TNF Prevents Establishment of Anti-Tumor Immunity and Elucidates Toxicities Following Myxoma Virus Based Oncolytic Virotherapy

Tumor Necrosis Factor Alpha (TNF) can lead to tumor regression through its direct cytolytic activity, yet it has also been implicated to facilitate tumor progression. This scenario complicates the efficacy and applicability of TNF based therapeutics as treatment for malignancies. In the context of oncolytic virotherapy (OV) which uses replicating viruses to treat tumors and acts by triggering production of pro-inflammatory cytokines, exploring such mechanisms is vital. Here we show that a Myxoma based oncolytic virus (vPD1/IL12) can induce large amounts TNF. The presence of TNF in the context of vPD1/IL12 plays a detrimental role both for tumor regression by preventing establishment of anti-tumor immunity and inducing toxicities. Both phenomena can be alleviated by targeting certain forms of TNF using FDA approved TNF blockers. These data suggest that some aspects of OV-induced inflammation might represent a double-edged sword during therapy and that specific blockade of TNF might enhance the efficacy of these treatments.