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Immunomodulatory Arming Factors-The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules.

ABSTRACT: The dogma of engineering oncolytic viral vectors has shifted from emphasizing the viral lysis of individual cancer cells to the recruitment and coordination of the adaptive immune system to clear the tumor. To accomplish this, researchers have been adding several classes of transgenes to their preferred viral platforms. The most prevalent of these include antibodies and targeting moieties, interleukins and cytokines, and genes which rely on small molecule co-administration for tumor killing. Most current vectors rely exclusively on one of these types of transgenes to elicit the desired immune response to clear tumors, but are not mutually exclusive, with several larger OVs armed with several of these factors. The common theme of emerging armed vectors is to simply initiate or enhance infiltration of effector CD8+ T cells to clear the tumor locally at OV infection sites, and systemically throughout the body where the OV has not infected tumor cells. The precision of oncolytic vectors to target a cell type or tissue remains its key advantage over small-molecule drugs. Unlike chemo- and other drug therapies, viral vectors can be made to specifically infect and grow within tumor cells. This ensures localized expression of the therapeutic transgene to the diseased tissue, thereby limiting systemic toxicity. This review will examine the immunomodulating transgenes of current OVs, describe their general effect on the immune system, and provide the rationale for each vector's use in clearing its targeted tumor.

SUBMITTER: Peters CWD

PROVIDER: S-EPMC8396515 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Identification of the immune suppressive mechanisms active within the tumor microenvironment led to development of immunotherapeutic strategies aiming to reverse the immunosuppression and to enhance the function of tumor-infiltrating lymphocytes. Of those, cancer therapy with antibodies targeting the immune costimulatory and coinhibitory receptors has demonstrated significant promise in the recent years, with multiple antibodies entering clinical testing. The responses to these agents, however, have not been universal and have not been observed in all cancer types, calling for identification of appropriate predictive biomarkers and development of combinatorial strategies. Pre-existing immune infiltration in tumors has been demonstrated to have a strong association with response to immunotherapies, with the type I interferon (IFN) pathway emerging as a key player in tumor innate immune recognition and activation of adaptive immunity. These findings provide a rationale for evaluation of strategies targeting the type I IFN pathway as a means to enhance tumor immune recognition and infiltration, which could potentially make them susceptible to therapeutics targeting the cosignaling receptors. To this end in particular, oncolytic viruses (OVs) have been demonstrated to enhance tumor recognition by the immune system through multiple mechanisms, which include upregulation of major histocompatibility complex and costimulatory molecules on cancer cells, immunogenic cell death and antigen release, and activation of the type I IFN pathway. Evidence is now emerging that combination therapies using OVs and agents targeting immune cosignaling receptors such as 4-1BB, PD-1, and CTLA-4 may work in concert to enhance antitumor immunity and therapeutic efficacy. Our evolving understanding of the interplay between OVs and the immune system demonstrates that the virus-induced antitumor immune responses can be harnessed to drive the efficacy of the agents targeting cosignaling receptors and provides a strong rationale for integration of such therapies in clinic.

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Immunomodulatory Arming Factors-The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules.

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