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Tang S, Yong L, Cui Y, Li H, Bischof E, Cai F. Harnessing Oncolytic Viruses for Targeted Therapy in Triple-Negative Breast Cancer. Int J Med Sci 2025; 22:2186-2207. [PMID: 40303488 PMCID: PMC12035831 DOI: 10.7150/ijms.105683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/19/2025] [Indexed: 05/02/2025] Open
Abstract
Breast cancer is the most prevalent malignant tumor among women, with triple-negative breast cancer (TNBC) being one of the most aggressive forms due to its high invasiveness and metastatic potential. Traditional treatments such as endocrine therapy and anti-HER2-targeted therapy are largely ineffective for TNBC, and while chemotherapy shows some promise, resistance remains a significant hurdle. Recently, there has been increasing interest in biological therapies, especially oncolytic viruses (OVs). OVs promote anti-tumor effects by selectively killing tumor cells and stimulating immune responses, and have achieved notable breakthroughs in breast cancer treatment. OVs have demonstrated effectiveness comparable to surgery, radiotherapy, or chemotherapy in selected cancers, but data are sparse in the context of TNBC. This review provides an overview of recent progress in the application of OVs as a tool for precision TNBC treatment.
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Affiliation(s)
- Shasha Tang
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
| | - Liyun Yong
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
| | - Yong Cui
- Department of General Surgery, People's Hospital of Otog Qianqi, Sharita Tara East Street, Aolezhaoqi Town, Otog Qianqi 016200, China
| | - Haibin Li
- Department of General Surgery, People's Hospital of Otog Qianqi, Sharita Tara East Street, Aolezhaoqi Town, Otog Qianqi 016200, China
| | - Evelyne Bischof
- Department of Medical Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Fengfeng Cai
- Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai 200065, China
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2
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Peter M, Mundt B, Menze A, Woller N, Volk V, Ernst AM, Öhler LA, Talbot SR, Wedemeyer H, Falk C, Feuerhake F, Wirth TC, Kühnel F. Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors. EMBO Mol Med 2025; 17:265-300. [PMID: 39789356 PMCID: PMC11821991 DOI: 10.1038/s44321-024-00187-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 01/12/2025] Open
Abstract
Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggests the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.
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Affiliation(s)
- Malin Peter
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bettina Mundt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arne Menze
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Norman Woller
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Valery Volk
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Amanda M Ernst
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Leon A Öhler
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steven R Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, 30625, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Christine Falk
- Institute of Transplantation Immunology, Hannover Medical School, Hannover, Germany
| | | | - Thomas C Wirth
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian Kühnel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Al-Obaidi I, Sandhu C, Qureshi B, Seymour LW. The implications of oncolytic viruses targeting fibroblasts in enhancing the antitumoural immune response. Heliyon 2024; 10:e39204. [PMID: 39502212 PMCID: PMC11535324 DOI: 10.1016/j.heliyon.2024.e39204] [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: 02/21/2024] [Revised: 09/28/2024] [Accepted: 10/09/2024] [Indexed: 11/08/2024] Open
Abstract
Oncolytic viruses (OVs) are an emerging immunotherapy platform that selectively target tumour cells, inducing immunogenic cell death. This reverses the 'immune-desert' phenotype of tumours, enhancing antitumour immunity. However, oncolytic virotherapy has shown limited efficacy in solid tumours due to the presence of protumoural, immunosuppressive cancer-associated fibroblasts (CAFs). Recent studies have explored OVs that specifically target CAFs to enhance antitumoural immune responses, with promising results. Nevertheless, detailed interrogation of the experimental design of these studies casts doubt on their potential for successful clinical translation. Most studies targeted CAFs non-specifically, failing to acknowledge CAF heterogeneity, with antitumoural CAFs also present. Thus, use of transcriptomics is advisable to provide more focused targeting, limiting potential off-target toxicity. Furthermore, experiments to date have largely been conducted in murine models that do not faithfully recapitulate tumour microenvironments, potentially biasing the efficacy observed. Future work should make use of humanised patient-derived xenograft murine models for animal studies, after which primary human tumour biopsies should be utilised to more closely represent the patient population for maximal translation relevance. Additionally, approaches to enhance the antitumoural immune responses of this therapy should be prioritised, with the ultimate aim of achieving complete remission, which has not yet been observed pre-clinically.
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Affiliation(s)
- Ibrahem Al-Obaidi
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
- The Queen's College, High Street. Oxford, OX1 4AW, UK
| | - Ciaran Sandhu
- The Queen's College, High Street. Oxford, OX1 4AW, UK
| | - Bilal Qureshi
- Somerville College, Woodstock Road, Oxford, OX2 6HD, UK
| | - Leonard W. Seymour
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
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Zhou Z, Mai Y, Zhang G, Wang Y, Sun P, Jing Z, Li Z, Xu Y, Han B, Liu J. Emerging role of immunogenic cell death in cancer immunotherapy: Advancing next-generation CAR-T cell immunotherapy by combination. Cancer Lett 2024; 598:217079. [PMID: 38936505 DOI: 10.1016/j.canlet.2024.217079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
Immunogenic cell death (ICD) is a stress-driven form of regulated cell death (RCD) in which dying tumor cells' specific signaling pathways are activated to release damage-associated molecular patterns (DAMPs), leading to the robust anti-tumor immune response as well as a reversal of the tumor immune microenvironment from "cold" to "hot". Chimeric antigen receptor (CAR)-T cell therapy, as a landmark in anti-tumor immunotherapy, plays a formidable role in hematologic malignancies but falls short in solid tumors. The Gordian knot of CAR-T cells for solid tumors includes but is not limited to, tumor antigen heterogeneity or absence, physical and immune barriers of tumors. The combination of ICD induction therapy and CAR-T cell immunotherapy is expected to promote the intensive use of CAR-T cell in solid tumors. In this review, we summarize the characteristics of ICD, stress-responsive mechanism, and the synergistic effect of various ICD-based therapies with CAR-T cells to effectively improve anti-tumor capacity.
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Affiliation(s)
- Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yumiao Mai
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Ge Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Henan Province Key Laboratory of Cardiac Injury and Repair, Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Yingjie Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Pan Sun
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Zhaohe Jing
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yudi Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Jian Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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6
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Gao X, Liu J, Sun R, Zhang J, Cao X, Zhang Y, Zhao M. Alliance between titans: combination strategies of CAR-T cell therapy and oncolytic virus for the treatment of hematological malignancies. Ann Hematol 2024; 103:2569-2589. [PMID: 37853078 DOI: 10.1007/s00277-023-05488-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023]
Abstract
There have been several clinical studies using chimeric antigen receptor (CAR)-T cell therapy for different hematological malignancies. It has transformed the therapy landscape for hematologic malignancies dramatically. Nonetheless, in acute myeloid leukemia (AML) and T cell malignancies, it still has a dismal prognosis. Even in the most promising locations, recurrence with CAR-T treatment remains a big concern. Oncolytic viruses (OVs) can directly lyse tumor cells or cause immune responses, and they can be manipulated to create therapeutic proteins, increasing anticancer efficacy. Oncolytic viruses have been proven in a rising number of studies to be beneficial in hematological malignancies. There are limitations that cannot be avoided by using either treatment alone, and the combination of CAR-T cell therapy and oncolytic virus therapy may complement the disadvantages of individual application, enhance the advantages of their respective treatment methods and improve the treatment effect. The alternatives for combining two therapies in hematological malignancies are discussed in this article.
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Affiliation(s)
- Xuejin Gao
- Emergency, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Jile Liu
- First Center Clinic College of Tianjin Medical University, Tianjin, 300192, China
| | - Rui Sun
- Nankai University School of Medicine, Tianjin, 300192, China
| | - Jingkun Zhang
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Xinping Cao
- First Center Clinic College of Tianjin Medical University, Tianjin, 300192, China
| | - Yi Zhang
- First Center Clinic College of Tianjin Medical University, Tianjin, 300192, China
| | - Mingfeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, China.
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7
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Thomas R, Jerome JM, Krieger KL, Ashraf N, Rowley DR. The reactive stroma response regulates the immune landscape in prostate cancer. JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS 2024; 8:249-77. [DOI: 10.20517/jtgg.2024.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Prostate cancer remains the most commonly diagnosed and the second leading cause of cancer-related deaths in men in the United States. The neoplastic transformation of prostate epithelia, concomitant with modulations in the stromal compartment, known as reactive stromal response, is critical for the growth, development, and progression of prostate cancer. Reactive stroma typifies an emergent response to disrupted tissue homeostasis commonly observed in wound repair and pathological conditions such as cancer. Despite the significance of reactive stroma in prostate cancer pathobiology, our understanding of the ontogeny, phenotypic and functional heterogeneity, and reactive stromal regulation of the immune microenvironment in prostate cancer remains limited. Traditionally characterized to have an immunologically "cold" tumor microenvironment, prostate cancer presents significant challenges for advancing immunotherapy compared to other solid tumors. This review explores the detrimental role of reactive stroma in prostate cancer, particularly its immunomodulatory function. Understanding the molecular characteristics and dynamic transcriptional program of the reactive stromal populations in tandem with tumor progression could offer insights into enhancing immunotherapy efficacy against prostate cancer.
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8
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Xiao R, Jin H, Huang F, Huang B, Wang H, Wang YG. Oncolytic virotherapy for hepatocellular carcinoma: A potent immunotherapeutic landscape. World J Gastrointest Oncol 2024; 16:2867-2876. [PMID: 39072175 PMCID: PMC11271782 DOI: 10.4251/wjgo.v16.i7.2867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 04/24/2024] [Accepted: 05/13/2024] [Indexed: 07/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a systemic disease with augmented malignant degree, high mortality and poor prognosis. Since the establishment of the immune mechanism of tumor therapy, people have realized that immunotherapy is an effective means for improvement of HCC patient prognosis. Oncolytic virus is a novel immunotherapy drug, which kills tumor cells and exempts normal cells by directly lysing tumor and inducing anti-tumor immune response, and it has been extensively examined as an HCC therapy. This editorial discusses oncolytic viruses for the treatment of HCC, emphasizing viral immunotherapy strategies and clinical applications related to HCC.
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Affiliation(s)
- Rong Xiao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Hao Jin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Fang Huang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Biao Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Hui Wang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
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Yuan Z, Zhang Y, Wang X, Wang X, Ren S, He X, Su J, Zheng A, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Wang Z, Xiao Z. The investigation of oncolytic viruses in the field of cancer therapy. Front Oncol 2024; 14:1423143. [PMID: 39055561 PMCID: PMC11270537 DOI: 10.3389/fonc.2024.1423143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024] Open
Abstract
Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in tumor therapy. The engineering approaches discussed include enhancing in vivo immune response, improving replication efficiency within the tumor cells, enhancing safety profiles, and improving targeting capabilities. In addition, this review describes the potential mechanisms of OVs combined with radiotherapy, chemotherapy, cell therapy and immune checkpoint inhibitors (ICIs), and summarizes the data of ongoing clinical trials. By continuously optimizing engineering strategies and combination therapy programs, we can achieve improved treatment outcomes and quality of life for cancer patients.
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Affiliation(s)
- Zijun Yuan
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Anfu Zheng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research And Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Zechen Wang
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
| | - Zhangang Xiao
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Department of Pharmacology, School of Pharmacy, Sichuan College of Traditional Chinese Medicine, Mianyang, China
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Chattopadhyay S, Hazra R, Mallick A, Gayen S, Roy S. A review exploring the fusion of oncolytic viruses and cancer immunotherapy: An innovative strategy in the realm of cancer treatment. Biochim Biophys Acta Rev Cancer 2024; 1879:189110. [PMID: 38754793 DOI: 10.1016/j.bbcan.2024.189110] [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: 03/24/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.
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Affiliation(s)
- Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India.
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11
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Franks ML, An JH, Leavenworth JW. The Role of Natural Killer Cells in Oncolytic Virotherapy: Friends or Foes? Vaccines (Basel) 2024; 12:721. [PMID: 39066359 PMCID: PMC11281503 DOI: 10.3390/vaccines12070721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/26/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Oncolytic virotherapy (OVT) has emerged as a promising cancer immunotherapy, and is capable of potentiating other immunotherapies due to its capacity to increase tumor immunogenicity and to boost host antitumor immunity. Natural killer (NK) cells are a critical cellular component for mediating the antitumor response, but hold a mixed reputation for their role in mediating the therapeutic efficacy of OVT. This review will discuss the pros and cons of how NK cells impact OVT, and how to harness this knowledge for the development of effective strategies that could modulate NK cells to improve OVT-based therapeutic outcomes.
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Affiliation(s)
- Michael L. Franks
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (M.L.F.)
- Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ju-Hyun An
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (M.L.F.)
| | - Jianmei W. Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (M.L.F.)
- The O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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12
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Qin X, Ning W, Liu H, Liu X, Luo W, Xia N. Stepping forward: T-cell redirecting bispecific antibodies in cancer therapy. Acta Pharm Sin B 2024; 14:2361-2377. [PMID: 38828136 PMCID: PMC11143529 DOI: 10.1016/j.apsb.2024.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/26/2023] [Accepted: 02/28/2024] [Indexed: 06/05/2024] Open
Abstract
T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens, thereby engaging with CD3 on the T cell receptor. This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells. These antibodies have emerged as one of the most promising avenues within tumor immunotherapy. However, despite success in treating hematological malignancies, significant advancements in solid tumors have yet to be explored. In this review, we aim to address the critical challenges associated with T cell-redirecting bispecific antibodies and explore novel strategies to overcome these obstacles, with the ultimate goal of expanding the application of this therapy to include solid tumors.
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Affiliation(s)
- Xiaojing Qin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
| | - Wenjing Ning
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
| | - Han Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
| | - Xue Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
| | - Wenxin Luo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry–Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
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13
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Lin C, Teng W, Tian Y, Li S, Xia N, Huang C. Immune landscape and response to oncolytic virus-based immunotherapy. Front Med 2024; 18:411-429. [PMID: 38453818 DOI: 10.1007/s11684-023-1048-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 11/15/2023] [Indexed: 03/09/2024]
Abstract
Oncolytic virus (OV)-based immunotherapy has emerged as a promising strategy for cancer treatment, offering a unique potential to selectively target malignant cells while sparing normal tissues. However, the immunosuppressive nature of tumor microenvironment (TME) poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents, as it restricts the activation and recruitment of immune cells. This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses. We examine the role of OVs in targeting specific immune cell populations, including dendritic cells, T cells, natural killer cells, and macrophages, and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis. Additionally, we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy. In conclusion, this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy, underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.
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Affiliation(s)
- Chaolong Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China
| | - Wenzhong Teng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China
| | - Yang Tian
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China
| | - Shaopeng Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China.
| | - Chenghao Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361102, China.
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14
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Vazaios K, van Berkum RE, Calkoen FG, van der Lugt J, Hulleman E. OV Modulators of the Paediatric Brain TIME: Current Status, Combination Strategies, Limitations and Future Directions. Int J Mol Sci 2024; 25:5007. [PMID: 38732225 PMCID: PMC11084613 DOI: 10.3390/ijms25095007] [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: 03/12/2024] [Revised: 04/26/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024] Open
Abstract
Oncolytic viruses (OVs) are characterised by their preference for infecting and replicating in tumour cells either naturally or after genetic modification, resulting in oncolysis. Furthermore, OVs can elicit both local and systemic anticancer immune responses while specifically infecting and lysing tumour cells. These characteristics render them a promising therapeutic approach for paediatric brain tumours (PBTs). PBTs are frequently marked by a cold tumour immune microenvironment (TIME), which suppresses immunotherapies. Recent preclinical and clinical studies have demonstrated the capability of OVs to induce a proinflammatory immune response, thereby modifying the TIME. In-depth insights into the effect of OVs on different cell types in the TIME may therefore provide a compelling basis for using OVs in combination with other immunotherapy modalities. However, certain limitations persist in our understanding of oncolytic viruses' ability to regulate the TIME to enhance anti-tumour activity. These limitations primarily stem from the translational limitations of model systems, the difficulties associated with tracking reliable markers of efficacy throughout the course of treatment and the role of pre-existing viral immunity. In this review, we describe the different alterations observed in the TIME in PBTs due to OV treatment, combination therapies of OVs with different immunotherapies and the hurdles limiting the development of effective OV therapies while suggesting future directions based on existing evidence.
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Affiliation(s)
| | | | | | | | - Esther Hulleman
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (K.V.); (F.G.C.); (J.v.d.L.)
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15
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Deng S, Zhang Y, Wang H, Liang W, Xie L, Li N, Fang Y, Wang Y, Liu J, Chi H, Sun Y, Ye R, Shan L, Shi J, Shen Z, Wang Y, Wang S, Brosseau JP, Wang F, Liu G, Quan Y, Xu J. ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion. Cell 2024; 187:2305-2323.e33. [PMID: 38614099 DOI: 10.1016/j.cell.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 11/13/2023] [Accepted: 03/13/2024] [Indexed: 04/15/2024]
Abstract
Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.
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Affiliation(s)
- Shouyan Deng
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Yibo Zhang
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | | | - Wenhua Liang
- Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Lu Xie
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, China
| | - Ning Li
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China
| | - Yuan Fang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China
| | - Yiting Wang
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Jiayang Liu
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Hao Chi
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Yufan Sun
- BioTroy Therapeutics, Shanghai 201400, China
| | - Rui Ye
- BioTroy Therapeutics, Shanghai 201400, China
| | - Lishen Shan
- BioTroy Therapeutics, Shanghai 201400, China
| | - Jiawei Shi
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Zan Shen
- Department of Oncology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 600, Yishan Road, Shanghai 200233, China
| | - Yonggang Wang
- Department of Oncology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 600, Yishan Road, Shanghai 200233, China
| | - Shuhang Wang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China
| | - Jean-Philippe Brosseau
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Feng Wang
- Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Grace Liu
- Arctic Animal Hospital, Fuzhou, Fujian 350007, China
| | | | - Jie Xu
- Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China.
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16
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Nia GE, Nikpayam E, Farrokhi M, Bolhassani A, Meuwissen R. Advances in cell-based delivery of oncolytic viruses as therapy for lung cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200788. [PMID: 38596310 PMCID: PMC10976516 DOI: 10.1016/j.omton.2024.200788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Lung cancer's intractability is enhanced by its frequent resistance to (chemo)therapy and often high relapse rates that make it the leading cause of cancer death worldwide. Improvement of therapy efficacy is a crucial issue that might lead to a significant advance in the treatment of lung cancer. Oncolytic viruses are desirable combination partners in the developing field of cancer immunotherapy due to their direct cytotoxic effects and ability to elicit an immune response. Systemic oncolytic virus administration through intravenous injection should ideally lead to the highest efficacy in oncolytic activity. However, this is often hampered by the prevalence of host-specific, anti-viral immune responses. One way to achieve more efficient systemic oncolytic virus delivery is through better protection against neutralization by several components of the host immune system. Carrier cells, which can even have innate tumor tropism, have shown their appropriateness as effective vehicles for systemic oncolytic virus infection through circumventing restrictive features of the immune system and can warrant oncolytic virus delivery to tumors. In this overview, we summarize promising results from studies in which carrier cells have shown their usefulness for improved systemic oncolytic virus delivery and better oncolytic virus therapy against lung cancer.
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Affiliation(s)
- Giti Esmail Nia
- Faculty of Allied Medicine, Cellular and Molecular Research Centre, Iran University of Medical Science, Tehran, Iran
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Elahe Nikpayam
- Department of Regenerative and Cancer Biology, Albany Medical College, Albany, NY, USA
| | | | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Ralph Meuwissen
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
- Ege University Translational Pulmonary Research Center (EgeSAM), Ege University, Izmir, Turkey
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17
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Le ND, Nguyen BL, Patil BR, Chun H, Kim S, Nguyen TOO, Mishra S, Tandukar S, Chang JH, Kim DY, Jin SG, Choi HG, Ku SK, Kim J, Kim JO. Antiangiogenic Therapeutic mRNA Delivery Using Lung-Selective Polymeric Nanomedicine for Lung Cancer Treatment. ACS NANO 2024; 18:8392-8410. [PMID: 38450656 DOI: 10.1021/acsnano.3c13039] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2024]
Abstract
Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.
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Affiliation(s)
- Ngoc Duy Le
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Bao Loc Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | | | - HeeSang Chun
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - SiYoon Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | | | - Sunil Mishra
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Sudarshan Tandukar
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Dong Young Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Sung Giu Jin
- Department of Pharmaceutical Engineering, Dankook University, Cheonan, 31116, Republic of Korea
| | - Han-Gon Choi
- College of Pharmacy, Hanyang University, Ansan, 15588, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea
| | - Jeonghwan Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
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18
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Mirbahari SN, Da Silva M, Zúñiga AIM, Kooshki Zamani N, St-Laurent G, Totonchi M, Azad T. Recent progress in combination therapy of oncolytic vaccinia virus. Front Immunol 2024; 15:1272351. [PMID: 38558795 PMCID: PMC10979700 DOI: 10.3389/fimmu.2024.1272351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.
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Affiliation(s)
- Seyedeh Nasim Mirbahari
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Miles Da Silva
- Department of Microbiology and Immunology, University of British Colombia, Vancouver, BC, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Abril Ixchel Muñoz Zúñiga
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Nika Kooshki Zamani
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Gabriel St-Laurent
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Taha Azad
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
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19
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Wei W, Tian L, Zheng X, Zhong L, Chen Y, Dong H, Zhang G, Wang S, Tong X. Expression of GPX4 by oncolytic vaccinia virus can significantly enhance CD8 +T cell function and its impact against pancreatic ductal adenocarcinoma. Oncoimmunology 2024; 13:2322173. [PMID: 38419758 PMCID: PMC10900272 DOI: 10.1080/2162402x.2024.2322173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 02/19/2024] [Indexed: 03/02/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently difficult to treat, even when therapies are combined with immune checkpoint blockade (ICB). A novel strategy for immunotherapy would be to maximize the therapeutic potential of oncolytic viruses (OVs), which have been proven to engage the regulation of tumor microenvironment (TME) and cause-specific T-cell responses. To boost tumor sensitivity to ICB therapy, this study aimed to investigate how glutathione peroxide 4 (GPX4)-loaded OVs affect CD8+ T cells and repair the immunosuppressive environment. Here, we successfully constructed a novel recombinant oncolytic vaccinia virus (OVV) encoding the mouse GPX4 gene. We found the OVV-GPX4 effectively replicated in tumor cells and prompted the expression of GPX4 in T cells. Our research indicated that OVV-GPX4 could reshape the TME, rectify the depletion of CD8+T cells, and enhance the antitumor effects of ICB therapy.
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Affiliation(s)
- Wei Wei
- Zhejiang Provincial People’s Hospital Affiliated People’s Hospital, Hangzhou Medical College, Postgraduate Training Base of Jinzhou Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Linqing Tian
- Department of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Xiaoyan Zheng
- Department of Laboratory Medicine, Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, China
| | - Lei Zhong
- Department of Laboratory Medicine, Tongxiang Traditional Chinese Medicine Hospital, Tongxiang, Zhejiang, China
| | - Yuan Chen
- Department of Pathology, Zhejiang Provincial People’s Hospital Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hui Dong
- Department of Stomatology, Punan Hospital of Pudong New District, Shanghai, China
| | - Guibing Zhang
- Department of Hematology, Hangzhou Fuyang First People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Shibing Wang
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiangmin Tong
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Clinical Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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20
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Zarezadeh Mehrabadi A, Tat M, Ghorbani Alvanegh A, Roozbahani F, Esmaeili Gouvarchin Ghaleh H. Revolutionizing cancer treatment: the power of bi- and tri-specific T-cell engagers in oncolytic virotherapy. Front Immunol 2024; 15:1343378. [PMID: 38464532 PMCID: PMC10921556 DOI: 10.3389/fimmu.2024.1343378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/09/2024] [Indexed: 03/12/2024] Open
Abstract
Bi- or tri-specific T cell engagers (BiTE or TriTE) are recombinant bispecific proteins designed to stimulate T-cell immunity directly, bypassing antigen presentation by antigen-presenting cells (APCs). However, these molecules suffer from limitations such as short biological half-life and poor residence time in the tumor microenvironment (TME). Fortunately, these challenges can be overcome when combined with OVs. Various strategies have been developed, such as encoding secretory BiTEs within OV vectors, resulting in improved targeting and activation of T cells, secretion of key cytokines, and bystander killing of tumor cells. Additionally, oncolytic viruses armed with BiTEs have shown promising outcomes in enhancing major histocompatibility complex I antigen (MHC-I) presentation, T-cell proliferation, activation, and cytotoxicity against tumor cells. These combined approaches address tumor heterogeneity, drug delivery, and T-cell infiltration, offering a comprehensive and effective solution. This review article aims to provide a comprehensive overview of Bi- or TriTEs and OVs as promising therapeutic approaches in the field of cancer treatment. We summarize the cutting-edge advancements in oncolytic virotherapy immune-related genetic engineering, focusing on the innovative combination of BiTE or TriTE with OVs.
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Affiliation(s)
| | - Mahdi Tat
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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21
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Wang Y, Cheng P. Arming oncolytic viruses with bispecific T cell engagers: The evolution and current status. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166962. [PMID: 37984801 DOI: 10.1016/j.bbadis.2023.166962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/22/2023]
Abstract
Oncolytic viruses (OVs) are emerging as therapeutically relevant anticancer agents as contemporary immunotherapy gains traction. Furthermore, OVs are an ideal platform for genetic modification to express therapeutic transgenes. Bispecific T cell engagers (BiTEs) can redirect T cells to tumor cells, resulting in targeted cytotoxicity. BiTEs have demonstrated success in hematological cancers but are rarely used in solid tumors. The drawbacks of BiTEs, including inadequate delivery and on-target-off-tumor activity have limited their efficacy. Combining OVs with BiTEs is a prospective area to investigate. This combined strategy can benefit from the best qualities of both therapies while overcoming the limitations.
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Affiliation(s)
- Yunmeng Wang
- Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu 610041, PR China
| | - Ping Cheng
- Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu 610041, PR China.
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22
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Sakhi H, Arabi M, Ghaemi A, Movafagh A, Sheikhpour M. Oncolytic viruses in lung cancer treatment: a review article. Immunotherapy 2024; 16:75-97. [PMID: 38112057 DOI: 10.2217/imt-2023-0124] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 11/21/2023] [Indexed: 12/20/2023] Open
Abstract
Lung cancer has a high morbidity rate worldwide due to its resistance to therapy. So new treatment options are needed to improve the outcomes of lung cancer treatment. This study aimed to evaluate the effectiveness of oncolytic viruses (OVs) as a new type of cancer treatment. In this study, 158 articles from PubMed and Scopus from 1994 to 2022 were reviewed on the effectiveness of OVs in the treatment of lung cancer. The oncolytic properties of eight categories of OVs and their interactions with treatment options were investigated. OVs can be applied as a promising immunotherapy option, as they are reproduced selectively in different types of cancer cells, cause tumor cell lysis and trigger efficient immune responses.
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Affiliation(s)
- Hanie Sakhi
- Department of Mycobacteriology & Pulmonary Research, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Mohadeseh Arabi
- Department of Mycobacteriology & Pulmonary Research, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Abolfazl Movafagh
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 1983969411, Iran
| | - Mojgan Sheikhpour
- Department of Mycobacteriology & Pulmonary Research, Pasteur Institute of Iran, Tehran, 1316943551, Iran
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Volovat SR, Scripcariu DV, Vasilache IA, Stolniceanu CR, Volovat C, Augustin IG, Volovat CC, Ostafe MR, Andreea-Voichița SG, Bejusca-Vieriu T, Lungulescu CV, Sur D, Boboc D. Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy. Int J Mol Sci 2024; 25:1180. [PMID: 38256250 PMCID: PMC10816814 DOI: 10.3390/ijms25021180] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.
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Affiliation(s)
- Simona Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Dragos Viorel Scripcariu
- Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Ingrid Andrada Vasilache
- Department of Obstetrics and Gynecology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics—Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Constantin Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | | | - Madalina-Raluca Ostafe
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Slevoacă-Grigore Andreea-Voichița
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Toni Bejusca-Vieriu
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | - Daniel Sur
- 11th Department of Medical Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
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24
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Xu L, Sun H, Lemoine NR, Xuan Y, Wang P. Oncolytic vaccinia virus and cancer immunotherapy. Front Immunol 2024; 14:1324744. [PMID: 38283361 PMCID: PMC10811104 DOI: 10.3389/fimmu.2023.1324744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/29/2023] [Indexed: 01/30/2024] Open
Abstract
Oncolytic virotherapy (OVT) is a promising form of cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger anti-tumor immune response. In addition to killing cancer cells, oncolytic viruses can also remodel the tumor microenvironment and stimulate a long-term anti-tumor immune response. Despite achieving positive results in cellular and organismal studies, there are currently only a few approved oncolytic viruses for clinical use. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs. The safety and efficacy of different viral backbones are explored, as well as the effects of oncolytic VACVs on the tumor microenvironment. The potential combination of oncolytic VACVs with immunotherapy or traditional therapies is also highlighted. The review concludes by addressing prospects and challenges in the field of oncolytic VACVs, with the aim of promoting further research and application in cancer therapy.
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Affiliation(s)
- Lihua Xu
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Huihui Sun
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Nicholas R. Lemoine
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Yujing Xuan
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Pengju Wang
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
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25
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Chen L, Zuo M, Zhou Q, Wang Y. Oncolytic virotherapy in cancer treatment: challenges and optimization prospects. Front Immunol 2023; 14:1308890. [PMID: 38169820 PMCID: PMC10758479 DOI: 10.3389/fimmu.2023.1308890] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024] Open
Abstract
Oncolytic viruses (OVs) are emerging cancer therapeutics that offer a multifaceted therapeutic platform for the benefits of replicating and lysing tumor cells, being engineered to express transgenes, modulating the tumor microenvironment (TME), and having a tolerable safety profile that does not overlap with other cancer therapeutics. The mechanism of OVs combined with other antitumor agents is based on immune-mediated attack resistance and might benefit patients who fail to achieve durable responses after immune checkpoint inhibitor (ICI) treatment. In this Review, we summarize data on the OV mechanism and limitations of monotherapy, which are currently in the process of combination partner development, especially with ICIs. We discuss some of the hurdles that have limited the preclinical and clinical development of OVs. We also describe the available data and provide guidance for optimizing OVs in clinical practice, as well as a summary of approved and promising novel OVs with clinical indications.
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Affiliation(s)
- Lingjuan Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Mengsi Zuo
- Department of Oncology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Qin Zhou
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), College of Bioengineering, Hubei University of Technology, Wuhan, China
| | - Yang Wang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), College of Bioengineering, Hubei University of Technology, Wuhan, China
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26
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Houel A, Foloppe J. [Oncolytic viruses: Actors and deliverers of therapeutic proteins against tumors]. Med Sci (Paris) 2023; 39:845-854. [PMID: 38018928 DOI: 10.1051/medsci/2023161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2023] Open
Abstract
The discovery of the unique ability of certain viruses to specifically target cancer cells has led to significant advancements in cancer immunotherapy research. In addition to inducing specific lysis of cancer cells, oncolytic viruses (OV) have been genetically modified to express molecules of interest within the tumor bed. The use of OV as vectors for therapeutic molecules has allowed to enhance antitumor responses while limiting the adverse effects associated with systemic administration of the molecule. Other studies are currently focused on delaying the neutralization and clearance of the virus by the host's immune system and improving its delivery insight tumors.
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Affiliation(s)
- Ana Houel
- UMRS 1 135 Sorbonne université, Paris, France - Inserm U1135, Paris, France - Équipe « Microenvironnement immunitaire et immunothérapie », centre d'immunologie et des maladies infectieuses (Cimi), faculté de médecine, Sorbonne université, Paris, France - Transgene, Illkirch-Graffenstaden, France
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27
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Liu S, Li F, Deng L, Ma Q, Lu W, Zhao Z, Liu H, Zhou Y, Hu M, Wang H, Yan Y, Zhao M, Zhang H, Du M. Claudin18.2 bispecific T cell engager armed oncolytic virus enhances antitumor effects against pancreatic cancer. Mol Ther Oncolytics 2023; 30:275-285. [PMID: 37701851 PMCID: PMC10493249 DOI: 10.1016/j.omto.2023.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 08/22/2023] [Indexed: 09/14/2023] Open
Abstract
Bispecific T cell engagers (BiTEs) represent a promising immunotherapy, but their efficacy against immunologically cold tumors such as pancreatic ductal adenocarcinoma remains unclear. Oncolytic viruses (OVs) can transform the immunosuppressive tumor microenvironment into the active state and also serve as transgene vectors to selectively express the desired genes in tumor cells. This study aimed to investigate whether the therapeutic benefits of tumor-targeting Claudin18.2 BiTE can be augmented by combining cancer selectively and immune-potentiating effects of OVs. Claudin18.2/CD3 BiTE was inserted into herpes simplex virus type 1 (HSV-1) to construct an OV-BiTE. Its expression and function were assessed using reporter cells and peripheral blood mononuclear cell (PBMC) co-culture assays. Intratumoral application of OV-BiTE restrained tumor growth and prolonged mouse survival compared with the unarmed OV in xenograft models and syngeneic mice bearing CLDN18.2-expressing KPC or Pan02 pancreatic cancer cells. Flow cytometry of tumor-infiltrating immune cells suggested both OV-BiTE and the unarmed OV remodeled the tumor microenvironment by increasing CD4+ T cell infiltration and decreasing regulatory T cells. OV-BiTE further reprogrammed macrophages to a more pro-inflammatory antitumor state, and OV-BiTE-induced macrophages exhibited greater cytotoxicity on the co-cultured tumor cell. This dual cytotoxic and immunomodulatory approach warrants further development for pancreatic cancer before clinical investigation.
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Affiliation(s)
- Shiyu Liu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Fan Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Li Deng
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Qiongqiong Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Wenyi Lu
- Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Zhuoqian Zhao
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Huanzhen Liu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Yixuan Zhou
- Department of Oromaxillofacial-Head and Neck Surgery, Tianjin Stomatological Hospital, Tianjin 300041, China
| | - Manli Hu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Hui Wang
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Yingbin Yan
- Department of Oromaxillofacial-Head and Neck Surgery, Tianjin Stomatological Hospital, Tianjin 300041, China
| | - Mingfeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Hongkai Zhang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing 100176, China
| | - Mingjuan Du
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
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Hamdan F, Fusciello M, Cerullo V. Personalizing Oncolytic Virotherapy. Hum Gene Ther 2023; 34:870-877. [PMID: 37698876 DOI: 10.1089/hum.2023.122] [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] [Indexed: 09/13/2023] Open
Abstract
The use of oncolytic viruses has become an attractive tool in the clinics for the treatment of various tumor types. Such viruses are genetically modified to conditionally replicate in malignant cells while unharming healthy cells. This platform offers a highly specific tumor killing with exceptional safety profiles. However, the use of oncolytic viruses as sole oncolytic platforms has not achieved full tumor clearance in murine models and in the clinics. In fact, the formation of anti-tumor immune responses is attributed to the effectiveness of oncolytic viruses. In this review, we will discuss the various strategies that scientists have employed to enhance the anti-tumor immune responses driven by oncolytic viruses. Moreover, focus will be drawn into personalizing such anti-tumor responses by the addition of tumor-associated peptides.
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Affiliation(s)
- Firas Hamdan
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
- Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Manlio Fusciello
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
- Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Vincenzo Cerullo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
- Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Sadri M, Najafi A, Rahimi A, Behranvand N, Hossein Kazemi M, Khorramdelazad H, Falak R. Hypoxia effects on oncolytic virotherapy in Cancer: Friend or Foe? Int Immunopharmacol 2023; 122:110470. [PMID: 37433246 DOI: 10.1016/j.intimp.2023.110470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods.
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Affiliation(s)
- Maryam Sadri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nafiseh Behranvand
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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30
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Li M, Zhang M, Ye Q, Liu Y, Qian W. Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy: a comprehensive review. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0202. [PMID: 37615308 PMCID: PMC10546091 DOI: 10.20892/j.issn.2095-3941.2023.0202] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/19/2023] [Indexed: 08/25/2023] Open
Abstract
Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration. Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication; however, recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments. Specifically, oncolytic vaccinia virus (OVV) has gained popularity owing to its safety, potential for systemic delivery, and large gene insertion capacity. This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo, and provides an overview of ongoing clinical trials and combination therapies. In addition, we discuss the potential benefits and drawbacks of OVV as a cancer therapy, and explore different perspectives in this field.
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Affiliation(s)
- Mengyuan Li
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Minghuan Zhang
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Qian Ye
- Hangzhou Rong-Gu Biotechnology Limited Company, Hangzhou 310056, China
| | - Yunhua Liu
- Department of Pathology & Pathophysiology and Department of Surgical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Wenbin Qian
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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31
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Muthukutty P, Yoo SY. Oncolytic Virus Engineering and Utilizations: Cancer Immunotherapy Perspective. Viruses 2023; 15:1645. [PMID: 37631987 PMCID: PMC10459766 DOI: 10.3390/v15081645] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Oncolytic viruses have positively impacted cancer immunotherapy over the past 20 years. Both natural and genetically modified viruses have shown promising results in treating various cancers. Various regulatory authorities worldwide have approved four commercial oncolytic viruses, and more are being developed to overcome this limitation and obtain better anti-tumor responses in clinical trials at various stages. Faster advancements in translating research into the commercialization of cancer immunotherapy and a comprehensive understanding of the modification strategies will widen the current knowledge of future technologies related to the development of oncolytic viruses. In this review, we discuss the strategies of virus engineering and the progress of clinical trials to achieve virotherapeutics.
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Affiliation(s)
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
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Wang X, Shen Y, Wan X, Hu X, Cai WQ, Wu Z, Xin Q, Liu X, Gui J, Xin HY, Xin HW. Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy. J Transl Med 2023; 21:500. [PMID: 37491263 PMCID: PMC10369732 DOI: 10.1186/s12967-023-04360-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/16/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. MAIN BODY Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. CONCLUSION OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.
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Affiliation(s)
- Xianwang Wang
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
| | - Yihua Shen
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xingxia Wan
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xiaoqing Hu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Wen-Qi Cai
- Xinzhou Traditional Chinese Medicine Hospital, Zhongnan Hospital of Wuhan University (Xinzhou), Wuhan, 430000, Hubei, China
| | - Zijun Wu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Qiang Xin
- School of Graduate Students, Inner Mongolia Medical University, Inner Mongolian Autonomous Region, Hohhot, 010110, China
| | - Xiaoqing Liu
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Jingang Gui
- Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Hong-Yi Xin
- The Doctoral Scientific Research Center, People's Hospital of Lianjiang, Guangdong, 524400, China.
- The Doctoral Scientific Research Center, Affiliated People's Hospital of Lianjiang, Guangdong Medical University, Guangdong, 524400, China.
| | - Hong-Wu Xin
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
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Zhu L, Lei Y, Huang J, An Y, Ren Y, Chen L, Zhao H, Zheng C. Recent advances in oncolytic virus therapy for hepatocellular carcinoma. Front Oncol 2023; 13:1172292. [PMID: 37182136 PMCID: PMC10169724 DOI: 10.3389/fonc.2023.1172292] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/07/2023] [Indexed: 05/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly refractory cancer and the fourth leading cause of cancer-related mortality worldwide. Despite the development of a detailed treatment strategy for HCC, the survival rate remains unsatisfactory. Oncolytic virus has been extensively researched as a new cancer therapeutic agent in the treatment of HCC. Researchers have designed a variety of recombinant viruses based on natural oncolytic diseases, which can increase the targeting of oncolytic viruses to HCC and their survival in tumors, as well as kill tumor cells and inhibit the growth of HCC through a variety of mechanisms. The overall efficacy of oncolytic virus therapy is known to be influenced by anti-tumor immunity, toxic killing effect and inhibition of tumor angiogenesis, etc. Therefore, a comprehensive review of the multiple oncolytic mechanisms of oncolytic viruses in HCC has been conducted. So far, a large number of relevant clinical trials are under way or have been completed, and some encouraging results have been obtained. Studies have shown that oncolytic virus combined with other HCC therapies may be a feasible method, including local therapy, chemotherapy, molecular targeted therapy and immunotherapy. In addition, different delivery routes for oncolytic viruses have been studied so far. These studies make oncolytic virus a new and attractive drug for the treatment of HCC.
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Affiliation(s)
- Licheng Zhu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Lei
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yahang An
- The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huangxuan Zhao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lin D, Shen Y, Liang T. Oncolytic virotherapy: basic principles, recent advances and future directions. Signal Transduct Target Ther 2023; 8:156. [PMID: 37041165 PMCID: PMC10090134 DOI: 10.1038/s41392-023-01407-6] [Citation(s) in RCA: 126] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 04/13/2023] Open
Abstract
Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune effects. With the progress in genetic engineering technology, OVs have been adopted as versatile platforms for developing novel antitumor strategies, used alone or in combination with other therapies. Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future. In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies based on their characteristics, biofunctions, and cancer hallmarks. Candidate OVs are expected to be designed as "qualified soldiers" first by improving target fidelity and safety, and then equipped with "cold weapons" for a proper cytocidal effect, "hot weapons" capable of activating cancer immunotherapy, or "auxiliary weapons" by harnessing tactics such as anti-angiogenesis, reversed metabolic reprogramming and decomposing extracellular matrix around tumors. Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects. Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.
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Affiliation(s)
- Danni Lin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China.
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
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35
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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.
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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
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36
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Basnet S, Santos JM, Quixabeira DCA, Clubb JHA, Grönberg-Vähä-Koskela SAM, Arias V, Pakola S, Kudling TV, Heiniö C, Havunen R, Cervera-Carrascon V, Sorsa S, Anttila M, Kanerva A, Hemminki A. Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors. Mol Ther Oncolytics 2023; 28:59-73. [PMID: 36699617 PMCID: PMC9842968 DOI: 10.1016/j.omto.2022.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated in vitro. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. In vivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.
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Affiliation(s)
- Saru Basnet
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
| | - Joao M Santos
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland
| | - Dafne C A Quixabeira
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
| | - James H A Clubb
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland
| | - Susanna A M Grönberg-Vähä-Koskela
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,Helsinki University Hospital (HUS), 00029, Helsinki, Finland
| | - Victor Arias
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
| | - Santeri Pakola
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,Helsinki University Hospital (HUS), 00029, Helsinki, Finland
| | - Tatiana V Kudling
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
| | - Camilla Heiniö
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
| | - Riikka Havunen
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland
| | - Victor Cervera-Carrascon
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland
| | - Suvi Sorsa
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland
| | - Marjukka Anttila
- Department of Pathology, Finnish Food Authority, 00790, Helsinki, Finland
| | - Anna Kanerva
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,Department of Gynecology and Obstetrics, Helsinki University Hospital, 00290, Helsinki, Finland
| | - Akseli Hemminki
- Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,TILT Biotherapeutics Ltd, 00290, Helsinki, Finland.,Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital, and University of Helsinki, 00029, Helsinki, Finland
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37
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Hamdan F, Cerullo V. Cancer immunotherapies: A hope for the uncurable? FRONTIERS IN MOLECULAR MEDICINE 2023; 3:1140977. [PMID: 39086690 PMCID: PMC11285639 DOI: 10.3389/fmmed.2023.1140977] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/07/2023] [Indexed: 08/02/2024]
Abstract
The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are crucially needed. In the review, we will discuss various forms of cancer immunotherapies that are being tested or already in the clinic. Moreover, we also highlight future directions to improve such therapies.
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Affiliation(s)
- Firas Hamdan
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- TRIMM, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Vincenzo Cerullo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- TRIMM, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
- Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Naples, Italy
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38
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Ma R, Li Z, Chiocca EA, Caligiuri MA, Yu J. The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer 2023; 9:122-139. [PMID: 36402738 PMCID: PMC9877109 DOI: 10.1016/j.trecan.2022.10.003] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/18/2022]
Abstract
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.
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Affiliation(s)
- Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute, Los Angeles, CA 91010, USA.
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39
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Shayan S, Arashkia A, Azadmanesh K. Modifying oncolytic virotherapy to overcome the barrier of the hypoxic tumor microenvironment. Where do we stand? Cancer Cell Int 2022; 22:370. [PMID: 36424577 PMCID: PMC9686061 DOI: 10.1186/s12935-022-02774-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 11/01/2022] [Indexed: 11/25/2022] Open
Abstract
Viruses are completely dependent on host cell machinery for their reproduction. As a result, factors that influence the state of cells, such as signaling pathways and gene expression, could determine the outcome of viral pathogenicity. One of the important factors influencing cells or the outcome of viral infection is the level of oxygen. Recently, oncolytic virotherapy has attracted attention as a promising approach to improving cancer treatment. However, it was shown that tumor cells are mostly less oxygenated compared with their normal counterparts, which might affect the outcome of oncolytic virotherapy. Therefore, knowing how oncolytic viruses could cope with stressful environments, particularly hypoxic environments, might be essential for improving oncolytic virotherapy.
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Affiliation(s)
- Sara Shayan
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
| | - Arash Arashkia
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
| | - Kayhan Azadmanesh
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
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40
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Wei M, Zuo S, Chen Z, Qian P, Zhang Y, Kong L, Gao H, Wei J, Dong J. Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors. Front Immunol 2022; 13:1017574. [PMID: 36451817 PMCID: PMC9702515 DOI: 10.3389/fimmu.2022.1017574] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/26/2022] [Indexed: 10/27/2023] Open
Abstract
Insufficient intratumoral T-cell infiltration and lack of tumor-specific immune surveillance in tumor microenvironment (TME) hinder the progression of cancer immunotherapy. In this study, we explored a recombinant vaccinia virus encoding an EpCAM BiTE (VV-EpCAM BiTE) to modulate the immune suppressive microenvironment to enhance antitumor immunity in several solid tumors. VV-EpCAM BiTE effectively infected, replicated and lysed malignant cells. The EpCAM BiTE secreted from infected malignants effectively mediated the binding of EpCAM-positive tumor cells and CD3ϵ on T cells, which led to activation of naive T-cell and the release of cytokines, such as IFN-γ and IL-2. Intratumoral administration of VV-EpCAM BiTE significantly enhanced antitumor activity in malignancies with high other than with low EpCAM expression level. In addition, immune cell infiltration was significantly increased in TME upon VV-EpCAM BiTE treatment, CD8+ T cell exhaustion was reduced and T-cell-mediated immune activation was markedly enhanced. Taken together, VV-EpCAM BiTE sophistically combines the antitumor advantages of bispecific antibodies and oncolytic viruses, which provides preclinical evidence for the therapeutic potential of VV-EpCAM BiTE.
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Affiliation(s)
- Min Wei
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Shuguang Zuo
- Liuzhou Key Laboratory of Molecular Diagnosis, Guangxi Key Laboratory of Molecular Diagnosis and Application, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Zhimin Chen
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
| | - Peng Qian
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Yenan Zhang
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Lingkai Kong
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Honglan Gao
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
| | - Jiwu Wei
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Jie Dong
- Affiliated Yancheng No.1 People’s Hospital, Medical School of Nanjing University, Yancheng, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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41
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Liguori L, Polcaro G, Nigro A, Conti V, Sellitto C, Perri F, Ottaiano A, Cascella M, Zeppa P, Caputo A, Pepe S, Sabbatino F. Bispecific Antibodies: A Novel Approach for the Treatment of Solid Tumors. Pharmaceutics 2022; 14:2442. [PMID: 36432631 PMCID: PMC9694302 DOI: 10.3390/pharmaceutics14112442] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Advancement in sequencing technologies allows for the identification of molecular pathways involved in tumor progression and treatment resistance. Implementation of novel agents targeting these pathways, defined as targeted therapy, significantly improves the prognosis of cancer patients. Targeted therapy also includes the use of monoclonal antibodies (mAbs). These drugs recognize specific oncogenic proteins expressed in cancer cells. However, as with many other types of targeting agents, mAb-based therapy usually fails in the long-term control of cancer progression due to the development of resistance. In many cases, resistance is caused by the activation of alternative pathways involved in cancer progression and the development of immune evasion mechanisms. To overcome this off-target resistance, bispecific antibodies (bsAbs) were developed to simultaneously target differential oncogenic pathway components, tumor-associated antigens (TAA) and immune regulatory molecules. As a result, in the last few years, several bsAbs have been tested or are being tested in cancer patients. A few of them are currently approved for the treatment of some hematologic malignancies but no bsAbs are approved in solid tumors. In this review, we will provide an overview of the state-of-the-art of bsAbs for the treatment of solid malignancies outlining their classification, design, main technologies utilized for production, mechanisms of action, updated clinical evidence and potential limitations.
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Affiliation(s)
- Luigi Liguori
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy
| | - Giovanna Polcaro
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Annunziata Nigro
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Valeria Conti
- Clinical Pharmacology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Carmine Sellitto
- Clinical Pharmacology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Francesco Perri
- Medical and Experimental Head and Neck Oncology Unit, INT IRCSS, Foundation “G. Pascale”, 80131 Naples, Italy
| | - Alessandro Ottaiano
- SSD Innovative Therapies for Abdominal Metastases, Abdominal Oncology, INT IRCCS Foundation “G. Pascale”, 80131 Naples, Italy
| | - Marco Cascella
- Unit of Anesthesiology and Pain Therapy, INT IRCCS Foundation “G. Pascale”, 80131 Naples, Italy
| | - Pio Zeppa
- Pathology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Alessandro Caputo
- Pathology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Stefano Pepe
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
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42
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Crupi MJF, Taha Z, Janssen TJA, Petryk J, Boulton S, Alluqmani N, Jirovec A, Kassas O, Khan ST, Vallati S, Lee E, Huang BZ, Huh M, Pikor L, He X, Marius R, Austin B, Duong J, Pelin A, Neault S, Azad T, Breitbach CJ, Stojdl DF, Burgess MF, McComb S, Auer R, Diallo JS, Ilkow CS, Bell JC. Oncolytic virus driven T-cell-based combination immunotherapy platform for colorectal cancer. Front Immunol 2022; 13:1029269. [PMID: 36405739 PMCID: PMC9670134 DOI: 10.3389/fimmu.2022.1029269] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/18/2022] [Indexed: 08/29/2023] Open
Abstract
Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer mortality worldwide, highlighting an urgent need for new therapeutic options and combination strategies for patients. The orchestration of potent T cell responses against human cancers is necessary for effective antitumour immunity. However, regression of a limited number of cancers has been induced by immune checkpoint inhibitors, T cell engagers (TCEs) and/or oncolytic viruses. Although one TCE has been FDA-approved for the treatment of hematological malignancies, many challenges exist for the treatment of solid cancers. Here, we show that TCEs targeting CEACAM5 and CD3 stimulate robust activation of CD4 and CD8-positive T cells in in vitro co-culture models with colorectal cancer cells, but in vivo efficacy is hindered by a lack of TCE retention in the tumour microenvironment and short TCE half-life, as demonstrated by HiBiT bioluminescent TCE-tagging technology. To overcome these limitations, we engineered Bispecific Engager Viruses, or BEVirs, a novel tumour-targeted vaccinia virus platform for intra-tumour delivery of these immunomodulatory molecules. We characterized virus-mediated TCE-secretion, TCE specificity and functionality from infected colorectal cancer cells and patient tumour samples, as well as TCE cytotoxicity in spheroid models, in the presence and absence of T cells. Importantly, we show regression of colorectal tumours in both syngeneic and xenograft mouse models. Our data suggest that a different profile of cytokines may contribute to the pro-inflammatory and immune effects driven by T cells in the tumour microenvironment to provide long-lasting immunity and abscopal effects. We establish combination regimens with immune checkpoint inhibitors for aggressive colorectal peritoneal metastases. We also observe a significant reduction in lung metastases of colorectal tumours through intravenous delivery of our oncolytic virus driven T-cell based combination immunotherapy to target colorectal tumours and FAP-positive stromal cells or CTLA4-positive Treg cells in the tumour microenvironment. In summary, we devised a novel combination strategy for the treatment of colorectal cancers using oncolytic vaccinia virus to enhance immune-payload delivery and boost T cell responses within tumours.
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Affiliation(s)
- Mathieu J. F. Crupi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Zaid Taha
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Thijs J. A. Janssen
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Julia Petryk
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Stephen Boulton
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Nouf Alluqmani
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Anna Jirovec
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Omar Kassas
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Sarwat T. Khan
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Sydney Vallati
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Emily Lee
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ben Zhen Huang
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Michael Huh
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Discovery Research, Turnstone Biologics Inc, Ottawa, ON, Canada
| | - Larissa Pikor
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Discovery Research, Turnstone Biologics Inc, Ottawa, ON, Canada
| | - Xiaohong He
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ricardo Marius
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Bradley Austin
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Jessie Duong
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Discovery Research, Turnstone Biologics Inc, Ottawa, ON, Canada
| | - Adrian Pelin
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Discovery Research, Turnstone Biologics Inc, Ottawa, ON, Canada
| | - Serge Neault
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Taha Azad
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | | | - David F. Stojdl
- Discovery Research, Turnstone Biologics Inc, Ottawa, ON, Canada
| | | | - Scott McComb
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Human Health Therapeutics Research Centre, National Research Council, Ottawa, ON, Canada
| | - Rebecca Auer
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Carolina S. Ilkow
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - John Cameron Bell
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
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Wang Z, Guo K, Liu Y, Huang C, Wu M. Dynamic impact of virome on colitis and colorectal cancer: Immunity, inflammation, prevention and treatment. Semin Cancer Biol 2022; 86:943-954. [PMID: 34656791 PMCID: PMC9008076 DOI: 10.1016/j.semcancer.2021.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 02/05/2023]
Abstract
The gut microbiome includes a series of microorganism genomes, such as bacteriome, virome, mycobiome, etc. The gut microbiota is critically involved in intestine immunity and diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC); however, the underlying mechanism remains incompletely understood. Clarifying the relationship between microbiota and inflammation may profoundly improve our understanding of etiology, disease progression, patient management, and the development of prevention and treatment. In this review, we discuss the latest studies of the influence of enteric viruses (i.e., commensal viruses, pathogenic viruses, and bacteriophages) in the initiation, progression, and complication of colitis and colorectal cancer, and their potential for novel preventative approaches and therapeutic application. We explore the interplay between gut viruses and host immune systems for its effects on the severity of inflammatory diseases and cancer, including both direct and indirect interactions between enteric viruses with other microbes and microbial products. Furthermore, the underlying mechanisms of the virome's roles in gut inflammatory response have been explained to infer potential therapeutic targets with examples in specific clinical trials. Given that very limited literature has thus far discussed these various topics with the gut virome, we believe these extensive analyses may provide insight into the understanding of the molecular pathogenesis of IBD and CRC, which could help add the design of improved therapies for these important human diseases.
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Affiliation(s)
- Zhihan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yingying Liu
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
| | - Min Wu
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA.
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44
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Zhu Z, McGray AJR, Jiang W, Lu B, Kalinski P, Guo ZS. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer 2022; 21:196. [PMID: 36221123 PMCID: PMC9554963 DOI: 10.1186/s12943-022-01664-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.
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Affiliation(s)
- Zhi Zhu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - A J Robert McGray
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Weijian Jiang
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Binfeng Lu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pawel Kalinski
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| | - Zong Sheng Guo
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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45
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Design Strategies and Precautions for Using Vaccinia Virus in Tumor Virotherapy. Vaccines (Basel) 2022; 10:vaccines10091552. [PMID: 36146629 PMCID: PMC9504998 DOI: 10.3390/vaccines10091552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/27/2022] [Accepted: 09/10/2022] [Indexed: 11/17/2022] Open
Abstract
Oncolytic virotherapy has emerged as a novel form of cancer immunotherapy. Oncolytic viruses (OVs) can directly infect and lyse the tumor cells, and modulate the beneficial immune microenvironment. Vaccinia virus (VACV) is a promising oncolytic vector because of its high safety, easy gene editing, and tumor intrinsic selectivity. To further improve the safety, tumor-targeting ability, and OV-induced cancer-specific immune activation, various approaches have been used to modify OVs. The recombinant oncolytic VACVs with deleting viral virulence factors and/or arming various therapeutic genes have displayed better therapeutic effects in multiple tumor models. Moreover, the combination of OVs with other cancer immunotherapeutic approaches, such as immune checkpoint inhibitors and CAR-T cells, has the potential to improve the outcome in cancer patients. This will open up new possibilities for the application of OVs in cancer treatment, especially for personalized cancer therapies.
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46
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Wang Q, Ma X, Wu H, Zhao C, Chen J, Li R, Yan S, Li Y, Zhang Q, Song K, Yuan C, Kong B. Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer. Oncoimmunology 2022; 11:2096362. [PMID: 35800156 PMCID: PMC9255048 DOI: 10.1080/2162402x.2022.2096362] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Qiuman Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Xinyue Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Huan Wu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Chen Zhao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Jingying Chen
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Shi Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Yingwei Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Qing Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Kun Song
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
- Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
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47
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Jin J, Wang R, Yang J, Hu H, Wang D, Cai L, Fang Z, Dong S, Hu S, Wang Y, Liu B. Bispecific Antibody Expressed by an Oncolytic Herpes Simplex Virus Type 2 Can Transform Heterologous T Cells Into Uniform Tumor Killer Cells. Hum Gene Ther 2022; 33:649-663. [PMID: 35272497 PMCID: PMC9242723 DOI: 10.1089/hum.2021.277] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BsAb (bispecific antibody)-armed oncolytic viruses (OVs) are effective in regulating tumor microenvironment. However, oHSV2 (oncolytic herpes simplex virus type 2) expressing immune checkpoints targeting BsAb molecules are not reported. Here, we generated oHSV2-armed PD-L1/CD3 BsAb and established pharmacodynamic evaluation models, which suggested that our oHSV2-BsAb molecules have an improved oncolytic potency in vitro and in vivo. The oHSV2 viruses armed with BsAb molecules targeting programmed cell death ligand 1 (PD-L1)/CD3 or CD19/CD3 (oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb) were constructed; besides inducing oncolysis in virus-infected tumor cells, the modified oncolytic virus oHSV2-PD-L1/CD3-BsAb can also activate peripheral blood mononuclear cells (PBMCs) by releasing PD-L1/CD3 BsAb and thereby induce PBMC-mediated killing of PD-L1-positive tumor cells, regardless of PD-L1 expression level. The expressed PD-L1/CD3 BsAb can upregulate the activation markers of T cells in PBMCs and induce different cytokine secretion. The activation of T cells and the enrichment of related immune regulatory pathways are further confirmed by proteomics. It also demonstrated that the OVs or PBMCs could upregulate PD-L1 expression on the surface of tumor cells through transforming "cold tumors" with low PD-L1 expression into "hot tumors" with high PD-L1 expression, which can facilitate the targeting of BsAb molecules and enhance the effect of oncolysis. oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb showed an enhanced oncolytic effect in vitro and in vivo compared to backbone virus oHSV2-GFP. Our results showed that the newly designed oHSV2-BsAb had enhanced therapeutic effects against solid tumors and provided a new option of immunotherapy.
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Affiliation(s)
- Jing Jin
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China
| | - Runyang Wang
- Wuhan Binhui Biopharmaceutical Co., Ltd., Wuhan, China
| | - Junhan Yang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China
| | - Han Hu
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China
| | - Di Wang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China
| | - Linkang Cai
- Wuhan Binhui Biopharmaceutical Co., Ltd., Wuhan, China
| | - Zhizheng Fang
- Wuhan Binhui Biopharmaceutical Co., Ltd., Wuhan, China
| | - Shuang Dong
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Hu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Prof. Sheng Hu, Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China.
| | - Yang Wang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China.,Correspondence: Prof. Binlei Liu and Prof. Yang Wang, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan 430068, China. ;
| | - Binlei Liu
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan, China.,Wuhan Binhui Biopharmaceutical Co., Ltd., Wuhan, China.,Correspondence: Prof. Binlei Liu and Prof. Yang Wang, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan 430068, China. ;
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48
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Wang L, Chard Dunmall LS, Cheng Z, Wang Y. Remodeling the tumor microenvironment by oncolytic viruses: beyond oncolysis of tumor cells for cancer treatment. J Immunother Cancer 2022; 10:e004167. [PMID: 35640930 PMCID: PMC9157365 DOI: 10.1136/jitc-2021-004167] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2022] [Indexed: 12/25/2022] Open
Abstract
Tumor cells manipulate the local environment in which they grow, creating a tumor microenvironment (TME) that promotes tumor survival and metastasis. The TME is an extremely complex environment rich in immunosuppressive cells and cytokines. Various methods to therapeutically target the complicated TME are emerging as a potential approach for cancer treatment. Oncolytic viruses (OVs) are one of the most promising methods for remodeling the TME into an antitumor environment and can be used alone or in combination with other immunotherapy options. OVs replicate specifically in tumor cells and can be genetically engineered to target multiple elements of the TME simultaneously, thus representing a therapeutic with the potential to modify the TME to promote activation of antitumor immune cells and overcome tumor therapeutic resistance and recurrence. In this review, we analyze the tropism of OVs towards tumor cells and explore the interaction between OVs and immune cells, tumor stroma, vasculature and the metabolic environment in detail to help understand how OVs may be one of our most promising prospects for long-term curative therapies. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field.
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Affiliation(s)
- Lihong Wang
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Louisa S Chard Dunmall
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Zhenguo Cheng
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
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49
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Mardi A, Shirokova AV, Mohammed RN, Keshavarz A, Zekiy AO, Thangavelu L, Mohamad TAM, Marofi F, Shomali N, Zamani A, Akbari M. Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction. Cancer Cell Int 2022; 22:168. [PMID: 35488303 PMCID: PMC9052538 DOI: 10.1186/s12935-022-02585-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a promising and rapidly expanding therapeutic option for a wide range of human malignancies. Despite the ongoing progress of CAR T-cell therapy in hematologic malignancies, the application of this therapeutic strategy in solid tumors has encountered several challenges due to antigen heterogeneity, suboptimal CAR T-cell trafficking, and the immunosuppressive features of the tumor microenvironment (TME). Oncolytic virotherapy is a novel cancer therapy that employs competent or genetically modified oncolytic viruses (OVs) to preferentially proliferate in tumor cells. OVs in combination with CAR T-cells are promising candidates for overcoming the current drawbacks of CAR T-cell application in tumors through triggering immunogenic cell death (ICD) in cancer cells. ICD is a type of cellular death in which danger-associated molecular patterns (DAMPs) and tumor-specific antigens are released, leading to the stimulation of potent anti-cancer immunity. In the present review, we discuss the biological causes of ICD, different types of ICD, and the synergistic combination of OVs and CAR T-cells to reach potent tumor-specific immunity.
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Affiliation(s)
- Amirhossein Mardi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anastasia V Shirokova
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Science, Cihan University of Sulaimaniya, Suleimanyah, Kurdistan region, Iraq.,College of. Veterinary Medicine, University of Sulaimani, Suleimanyah, Iraq
| | - Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Talar Ahmad Merza Mohamad
- Department of Pharmacology and Toxicology, Clinical Pharmacy, Hawler Medical University, College of Pharmacy, Kurdistan Region-Erbil, Iraq
| | - Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Lei W, Ye Q, Hao Y, Chen J, Huang Y, Yang L, Wang S, Qian W. CD19-targeted BiTE expression by an oncolytic vaccinia virus significantly augments therapeutic efficacy against B-cell lymphoma. Blood Cancer J 2022; 12:35. [PMID: 35228544 PMCID: PMC8885649 DOI: 10.1038/s41408-022-00634-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/06/2022] [Accepted: 02/14/2022] [Indexed: 12/28/2022] Open
Abstract
Immunotherapy with CD19-targeting bispecific T-cell engagers (CD19BiTEs) has demonstrated highly effective killing of cancer cells in patients with precursor acute lymphoblastic leukemia and non-Hodgkin's lymphomas. However, there are some drawbacks to this therapy, such as toxicity, short half-life in the serum, and immunosuppressive tumor microenvironment that could limit the use of CD19BiTEs in the clinic. Here, we generate an oncolytic vaccinia virus (OVV) encoding a CD19-specific BiTE (OVV-CD19BiTE). We demonstrate that OVV-CD19BiTE's ability to replicate and induce oncolysis was similar to that of its parental counterpart. Supernatants from OVV-CD19BiTE-infected cells could induce activation and proliferation of human T cells, and the bystander effect of the virus was also demonstrated. In vivo study showed that OVV-CD19BiTE selectively replicated within tumor tissue, and contributed to a more significantly increased percentage of CD3, CD8, and naïve CD8 T subpopulations within tumors in contrast to blinatumomab. More importantly, treatment with OVV-CD19BiTE both in vitro and in vivo resulted in potent antitumor activity in comparison with control OVV or blinatumomab, a first-in-class BiTE, thereby resulting in long-term tumor remissions without relapse. The study provides strong evidence for the therapeutic benefits of CD19-targeting BiTE expression by OVV, and suggests the feasibility of testing the approach in clinical trials.
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Affiliation(s)
- Wen Lei
- Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, P. R. China.,Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Qian Ye
- Hangzhou RongGu Biotechnology Limited Company, 310056, Hangzhou, Zhejiang, P. R. China
| | - Yuanyuan Hao
- Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, P. R. China.,Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Jie Chen
- Hangzhou RongGu Biotechnology Limited Company, 310056, Hangzhou, Zhejiang, P. R. China
| | - Yu Huang
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, 310053, Hangzhou, Zhejiang, P. R. China
| | - Liu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014, Hangzhou, Zhejiang, P. R. China
| | - Shibing Wang
- Cancer Center, Molecular Diagnosis Laboratory, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014, Hangzhou, Zhejiang, P. R. China.
| | - Wenbin Qian
- Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, P. R. China. .,Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China.
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