A Replication‐Defective Myxoma Virus Inducing Pro‐Inflammatory Responses as Monotherapy and an Adjuvant to Chemo‐ and DC Immuno‐Therapy for Ovarian Cancer

Myxoma virus (MYXV), a rabbit specific poxvirus and non-pathogenic to humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor associated macrophages (TAMs) are key to inhibit antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macropahges/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated M062R MYXV, activated both host DNA sensing pathway and the SAMD9 pathway. Treatment with M062R leads to therapeutic benefit as monotherapy comparable to wildtype replicating MYXV in preclinical models. Here we found that M062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit likely through promoting tumor antigen-specific T cell function. Moreover, we also tested M062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that M062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4+ T cells. Overall, M062R presents a promising immunotherapeutic platform and is as a beneficial adjuvant to chemotherapy and DC vaccine.