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 in 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 inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/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, , designated Δ MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with Δ confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that Δ 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 Δ MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that Δ treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4 T cells. Overall, Δ presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine.