Abstract
Oncolytic viruses (OVs) not only kill cancer cells by direct lysis but also generate a significant anti-tumor immune response that allows for prolonged cancer control and in some cases cures. How to best stimulate this effect is a subject of intense investigation in the OV field. While pharmacological manipulation of the cellular innate anti-viral immune response has been shown by several groups to improve viral oncolysis and spread, it is increasingly clear that pharmacological agents can also impact the anti-tumor immune response generated by OVs and related tumor vaccination strategies. This review covers recent progress in using pharmacological agents to improve the activity of OVs and their ability to generate robust anti-tumor immune responses.
Highlights
ONCOLYTIC VIRUSES: MULTI-MECHANISTIC BIOTHERAPEUTICS AGAINST CANCER Oncolytic viruses (OVs) are self-amplifying biotherapeutics that have been selected or engineered to preferentially infect and kill cancer cells
How much tumor infection and lysis are necessary to trigger these responses remains a topic of debate; it is clear that the combination of direct oncolysis and activation of anti-tumor immunity can lead to durable cures in pre-clinical mouse models of cancer
Profound tumor regression is common following treatment with OVs; for example, durable objective responses were observed in 3/14 patients following treatment with vaccinia virus JX-594 in a phase I trial [7]
Summary
ONCOLYTIC VIRUSES: MULTI-MECHANISTIC BIOTHERAPEUTICS AGAINST CANCER Oncolytic viruses (OVs) are self-amplifying biotherapeutics that have been selected or engineered to preferentially infect and kill cancer cells. Profound tumor regression is common following treatment with OVs; for example, durable objective responses were observed in 3/14 patients (hepatocarcinoma, lung cancer, and melanoma) following treatment with vaccinia virus JX-594 in a phase I trial [7] This virus has been deleted for viral thymidine kinase (TK), making it dependent on cellular TK that is overexpressed in cancer cells [7]. While widespread approval and clinical implementation of oncolytic virotherapy are in the foreseeable future, heterogeneity in clinical response to OVs remains a significant challenge as evidenced from a number of early and late-stage human clinical trials [6, 15, 16] This heterogeneity in response can be attributed to factors that impact OV delivery and spread within tumors, such as pre-existing immunity and remnant tumor anti-viral responses, as well as to a variably immunosuppressive tumor microenvironment that can prevent the generation of an effective anti-tumor immune response.
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