Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials

Abstract

Advances in the understanding of cancer immunotherapy and the development of multiple checkpoint inhibitors have dramatically changed the current landscape of cancer treatment. Recent large-scale phase III trials (e.g. PHOCUS, OPTiM) are establishing use of oncolytic viruses as another tool in the cancer therapeutics armamentarium. These viruses do not simply lyse cells to achieve their cancer-killing effects, but also cause dramatic changes in the tumor immune microenvironment. This review will highlight the major vector platforms that are currently in development (including adenoviruses, reoviruses, vaccinia viruses, herpesviruses, and coxsackieviruses) and how they are combined with checkpoint inhibitors. These vectors employ a variety of engineered capsid modifications to enhance infectivity, genome deletions or promoter elements to confer selective replication, and encode a variety of transgenes to enhance anti-tumor or immunogenic effects. Pre-clinical and clinical data have shown that oncolytic vectors can induce anti-tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8 + T cells) into the local tumor microenvironment. This “priming” by the viral infection can change a ‘cold’ tumor microenvironment into a ‘hot’ one with the influx of a multitude of immune cells and cytokines. This alteration sets the stage for subsequent checkpoint inhibitor delivery, as they are most effective in an environment with a large lymphocytic infiltrate. There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey-265), and the initial results are encouraging. It is clear that oncolytic viruses and checkpoint inhibitors will continue to evolve together as a combination therapy for multiple types of cancers.

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

“…Several other oncolytic viruses have shown efficacy in urothelial carcinomas and some are currently tested in clinical trials [38]. Combination of oncolytic viruses with immune checkpoint inhibitors and targeted therapies has been proven to be a successful strategy to enhance the efficiency of therapy response to oncolytic virus [39,40]. There are studies showing that targeting the JAK-STAT pathway in combination with the oncolytic herpes simplex virus and vesicular stomatitis viruses could enhance their efficiency possibly by modulating IFN signalling [41,42].…”

Oncolytic Viruses: Priming Time for Cancer Immunotherapy

“…Rational combination approaches to cancer immunotherapy include the use of OVs to inflame the tumor and recruit a variety of immune cells to the tumor microenvironment through inflammatory viral oncolysis in combination with ICI or ACT therapies to promote sustained antitumoral immune responses [103,104] (Fig. 1).…”

Poly(cyclodextrin)‐Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy

“…[ 17 ] In addition, various chemotherapeutic drugs and checkpoint inhibitors have been explored to enhance the therapeutic outcomes of OV. [ 77–81 ] Nevertheless, uncertainty of potential genetic interference into host cells is indicated as one of the main problems of OV. Herein, pPTX/pCD‐pSNO recapitulated some of the major distinctive antitumor mechanisms of OVs (Scheme 1).…”