22179376. [PMID: 34502287 PMCID: PMC8430744 DOI: 10.3390/ijms22179376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 11/16/2022] Open
Abstract
Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of time (over 25 years) since the first mention of this method, GDEPT has not yet reached the clinic. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. The advent of checkpoint immunotherapy has yielded new highly promising avenues of study in cancer therapy. For such therapy, it seems reasonable to use combinations of different immunomodulators alongside traditional methods, such as chemotherapy and radiotherapy, as well as GDEPT. In this review, we focused on non-viral gene immunotherapy systems combining the intratumoral production of toxins diffused by GDEPT and immunomodulatory molecules. Special attention was paid to the applications and mechanisms of action of the granulocyte-macrophage colony-stimulating factor (GM–CSF), a cytokine that is widely used but shows contradictory effects. Another method to enhance the formation of stable immune responses in a tumor, the use of danger signals, is also discussed. The process of dying from GDEPT cancer cells initiates danger signaling by releasing damage-associated molecular patterns (DAMPs) that exert immature dendritic cells by increasing antigen uptake, maturation, and antigen presentation to cytotoxic T-lymphocytes. We hypothesized that the combined action of this danger signal and GM–CSF issued from the same dying cancer cell within a limited space would focus on a limited pool of immature dendritic cells, thus acting synergistically and enhancing their maturation and cytotoxic T-lymphocyte attraction potential. We also discuss the problem of enhancing the cancer specificity of the combined GDEPT–GM–CSF–danger signal system by means of artificial cancer specific promoters or a modified delivery system.
Collapse
Affiliation(s)
- Irina Alekseenko
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
- Institute of Oncogynecology and Mammology, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Correspondence: (I.A.); (E.S.)
| | - Alexey Kuzmich
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Liya Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Sofia Kondratieva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Victor Pleshkan
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Eugene Sverdlov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Correspondence: (I.A.); (E.S.)
| |
Collapse
|
|
29
|
Hofman L, Lawler SE, Lamfers MLM. The Multifaceted Role of Macrophages in Oncolytic Virotherapy. Viruses 2021; 13:v13081570. [PMID: 34452439 PMCID: PMC8402704 DOI: 10.3390/v13081570] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/16/2022] Open
Abstract
One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host’s immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival.
Collapse
Affiliation(s)
- Laura Hofman
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands;
| | - Sean E. Lawler
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA;
| | - Martine L. M. Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands;
- Correspondence: ; Tel.: +31-010-703-5993
| |
Collapse
|
|
30
|
Warricker F, Khakoo SI, Blunt MD. The role of NK cells in oncolytic viral therapy: a focus on hepatocellular carcinoma. JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS 2021; 5:304-322. [PMID: 34888493 PMCID: PMC7612080 DOI: 10.20517/jtgg.2021.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Natural killer (NK) cells have a key role in host anti-tumour immune responses via direct killing of tumour cells and promotion of adaptive immune responses. They are therefore attractive targets to promote the anti-tumour efficacy of oncolytic viral therapies. However, NK cells are also potent components of the host anti-viral immune response, and therefore have the potential for detrimental anti-viral responses, limiting the spread and persistence of oncolytic viruses. Oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma (HCC), a leading cause of cancer-related death with a high unmet clinical need. In this review, we highlight the role of NK cells in oncolytic virus therapy, their potential for improving treatment options for patients with HCC, and discuss current and potential strategies targeting NK cells in combination with oncolytic viral therapies.
Collapse
Affiliation(s)
- Frazer Warricker
- Clinical and Experimental Sciences Unit, University of Southampton, Southampton SO16 6YD, UK
| | - Salim I Khakoo
- Clinical and Experimental Sciences Unit, University of Southampton, Southampton SO16 6YD, UK
| | - Matthew D Blunt
- Clinical and Experimental Sciences Unit, University of Southampton, Southampton SO16 6YD, UK
| |
Collapse
|
|
31
|
Vile RG, Melcher A, Pandha H, Harrington KJ, Pulido JS. APOBEC and Cancer Viroimmunotherapy: Thinking the Unthinkable. Clin Cancer Res 2021; 27:3280-3290. [PMID: 33558423 PMCID: PMC8281496 DOI: 10.1158/1078-0432.ccr-20-1888] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/25/2020] [Accepted: 01/19/2021] [Indexed: 01/21/2023]
Abstract
The apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) family protects against infection by degrading incoming viral genomes through cytosine deamination. Here, we review how the potential to unleash these potent DNA mutagens comes at a price as APOBEC DNA mutagenesis can contribute to development of multiple types of cancer. In addition, because viral infection induces its expression, APOBEC is seen as the enemy of oncolytic virotherapy through mutation of the viral genome and by generating virotherapy-resistant tumors. Therefore, overall APOBEC in cancer has received very poor press. However, we also speculate how there may be silver linings to the storm clouds (kataegis) associated with APOBEC activity. Thus, although mutagenic genomic chaos promotes emergence of ever more aggressive subclones, it also provides significant opportunity for cytotoxic and immune therapies. In particular, the superpower of cancer immunotherapy derives in part from mutation, wherein generation of tumor neoantigens-neoantigenesis-exposes tumor cells to functional T-cell repertoires, and susceptibility to immune checkpoint blockade. Moreover, APOBECs may be able to induce suprathreshold levels of cellular mutation leading to mitotic catastrophe and direct tumor cell killing. Finally, we discuss the possibility that linking predictable APOBEC-induced mutation with escape from specific frontline therapies could identify mutated molecules/pathways that can be targeted with small molecules and/or immunotherapies in a Trap and Ambush strategy. Together, these considerations lead to the counterintuitive hypothesis that, instead of attempting to expunge and excoriate APOBEC activity in cancer therapy, it might be exploited-and even, counterintuitively, encouraged.
Collapse
Affiliation(s)
- Richard G Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Alan Melcher
- The Institute of Cancer Research/Royal Marsden, National Institute for Health Research Biomedical Research Centre, London, United Kingdom
| | - Hardev Pandha
- Surrey Cancer Research Institute, Faculty of Health and Medical Sciences, University of Surrey Guildford, Surrey, United Kingdom
| | - Kevin J Harrington
- The Institute of Cancer Research/Royal Marsden, National Institute for Health Research Biomedical Research Centre, London, United Kingdom
| | - Jose S Pulido
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
- Will's Eye Hospital, Philadelphia, Pennsylvania
| |
Collapse
|
|
32
|
Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells. Cancers (Basel) 2021; 13:cancers13061287. [PMID: 33799381 PMCID: PMC7999647 DOI: 10.3390/cancers13061287] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Proteins secreted by cancer cells in response to oncolytic virus anti-tumor therapy constitute the instructions for the immune cells. Yet as there are hundreds of proteins, including those encapsulated in vesicles, whose message drives the mobilization of immune cells, we aimed to decipher the instruction sent by cancer cells in response to therapy. Searching the cataloged vesicle and vesicle-free secreted proteins, we found that the proteins associated with the favorable survival of brain cancer patients were those that have the power to mobilize the immune cells. Thus, this approach established cancer-secreted contributors to the immune–therapeutic effect of the oncolytic virus. Abstract Oncolytic virus (OV) therapy, which is being tested in clinical trials for glioblastoma, targets cancer cells, while triggering immune cells. Yet OV sensitivity varies from patient to patient. As OV therapy is regarded as an anti-tumor vaccine, by making OV-infected cancer cells secrete immunogenic proteins, linking these proteins to transcriptome would provide a measuring tool to predict their sensitivity. A set of six patient-derived glioblastoma cells treated ex-vivo with herpes simplex virus type 1 (HSV1) modeled a clinical setting of OV infection. The cellular transcriptome and secreted proteome (separated into extracellular vesicles (EV) and EV-depleted fractions) were analyzed by gene microarray and mass-spectroscopy, respectively. Data validation and in silico analysis measured and correlated the secretome content with the response to infection and patient survival. Glioblastoma cells reacted to the OV infection in a seemingly dissimilar fashion, but their transcriptomes changed in the same direction. Therefore, the upregulation of transcripts encoding for secreted proteins implies a common thread in the response of cancer cells to infection. Indeed, the OV-driven secretome is linked to the immune response. While these proteins have distinct membership in either EV or EV-depleted fractions, it is their co-secretion that augments the immune response and associates with favorable patient outcomes.
Collapse
|
|
33
|
McKenna MK, Englisch A, Brenner B, Smith T, Hoyos V, Suzuki M, Brenner MK. Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity. Mol Ther 2021; 29:1808-1820. [PMID: 33571680 DOI: 10.1016/j.ymthe.2021.02.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 01/05/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022] Open
Abstract
The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.
Collapse
Affiliation(s)
- Mary K McKenna
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Alexander Englisch
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Benjamin Brenner
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208, USA
| | - Tyler Smith
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Valentina Hoyos
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Masataka Suzuki
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Malcolm K Brenner
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA.
| |
Collapse
|
|
34
|
Combining vanadyl sulfate with Newcastle disease virus potentiates rapid innate immune-mediated regression with curative potential in murine cancer models. MOLECULAR THERAPY-ONCOLYTICS 2021; 20:306-324. [PMID: 33614913 PMCID: PMC7868934 DOI: 10.1016/j.omto.2021.01.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/16/2021] [Indexed: 02/08/2023]
Abstract
The avian paramyxovirus, Newcastle disease virus (NDV), is a promising oncolytic agent that has been shown to be safe and effective in a variety of pre-clinical cancer models and human clinical trials. NDV preferentially replicates in tumor cells due to signaling defects in apoptotic and antiviral pathways acquired during the transformation process and is a potent immunostimulatory agent. However, when used as a monotherapy NDV lacks the ability to consistently generate durable remissions. Here we investigate the use of viral sensitizer-mediated combination therapy to enhance the anti-neoplastic efficacy of NDV. Intratumoral injection of vanadyl sulfate, a pan-inhibitor of protein tyrosine phosphatases, in combination with NDV significantly increased the number and activation status of natural killer (NK) cells in the tumor microenvironment, concomitant with increased expression of interferon-β, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1, leading to rapid tumor regression and long-term cures in mice bearing syngeneic B16-F10 melanomas. The anti-tumor efficacy of this combination therapy was abrogated when NK cells were depleted and when interferon-β expression was transiently suppressed. Tumor-specific CD8+ T cell responses were not detected, nor were mice whose tumors regressed protected from re-challenge. This suggested efficacy of the combination therapy predominantly relied on the innate immune system. Importantly, efficacy was not limited to melanoma; it was also demonstrated in a murine prostate cancer model. Taken together, these results suggest that combining NDV with vanadyl sulfate potentiates an innate immune response that can potentiate rapid clearance of tumors, with type I interferon signaling and NK cells being important mechanisms of action.
Collapse
|
|
35
|
Turkington CJR, Varadan AC, Grenier SF, Grasis JA. The Viral Janus: Viruses as Aetiological Agents and Treatment Options in Colorectal Cancer. Front Cell Infect Microbiol 2021; 10:601573. [PMID: 33489934 PMCID: PMC7817644 DOI: 10.3389/fcimb.2020.601573] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/23/2020] [Indexed: 12/24/2022] Open
Abstract
In recent years, our understanding of the importance of microorganisms on and within our bodies has been revolutionized by the ability to characterize entire microbial communities. No more so is this true than in cases of disease. Community studies have revealed strong associations between microbial populations and disease states where such concomitance was previously absent from aetiology: including in cancers. The study of viruses, in particular, has benefited from the development of new community profiling techniques and we are now realising that their prominence within our physiology is nearly as broad as the diversity of the organisms themselves. Here, we examine the relationship between viruses and colorectal cancer (CRC), the leading cause of gastrointestinal cancer-related death worldwide. In CRC, viruses have been suggested to be involved in oncogenesis both directly, through infection of our cells, and indirectly, through modulating the composition of bacterial communities. Interestingly though, these characteristics have also led to their examination from another perspective—as options for treatment. Advances in our understanding of molecular and viral biology have caused many to look at viruses as potential modular biotherapeutics, where deleterious characteristics can be tamed and desirable characteristics exploited. In this article, we will explore both of these perspectives, covering how viral infections and involvement in microbiome dynamics may contribute to CRC, and examine ways in which viruses themselves could be harnessed to treat the very condition their contemporaries may have had a hand in creating.
Collapse
Affiliation(s)
| | - Ambarish C Varadan
- School of Natural Sciences, University of California Merced, Merced, CA, United States
| | - Shea F Grenier
- Department of Biology, San Diego State University, San Diego, CA, United States
| | - Juris A Grasis
- School of Natural Sciences, University of California Merced, Merced, CA, United States
| |
Collapse
|
|
36
|
Malinzi J, Basita KB, Padidar S, Adeola HA. Prospect for application of mathematical models in combination cancer treatments. INFORMATICS IN MEDICINE UNLOCKED 2021. [DOI: 10.1016/j.imu.2021.100534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
|
|
37
|
Burmeister AR, Hansen E, Cunningham JJ, Rego EH, Turner PE, Weitz JS, Hochberg ME. Fighting microbial pathogens by integrating host ecosystem interactions and evolution. Bioessays 2020; 43:e2000272. [PMID: 33377530 DOI: 10.1002/bies.202000272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/22/2020] [Accepted: 11/30/2020] [Indexed: 12/19/2022]
Abstract
Successful therapies to combat microbial diseases and cancers require incorporating ecological and evolutionary principles. Drawing upon the fields of ecology and evolutionary biology, we present a systems-based approach in which host and disease-causing factors are considered as part of a complex network of interactions, analogous to studies of "classical" ecosystems. Centering this approach around empirical examples of disease treatment, we present evidence that successful therapies invariably engage multiple interactions with other components of the host ecosystem. Many of these factors interact nonlinearly to yield synergistic benefits and curative outcomes. We argue that these synergies and nonlinear feedbacks must be leveraged to improve the study of pathogenesis in situ and to develop more effective therapies. An eco-evolutionary systems perspective has surprising and important consequences, and we use it to articulate areas of high research priority for improving treatment strategies.
Collapse
Affiliation(s)
- Alita R Burmeister
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, USA.,BEACON Center for the Study of Evolution in Action, Michigan State University, East Lansing, Michigan, USA
| | - Elsa Hansen
- Department of Biology, Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Jessica J Cunningham
- Department of Integrated Mathematical Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - E Hesper Rego
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Paul E Turner
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, USA.,BEACON Center for the Study of Evolution in Action, Michigan State University, East Lansing, Michigan, USA.,Program in Microbiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Joshua S Weitz
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA.,School of Physics, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Michael E Hochberg
- Institute of Evolutionary Sciences, University of Montpellier, Montpellier, France.,Santa Fe Institute, Santa Fe, New Mexico, USA
| |
Collapse
|
|
38
|
Flores EB, Bartee E. Decreasing the Susceptibility of Malignant Cells to Infection Does Not Impact the Overall Efficacy of Myxoma Virus-Based Oncolytic Virotherapy. Mol Ther Oncolytics 2020; 19:323-331. [PMID: 33335977 PMCID: PMC7720075 DOI: 10.1016/j.omto.2020.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/20/2020] [Indexed: 11/19/2022] Open
Abstract
Oncolytic virotherapy relies on the induction of anti-tumor immune responses to achieve therapeutic efficacy. The factors that influence the induction of these responses, however, are not well understood. To begin to address this lack of knowledge, we asked how decreasing the susceptibility of malignant cells to direct viral infection would impact the induction of immune responses and therapeutic efficacy caused by oncolytic myxoma virus treatment. To accomplish this, we used CRISPR-Cas9 genome editing to remove the essential sulfation enzyme N-deacetylase/N-sulfotransferase-1 from B16/F10 murine melanoma cells. This eliminates the negative cell surface charges associated with glycosaminoglycan sulfation, which reduces a cell's susceptibility to infection with the myxoma virus by ∼3- to 10-fold. With the use of these cells as a model of reduced susceptibility to oncolytic infection, our data demonstrate that 3- to 10-fold reductions in in vivo infection do not hinder the ability of the oncolytic myxoma virus to induce anti-tumor immunity and do not lower the overall efficacy of localized treatment. Additionally, our data show that in mice bearing multiple distinct tumor masses, the choice to treat a less-susceptible tumor mass does not reduce the overall therapeutic impact against either the injected or noninjected lesion. Taken together, these data suggest that minor changes in the susceptibility of malignant cells to direct oncolytic infection do not necessarily influence the overall outcomes of treatment.
Collapse
Affiliation(s)
- Erica B. Flores
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Eric Bartee
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| |
Collapse
|
|
39
|
Neoadjuvant Use of Oncolytic Herpes Virus G47Δ Enhances the Antitumor Efficacy of Radiofrequency Ablation. MOLECULAR THERAPY-ONCOLYTICS 2020; 18:535-545. [PMID: 32995479 PMCID: PMC7501409 DOI: 10.1016/j.omto.2020.08.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 08/19/2020] [Indexed: 12/22/2022]
Abstract
G47Δ is a triple-mutated oncolytic herpes simplex virus type 1 designed to induce antitumor immune responses efficiently. We examine the usefulness of G47Δ as a neoadjuvant therapy for radiofrequency ablation (RFA), a standard local treatment for certain cancers such as liver cancer, but remote recurrences within the same organ often occur. In A/J mice harboring bilateral subcutaneous Neuro2a tumors, the left tumors were treated with G47Δ intratumoral injections followed by RFA. Whereas the RFA-treated tumors were all eradicated, the growth of the right tumors was evaluated and tumor-infiltrating lymphocytes were analyzed. The G47Δ+RFA treatment caused smaller volumes of right tumors, accompanied by increased CD8+/CD45+ T cells, compared with G47Δ monotherapy. After depletion of CD8+ T cells, the enhanced efficacy on the contralateral tumors was completely abolished. Neoadjuvant G47Δ led to rejection of rechallenged tumors, which was caused by efficient induction of specific antitumor immune responses shown by enzyme-linked immunospot (ELISPOT) assays. Treatment of tumor-harboring animals with an anti-programmed cell death 1 ligand 1 (PD-L1) antibody led to even greater efficacy on contralateral tumors. Our study indicates that the neoadjuvant use of G47Δ effectively enhances the efficacy of RFA via CD8+ T cell-dependent immunity that is further augmented by an immune checkpoint inhibitor.
Collapse
|
|
40
|
Wang J, Liu T, Chen J. Oncolytic Measles Virus Encoding Interleukin-12 Mediated Antitumor Activity and Immunologic Control of Colon Cancer In Vivo and Ex Vivo. Cancer Biother Radiopharm 2020; 36:774-782. [PMID: 32783751 DOI: 10.1089/cbr.2019.3084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: In this study, we used an oncolytic measles virus encoding interleukin 12 (IL-12) to treat colon cancer in vivo and ex vivo to investigate its effect on the viability and apoptosis of colon cancer cells. Method: A rat model was established to evaluate the immunostimulatory capabilities and therapeutic efficacy of vectors encoding an IL-12 fusion protein (MeVac FmIL-12 vectors). TUNEL staining, western blot, and enzyme-linked immunosorbent assay were performed to examine the impacts of MeVac FmIL-12 on the expression of inflammatory cytokines. Cell transfection was carried out to validate the anti-tumor role of MeVac FmIL-12 in vitro. Flow cytometry and MTT assay were performed to assess the effects of MeVac FmIL-12 on cell apoptosis and viability. Result: High concentrations (10-1000 ng/mL) of murine IL-12 fusion protein (FmIL-12) decreased the production of interferon γ (IFN-γ) in a concentration-dependent manner and reflected FmIL-12-induced overstimulation. Rats treated with MeVac vectors encoding FmIL-12 showed a significantly increased level of FmIL-12 overtime and a concentration-dependent (0.01-10 ng/mL) increase in IFN-γ production. MeVac FmIL-12 also increased the expression of inflammatory cytokines (IFN-γ, tumor necrosis factor α, and IL-6) both in vivo and in vitro. MeVac FmIL-12 promoted cell apoptosis and reduced cell viability, which helped to trigger a systemic anti-tumor immune response, both in vivo and in vitro. Conclusion: In this study, we suggested that MeVac FmIL-12 enhanced the therapeutic efficacy of tumor treatment by improving anti-tumor immunity.
Collapse
Affiliation(s)
- Jian Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Tao Liu
- Department of Medical Oncology, and The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jie Chen
- Department of Pathology, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| |
Collapse
|
|
41
|
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.
Collapse
|
|
42
|
Zhang Y, Liu Z. Oncolytic Virotherapy for Malignant Tumor: Current Clinical Status. Curr Pharm Des 2020; 25:4251-4263. [PMID: 31682207 DOI: 10.2174/1381612825666191104090544] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
Abstract
Oncolytic viruses, as novel biological anti-tumor agents, provide anti-tumor therapeutic effects by different mechanisms including directly selective tumor cell lysis and secondary systemic anti-tumor immune responses. Some wide-type and genetically engineered oncolytic viruses have been applied in clinical trials. Among them, T-Vec has a significant therapeutic effect on melanoma patients and received the approval of the US Food and Drug Administration (FDA) as the first oncolytic virus to treat cancer in the US. However, the mechanisms of virus interaction with tumor and immune systems have not been clearly elucidated and there are still no "gold standards" for instructions of virotherapy in clinical trials. This Review collected the recent clinical trials data from 2005 to summarize the basic oncolytic viruses biology, describe the application in recent clinical trials, and discuss the challenges in the application of oncolytic viruses in clinical trials.
Collapse
Affiliation(s)
- Yuhui Zhang
- Department of Spine Surgery, Renji Hospital, Medical School, Shanghai Jiaotong University, Shanghai, China
| | - Zhuoming Liu
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States
| |
Collapse
|
|
43
|
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.
Collapse
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
| |
Collapse
|
|
44
|
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.
Collapse
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
| |
Collapse
|
|
45
|
Gesundheit B, Ben-David E, Posen Y, Ellis R, Wollmann G, Schneider EM, Aigner K, Brauns L, Nesselhut T, Ackva I, Weisslein C, Thaller A. Effective Treatment of Glioblastoma Multiforme With Oncolytic Virotherapy: A Case-Series. Front Oncol 2020; 10:702. [PMID: 32477944 PMCID: PMC7241257 DOI: 10.3389/fonc.2020.00702] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/15/2020] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma multiforme (GBM) remains an incurable condition, associated with a median survival time of 15 months with best standard of care and 5-year survival rate of <10%. We report on four GBM patients on combination treatment regimens that included oncolytic virus (OV) immunotherapy, who achieved clinical and radiological responses with long-term survival, thus far, of up to 14 years, and good quality of life. We discuss the radiological findings that provide new insights into this treatment, the scientific rationale of this innovative and promising therapy, and considerations for future research.
Collapse
Affiliation(s)
| | - Eliel Ben-David
- Department of Radiology, Shaare Zedek Medical Center, Jerusalem, Israel
| | | | | | - Guido Wollmann
- Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Innsbruck, Austria
| | - E Marion Schneider
- Division of Experimental Anesthesiology, University Hospital Ulm, Ulm, Germany
| | | | | | | | - Ingrid Ackva
- Praxisklinik fuer Allgemeinmedizin, Markt Berolzheim, Germany
| | | | - Arno Thaller
- Praxisklinik fuer Allgemeinmedizin, Markt Berolzheim, Germany
| |
Collapse
|
|
46
|
Keshavarz M, Ebrahimzadeh MS, Miri SM, Dianat-Moghadam H, Ghorbanhosseini SS, Mohebbi SR, Keyvani H, Ghaemi A. Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment. Virol J 2020; 17:64. [PMID: 32370750 PMCID: PMC7201980 DOI: 10.1186/s12985-020-01326-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022] Open
Abstract
Background Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor. Methods For this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME). Results Our findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 9) and increased infiltration of tumor microenvironment with CD11b + myeloid and Gr1 + MDSCs cells. Conclusions Our data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and apoptosis in the tumor microenvironment.
Collapse
Affiliation(s)
- Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.,Department of Medical Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Department of Medical Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran.
| |
Collapse
|
|
47
|
Kim J, Sestito LF, Im S, Kim WJ, Thomas SN. Poly(cyclodextrin)-Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1908788. [PMID: 33071710 PMCID: PMC7566879 DOI: 10.1002/adfm.201908788] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Indexed: 05/03/2023]
Abstract
Despite the approval of oncolytic virus therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, we report a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide incorporated polymerized β-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of oncolytic virus. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell activation and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of dendritic cells systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8+ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo- and immunotherapeutic synergies of paclitaxel and nitric oxide and suggests the potential for virus-free nanoformulations to mimic the therapeutic action and benefits of oncolytic viruses.
Collapse
Affiliation(s)
- Jihoon Kim
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, Georgia 30332; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, Georgia 30332, USA
| | - Lauren F Sestito
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Dr NW, Atlanta, Georgia 30332, USA and Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, USA
| | - Sooseok Im
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
| | - Won Jong Kim
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Department of Chemistry, POSTECH, Pohang 37673, Republic of Korea
| | - Susan N Thomas
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, Georgia 30332; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, Georgia 30332, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Dr NW, Atlanta, Georgia 30332, USA and Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, USA; Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, Georgia 30322, USA
| |
Collapse
|
|
48
|
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.
Collapse
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
| |
Collapse
|
|
49
|
Soekojo CY, Ooi M, de Mel S, Chng WJ. Immunotherapy in Multiple Myeloma. Cells 2020; 9:E601. [PMID: 32138182 PMCID: PMC7140529 DOI: 10.3390/cells9030601] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 02/27/2020] [Accepted: 02/27/2020] [Indexed: 12/15/2022] Open
Abstract
Multiple myeloma is a complex disease and immune dysfunction has been known to play an important role in the disease pathogenesis, progression, and drug resistance. Recent efforts in drug development have been focused on immunotherapies to modify the MM disease process. Here, we summarize the emerging immunotherapies in the MM treatment landscape.
Collapse
Affiliation(s)
| | | | | | - Wee Joo Chng
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System, 1E Kent Ridge Road, Singapore 119228, Singapore; (C.Y.S.); (M.O.); (S.d.M.)
| |
Collapse
|
|
50
|
Abstract
In addition of being directly tumoricidal, oncolytic viruses have emerged as potent partners for established and investigational immunotherapies due to their immune-stimulatory effects. The shifting focus on virus-mediated immune modulation calls for a comprehensive analysis of the tumor microenvironment (TME) and the factors orchestrating the antiviral and antitumor immune response. The oncolytic VSV-GP studied in our lab is a safe and potent antitumor agent with a fast replication cycle and killing of a broad range of different cancer types. It induces a robust local inflammatory conversion of the TME and drives a strong adaptive immune response toward the tumor. Here we present our multidisciplinary approach to study VSV-GP treatment effects in tumors by assessing both immune cells (tumor-infiltrating lymphocytes and tumor-associated macrophages) and immune-regulatory factors (cytokines) as well as characterizing immune signatures using an immune-targeted NanoString gene expression system.
Collapse
|