Abstract
The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers) have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future.
Highlights
Successful cancer therapy using oncolytic viruses (OV) is predicated on at least three major mechanisms of action
Zamarin and others demonstrated in mouse models that localized immunotherapy with oncolytic NDV combined with anti-CTLA4 Ab could cure the majority of treated tumorbearing mice, while treatment with NDV alone was effective in only 10% of cases
As we and others have previously suggested, this immunosuppressive property poses a doubleedge sword in consideration of OV-based immunotherapy. Such suppression limits immune regulation of viral replication in support of direct oncolysis, but it represents a major impediment to the development, targeting and operational integrity of protective antitumor immunity that appears crucial to the durable clinical success of OV-based interventional strategies
Summary
Successful cancer therapy using oncolytic viruses (OV) is predicated on at least three major (and coordinate) mechanisms of action. Oncolytic Immunotherapy Goes Combinatorial than 10 years ago, most, if not all, investigators thought that the direct oncolysis was the only major mechanism by which OVs inhibited tumor growth, leading to the terminology of “oncolytic virotherapy,” coined by Kirn in 2001 [4]. Investigators discovered that the host immune response was critical to the antitumor efficacy of oncolytic virotherapy This has been shown through multiple approaches including the use of [1] an OV encoding a tumor antigen to potently activate therapeutic T cell responses [5]; [2] reovirus infection of tumor cells to prime antitumor immunity capable of reducing metastatic disease burden [6]; and [3] CD8+ T cell depletion resulting in the loss of efficacy associated with OV-based treatment [7]. Our discussion will focus on combination regimens likely to yield superior antitumor immunity associated with improved treatment outcomes
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