Genetic modification of oncolytic viruses to enhance antitumor immunity

Oncolytic viruses (OVs) are novel and rapidly developing class of therapeutic agents for combating cancer, which can effectively infect and destroy tumor cells, leaving healthy tissues intact. Many viruses have a natural antitumor activity which causes cytolysis of cancer cells due to direct pathogenic action. Along with non-immunogenic cell death, oncolytic viruses have been shown to be capable of inducing immunogenic cancer cell death (necrosis, pyroptosis, etc.) accompanied by the release of OV-lysed tumor-associated antigens (TAAs). Releasing DAMPs and TAAs, in its turn, leads to the activation of adaptive antitumor immunity. In order to further enhance the antitumor immunity, OVs have been armed with immunostimulatory transgenes such as granulocyte-macrophage colony-stimulating factor (GM-CSF), type I interferons, interleukins (IL-2, 12, 15), costimulatory ligands (CD40, CD80), tumor antigens («prime-boost» vaccination), which further enhances the safety and effectiveness of oncolytic virotherapy. Preliminary results of randomized clinical trials of different approaches of oncolytic virotherapies in combination with immunotherapy confirm their high efficacy. However, there are some drawbacks, which necessitates their further study.

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Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies

Annals of Surgical Oncology ◽

10.1245/s10434-020-09477-4 ◽

2021 ◽

Author(s):

Chigozirim N. Ekeke ◽

Kira L. Russell ◽

Kyla Joubert ◽

David L. Bartlett ◽

James D. Luketich ◽

...

Keyword(s):

Measles Virus ◽

Antitumor Immunity ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Effective Strategies ◽

Current State ◽

Systemic Treatments ◽

High Incidence ◽

Tumor Specificity ◽

Thoracic Malignancies

AbstractThoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.

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Oncolytic Immunotherapy: Where Are We Clinically?

Scientifica ◽

10.1155/2014/862925 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Akseli Hemminki

Keyword(s):

Antitumor Immunity ◽

Clinical Work ◽

Mechanisms Of Action ◽

Oncolytic Viruses ◽

Immunostimulatory Activity ◽

Phase 3 ◽

Safety And Efficacy ◽

Relative Contribution ◽

Added Benefit ◽

Oncolytic Immunotherapy

Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of “pure” oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects.

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Current strategies to circumvent the antiviral immunity to optimize cancer virotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002086 ◽

2021 ◽

Vol 9 (4) ◽

pp. e002086

Author(s):

Dong Ho Shin ◽

Teresa Nguyen ◽

Bulent Ozpolat ◽

Frederick Lang ◽

Marta Alonso ◽

...

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Immune Responses ◽

Treatment Modality ◽

Antitumor Immunity ◽

Antiviral Immunity ◽

Clinical Impact ◽

Oncolytic Viruses ◽

Paradigm Shifting

Cancer virotherapy is a paradigm-shifting treatment modality based on virus-mediated oncolysis and subsequent antitumor immune responses. Clinical trials of currently available virotherapies showed that robust antitumor immunity characterizes the remarkable and long-term responses observed in a subset of patients. These data suggest that future therapies should incorporate strategies to maximize the immunotherapeutic potential of oncolytic viruses. In this review, we highlight the recent evidence that the antiviral immunity of the patients may limit the immunotherapeutic potential of oncolytic viruses and summarize the most relevant approaches to strategically redirect the immune response away from the viruses and toward tumors to heighten the clinical impact of viro-immunotherapy platforms.

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Current strategies in engaging oncolytic viruses with antitumor immunity

Molecular Therapy — Oncolytics ◽

10.1016/j.omto.2021.05.002 ◽

2021 ◽

Author(s):

Drew Ashton Boagni ◽

Divya Ravirala ◽

Shaun Xiaoliu Zhang

Keyword(s):

Antitumor Immunity ◽

Oncolytic Viruses

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Oncolytic Viruses and Cancer, Do You Know the Main Mechanism?

Frontiers in Oncology ◽

10.3389/fonc.2021.761015 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wesam Kooti ◽

Hadi Esmaeili Gouvarchin Ghaleh ◽

Mahdieh Farzanehpour ◽

Ruhollah Dorostkar ◽

Bahman Jalali Kondori ◽

...

Keyword(s):

Cell Death ◽

Cancer Treatment ◽

Cancer Cells ◽

Antitumor Immunity ◽

Malignant Tumors ◽

Mechanisms Of Action ◽

Oncolytic Viruses ◽

Global Rate ◽

Recent Developments ◽

Review Study

The global rate of cancer has increased in recent years, and cancer is still a threat to human health. Recent developments in cancer treatment have yielded the understanding that viruses have a high potential in cancer treatment. Using oncolytic viruses (OVs) is a promising approach in the treatment of malignant tumors. OVs can achieve their targeted treatment effects through selective cell death and induction of specific antitumor immunity. Targeting tumors and the mechanism for killing cancer cells are among the critical roles of OVs. Therefore, evaluating OVs and understanding their precise mechanisms of action can be beneficial in cancer therapy. This review study aimed to evaluate OVs and the mechanisms of their effects on cancer cells.

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Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses

Frontiers in Oncology ◽

10.3389/fonc.2020.561372 ◽

2021 ◽

Vol 10 ◽

Author(s):

Bin Zhang ◽

Xilei Wang ◽

Ping Cheng

Keyword(s):

Antitumor Immunity ◽

Antitumor Agents ◽

Genetically Engineered ◽

Carcinoma Cells ◽

Oncolytic Viruses ◽

Host Immune System ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Therapeutic Mechanisms ◽

Potential Antitumor

Oncolytic viruses (OVs) are potential antitumor agents with unique therapeutic mechanisms. They possess the ability of direct oncolysis and the induction of antitumor immunity. OV can be genetically engineered to potentiate antitumor efficacy by remodeling the tumor immune microenvironment. The present mini review mainly describes the effect of OVs on remodeling of the tumor immune microenvironment and explores the mechanism of regulation of the host immune system and the promotion of the immune cells to destroy carcinoma cells by OVs. Furthermore, this article focuses on the utilization of OVs as vectors for the delivery of immunomodulatory cytokines or antibodies.

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An engineered oncolytic vaccinia virus encoding a single-chain variable fragment against TIGIT induces effective antitumor immunity and synergizes with PD-1 or LAG-3 blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002843 ◽

2021 ◽

Vol 9 (12) ◽

pp. e002843

Author(s):

Shuguang Zuo ◽

Min Wei ◽

Tiancheng Xu ◽

Lingkai Kong ◽

Bohao He ◽

...

Keyword(s):

T Cell ◽

Antitumor Immunity ◽

Complete Response ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Antitumor Efficacy ◽

Single Chain Variable Fragment ◽

Single Chain ◽

Tumor Bearing ◽

T Cell Infiltration

BackgroundIn addition to directly lysing tumors, oncolytic viruses also induce antitumor immunity by recruiting and activating immune cells in the local tumor microenvironment. However, the activation of the immune cells induced by oncolytic viruses is always accompanied by high-level expression of immune checkpoints in these cells, which may reduce the efficacy of the oncolytic viruses. The aim of this study is to arm the oncolytic vaccinia virus (VV) with immune checkpoint blockade to enhance its antitumor efficacy.MethodsThrough homologous recombination with the parental VV, an engineered VV-scFv-TIGIT was produced, which encodes a single-chain variable fragment (scFv) targeting T-cell immunoglobulin and ITIM domain (TIGIT). The antitumor efficacy of the VV-scFv-TIGIT was explored in several subcutaneous and ascites tumor models. The antitumor efficacy of VV-scFv-TIGIT combined with programmed cell death 1 (PD-1) or lymphocyte-activation gene 3 (LAG-3) blockade was also investigated.ResultsThe VV-scFv-TIGIT effectively replicated in tumor cells and lysed them, and prompt the infected tumor cells to secret the functional scFv-TIGIT. Compared with control VV, intratumoral injection of VV-scFv-TIGIT in several mouse subcutaneous tumor models showed superior antitumor efficacy, accompanied by more T cell infiltration and a higher degree of CD8+ T cells activation. Intraperitoneal injection of VV-scFv-TIGIT in a mouse model of malignant ascites also significantly improved T cell infiltration and CD8+ T cell activation, resulting in more than 90% of the tumor-bearing mice being cured. Furthermore, the antitumor immune response induced by VV-scFv-TIGIT was dependent on CD8+ T cells which mediated a long-term immunological memory and a systemic antitumor immunity against the same tumor. Finally, the additional combination of PD-1 or LAG-3 blockade further enhanced the antitumor efficacy of VV-scFv-TIGIT, increasing the complete response rate of tumor-bearing mice.ConclusionsOncolytic virotherapy using engineered VV-scFv-TIGIT was an effective strategy for cancer immunotherapy. Administration of VV-scFv-TIGIT caused a profound reshaping of the suppressive tumor microenvironment from ‘cold’ to ‘hot’ status. VV-scFv-TIGIT also synergized with PD-1 or LAG-3 blockade to achieve a complete response to tumors with poor response to VV or immune checkpoint blockade monotherapy.

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