Enhancing the Efficacy of Breast Cancer Immunotherapy Using a Smac-Armed Oncolytic Virus.

Simple Summary: Immune checkpoint inhibitors (ICIs) are the most recent breakthrough in cancer treatments. Several drugs have been approved by the FDA including anti-PD-1 antibodies (Nivolumab, Pembrolizumab, and Cemiplimab). Their treatment is most effective for melanoma, non-small cell lung cancer, or bladder cancer. However, ICI response rates are very low for breast cancer patients, even for those with triple negative breast cancer (TNBC) who are expected to be more responsive to ICI treatment. Improved treatments are in demand for patient benefits. Our armed oncolytic virus is one therapeutic agent that can improve the outcome of TNBC treatment, especially in combination with ICIs, as demonstrated by this study. It has been shown that the response rate of TNBC is dependent on the level of PD-L1 and the tumor microenvironment (TME). Approaches that alter the TME can improve the efficacy of ICIs. Background: We have engineered a Smac-armed oncolytic virus by inserting a Smac transgene into the genome of a vesicular stomatitis virus to generate VSV-S. Our previous study shows that the anticancer efficacy of VSV-S is more potent than that of wild-typed VSV in a subcutaneous TNBC mouse model. VSV-S treatment reverts the immunosuppressive TME by reducing MDSCs and TAMs, while increasing infiltration of neutrophils and CD8+ T cells. Methods: VSV-S was used to treat TNBC in an orthotopic mouse model, and in a combination therapy with an anti-PD-1 antibody to treat metastatic TNBC in a mouse model. Changes in the TME were evaluated. Results: In this current study, we show that neoadjuvant VSV-S treatment of primary orthotopic TNBC tumors in mice drastically lowered lung metastasis after surgical removal of the primary tumor, and significantly increased the survival rate. The mechanism of action and changes to the TME were delineated, among which one significant marker is the elevation of PD-L1 expression in tumors. In the TNBC lung metastasis mouse model, pulmonary treatment with VSV-S greatly enhanced the efficacy of ICI treatment. Conclusions: Our results suggest that the combination of oncolytic virus and ICI therapies has the potential to substantially improve the outcome of TNBC treatment. [ABSTRACT FROM AUTHOR]