Immune recruitment and therapeutic synergy: keys to optimizing oncolytic viral therapy?

Abstract

Oncolytic viruses consist of a diverse range of DNA and RNA viruses traditionally thought to mediate their effects by exploiting aberrations in tumor pathways, allowing preferential viral replication in, and killing of, tumor cells. Clinical development has progressed to late-phase trials, potentially heralding their introduction into clinical practice. However, despite this promise, the activity of oncolytic viruses has yet to achieve the potential suggested in preclinical models. To address this disparity, we need to recognize the complex interaction among oncolytic viruses, tumor, chemotherapy, and host immune system, and appreciate that direct oncolysis may not be the only factor to play an important role in oncolytic virus-mediated antitumor efficacy. Although key in inactivating viruses, the host immune system can also act as an ally against tumors, interacting with oncolytic viruses under the right conditions to generate useful and long-lasting antitumor immunity. Preclinical data also suggest that oncolytic viruses show synergy with standard therapies, which may offer improved clinical response rates. Here, we explore clinical and preclinical data on clinically relevant oncolytic viruses, highlighting areas of progress, uncertainty, and translational opportunity, with respect to immune recruitment and therapeutic synergy.

Fig. 1

Tumor selective replication of oncolytic viruses: The figure illustrates aberrant tumor pathways that offer redundancy to oncolytic viral genes contributing to tumor selectivity: [1] Activation of EGFR abrogates vgf that normally stimulates EGFR, in readiness for vaccinia infection; [2] Activation of RAS induces an inhibitor of PKR, that would normally prevent translation of RNA viral (reovirus or NDV) genes, to control infection; [3] Aberrantly activated protein expression compensates for ICP-34 absence (ICP-34 normally induces protein expression) restricting replication to dividing (tumor) cells; [4] Tumor suppressor inactivation can compensate for absent viral proteins, e.g. E1B is normally required to inactivate p53; [5] Up-regulated cellular TK in tumor compensates for absent TK in tk deleted VV (tk-); [6] Interferon responses are powerful mediators of anti-viral responses, and often impaired in tumors especially benefitting RNA viruses NDV and VSV. Downstream attenuation of PKR also benefits the replication of reovirus and ICP34 deleted HSV. Clinically relevant OV examples are given in brackets.