Abstract 5428: Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response

Abstract

Abstract Ionizing radiation has largely been recognized as a local targeted therapy by a variety of mechanisms, including inducing direct DNA damage of cancerous tissue or contributing to systemic antitumor immunity. The capacity of cancer cells to recognize DNA damages and initiate repair plays a major role in radio-resistance. Furthermore, the irradiated tumor cell death can enhance antitumor immunity by inducing antigen expression on tumor cells and activating lymphocytes. Recent evidence indicates that cancer cells can be made more sensitive to the effects of radiation (radio-sensitization) through inhibition of DNA repair pathways, and a growing body of evidence indicates that cancer immunotherapy may also have radio-sensitizing effects. The combination of radiation therapy and DDR inhibitors/immunotherapy presents a promising strategy for cancer therapy.In order to provide guidance on clinical therapeutic strategy selection, we established a beam-focused radiation platform (RadSource 2000 X-ray irradiator) to evaluate the anti-tumor efficacy of fractionated radiotherapy combination in a panel of cell lines and mouse models. We have tested the combination effect of DDR inhibitor in combination with radiotherapy in vitro and in vivo, both showing radio-sensitization effects and improvement in anti-tumor activity. We have also chosen several syngeneic models to test the combination strategy of radiotherapy and immune checkpoint inhibitors (PD-1 and PD-L1), and performed TIL analysis to explore the possible mechanisms of combination effect. In summary, our beam-focused radiation platform provides insights into the design of new therapeutic strategies and has become an effective tool in pre-clinical research of anti-cancer therapy. Citation Format: Feifei Fan. Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5428.