Abstract Breast cancer is the most common malignancy among women in the United States and the second leading cause of cancer deaths in women. Disease prognosis, local recurrence rates and response to therapy are all related to receptor status of the individual cancer. Triple negative breast cancer (TNBC; ER-, PR-, and HER2-negative) is a subset of breast cancer with poor prognosis and high rate of local recurrence and metastasis with limited therapeutic options. The oncolytic poliovirus, PVSRIPO, is a recombinant polio:rhinovirus chimera that has been engineered to eliminate neuropathogenicity and has demonstrated promising responses in patients with recurrent glioblastoma. PVSRIPO is oncolytic in tumor cells and enters cells via its receptor CD155, which is overexpressed in solid malignancies, including TNBC. Treatment of primary TNBC tissue with PVSRIPO induces IFN-I and pro-inflammatory cytokines. In a murine immunotherapy model, intratumoral injection of PVSRIPO induces IFN-I, IL12 and IFN-γ and rapid recruitment of neutrophils into the tumor followed by infiltration of DCs, T cells and B cells. Treatment of orthotopic breast tumors with PVSRIPO results in delayed tumor growth and increased survival in an immunocompetent murine immunotherapy model. We have designed a pilot study to examine the effects of intratumoral injection of PVSRIPO into six women with TNBC with at least 1 cm of residual tumor after chemotherapy. The primary exploratory objective is to describe the changes in the amount of tumor infiltrating immune cells in tumor tissue pre- and post-injection of PVSRIPO. We will also collect blood at different time points during PVSRIPO treatment to evaluate inflammatory and immune signatures. We hypothesize that intratumoral administration of PVSRIPO will cause inflammation thus stimulating innate and adaptive immune activation. This study is funded by the Department of Defense Breast Cancer Research Program award W81XWH-16-1-0354 (PI, Smita Nair). Citation Format: Karenia Landa, Eda Holl, Michael Brown, James Herndon, Lars Grimm, Jeremy Force, Darell Bigner, Shelley Hwang, Matthias Gromeier, Smita Nair. Oncolytic poliovirus-mediated inflammation and immunity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-302.