Tune Up In Situ Autovaccination against Solid Tumors with Oncolytic Viruses

Abstract

With the progress of immunotherapy in cancer, oncolytic viruses (OVs) have attracted more and more attention during the past decade. Due to their cancer-selective and immunogenic properties, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. The main challenge in OV approaches is how to redirect the host immunity from anti-virus to anti-tumor and optimize the clinical outcome of cancer patients. Here, we summarize the conceptual updates on oncolytic virotherapy and immunotherapy in cancer, and the development of strategies to enhance the virus-mediated anti-tumor immune response, including: (1) arm OVs with cytokines to modulate innate and adaptive immunity; (2) combining OVs with immune checkpoint inhibitors to release T cell inhibition; (3) combining OVs with immune co-stimulators to enhance T cell activation. Future studies need to be enforced on developing strategies to augment the systemic effect on metastasized tumors.

Keywords: cytokine; immune checkpoint inhibitor; immune co-stimulator; in situ autovaccination; oncolytic virus.

Figure 1

Strategies to improve oncolytic virus-mediated anti-tumor immunity. Oncolytic viruses (OVs) infect and replicate inside cancer cells, resulting in cell lysis and propagation of virions to infect nearby cancer cells. This process generates pathogen-associated molecular patterns (PAMPs) and damage- (or danger-) associated molecular patterns (DAMPs) that trigger an innate immune response to modulate the tumor microenvironment, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. In the infected tumor cells, OVs also induce autophagy (autophagosome formation) and activity of proteasome to increase their capability to function as APC to present tumor-associated antigens (TAAs) to T cells. OVs have been combined with immune modulators to enhance immunity against the tumor. Cytokines expressed by OVs stimulate innate and adaptive immunity within the tumor. Combination of OVs with immune checkpoint blockade through antibodies to inhibit the interaction between immune checkpoint ligand (ICL) and receptor (ICR), or with agonist antibody or expression of the co-stimulatory ligand (CSL) to bind with the co-stimulatory receptor (CSR) augments T cell receptor (TCR) signaling initiated by the virus through presenting TAAs with major histocompatibility complex (MHC), leading to enhanced T cell activation against the tumor.