Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

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.

Keywords: ICD inducer; T cells; antigen; antitumor immunity; combination; cross-presentation; immune checkpoint blockade; immunogenic cell death.

Figure 1

Proposed model for ICD and pro-inflammatory cytokines/chemokines (Th1) promotion of oncolytic virus (OV)-mediated antitumor-immunity. (1) OV infects tumor cells and induces ICD, leading to the release/presentation of signal 0 [damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)], along with tumor-associated antigens (TAAs) to dendritic cells (DCs), resulting in DC activation and Ag cross-presentation to antiviral and antitumor immune cells (activated NK cells, CD4⁺ and CD8⁺ T cells), followed by clonal expansion and maturation of antitumor T effector cells. (2) Cytokines/chemokines released during the acute inflammation in the tumor microenvironment (TME) promote trafficking of therapy-induced immune cells into the TME; (3) inflammation in the TME is sponsored by both viral- and tumor-reactive T cells, with immune-mediated eradication of tumor cells and tumor-associated stromal cells. Additional danger signals (signal 0), inflammatory cytokines, and chemokines (signal 3) and TAAs (signal 1) further activate tumor-associated DCs, overcoming local immunosuppression and prolonging the survival and functionality of antitumor immune cell populations; (4) reiterative rounds of DC-mediated cross-priming continue to allow for delivery of new (reinforcement) T immune effector cells into the TME (5) allowing for sustained antitumor efficacy within disseminated sites of disease.