Cancer Immunotherapy with IL-15Rα-armed Oncolytic Myxoma Virus Enhances Antitumor Immunity Against Solid Tumors 2260773

Abstract

Abstract Introduction Immunologically cold tumors and metastatic lesions are a major therapeutic challenge due in part to tumor heterogeneity, a lack of immune infiltration, and defects in tumor-associated antigen presentation. Oncolytic virotherapy is a promising strategy that can overcome immunosuppression and enhance antitumor responses. Myxoma virus (MYXV), a rabbit-specific poxvirus, can infect and kill cancer cells while leaving healthy cells unharmed. MYXV can be genetically modified to delete non-essential host-regulatory genes to enhance oncolytic activity; or to insert cytokines that improve immune cell recruitment and activation. The present study evaluated and compared the local and distant anti-tumor efficacy of a MYXV engineered to express the IL15-IL15Rα cytokine complex and lacks the viral anti-apoptotic Bcl2 homolog M11L gene. Methods Immunocompetent mice bearing contralateral tumors of colon carcinoma or lung metastatic melanoma were treated intratumorally on one side with vMyx-M11KO-IL15Rα alone or in combination with Selinexor, an oral chemotherapeutic that inhibits the nuclear exporter XPO-1 and enhances MYXV replication in cancer cells. Results We observed a significant reduction in tumor burden of both treated and untreated sides (abscopal effect) with virus alone or in combination with Selinexor when compared to the untreated group. Combination therapy prolonged survival and ∼12% of mice had total tumor regression 60 days post-treatment. Mice treated with virus or combination therapy had significantly higher infiltration of CD45+ leukocytes, specifically CD8+- and CD4+-effector memory T cells, activated natural killer and dendritic cells. Conclusion This therapeutic combination enhanced viral replication and cancer cell death mediated by improved immune cell activation and infiltration into the tumor bed. Our results indicate that engineered oncolytic MYXV is synergistic to chemotherapy and produces an abscopal effect that targets untreated distal tumors and prolongs survival. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)