Radiation Therapy And Immune Checkpoint Inhibitor Combinations In The E0771 Medullary Breast Adenocarcinoma.

Abstract Greater than 50% of all cancer patients receive radiation therapy at some point during their cancer treatment to control solid tumor growth (Harrington 2011). In addition to the direct action of radiation on tumor cell proliferation, radiation also has the potential to stimulate an anti-tumor immune response (Weichselbaum 2017). The success of immune checkpoint therapies such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitory antibodies has driven large investment into the discovery of novel immune-oncology therapies. While the clinical response to immune checkpoint inhibitors can be profound for those patients that respond, there still exists a large percentage of patients that do not see benefit. In order to expand the number of patients that may respond to immune checkpoint inhibition, combination with radiation therapy needs to be tested and in fact a large number of preclinical and clinical studies are being conducted (for review see Asna 2019). Preclinical syngeneic tumor models are a critical means to assess new immunotherapies and drive preclinical programs. E0771 is a medullary breast adenocarcinoma cell line originally isolated from a spontaneous tumor and can be implanted subcutaneously in C57BL/6 mice (Ewens 2005). In order to characterize the E0771 syngeneic breast tumor model for future studies with radiation and immunotherapy, we assessed the efficacy changes in response to various schedules of radiation doses with and without either anti-PD-1 or anti-CTLA-4 antibody therapies. In addition, we analyzed the tumor infiltrating immune cell populations following radiation therapy. E0771 is sensitive to radiation therapy with a clear dose response. Radiation administered either as a single dose, hypofractionated, or hyperfractionated gave similar tumor responses. Flow cytometry analysis shows a higher infiltration of T regulatory cells compared with CD8+ T cells at baseline, which is exacerbated by irradiation. The CD8/Treg ratio is reversed with the addition of anti-CTLA-4 treatment to radiation and resulted in curative responses for 9 of 10 mice in the combination group. Citation Format: Patrick Fadden, Thi Bui, Kelli Davis, David Hurtado, Emily Sugg, Abigail Svancarek, Ian Belle, Chassidy Hall. Radiation therapy and immune checkpoint inhibitor combinations in the E0771 medullary breast adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1558.