Abstract SY43-02: Adapting clinical radiation therapy to immune checkpoint blockade

Abstract

Abstract Focal radiation therapy has demonstrated to elicit inflammatory and immune responses that contribute to cancer immunosurveillance, but may also have unwanted systemic effects. The application of ionizing radiation to cancer, which is the basis for the field of radiation oncology, has evolved to define and exploit the therapeutic window between radiation cytocidal effects in tumors versus those in normal tissue. The original standardization of specific dose-fractionation regimens reflected the results of decades of empirical experience to find the best balance between local control of the irradiated cancer and the mitigation of risk for acute and late sequelae in the exposed normal tissues. More than a century of research in radiation biology has elucidated how radiation damage recruits a classical inflammation response, activates pathways to repair tissues through scavenging of cellular debris and canonical wound repair mechanisms that aim at recovering tissue integrity. Intrinsic to this process is a robust dampening of immunogenic signals, common to those associated with wound repair, to prevent triggering of auto-immune rejections of inflamed tissues. At the same time, radiation has proimmunogenic effects, that recruit both the innate arm of the immune system (acute induction of IFN pathways) and the adaptive arm, through radiation-induced neoepitopes and enhanced cross presentation. Strategies to uncouple these opposite effects are the focus of research efforts in multiple radiation biology laboratories, worldwide. The emergence of modern cancer immunotherapy offers the opportunity to further dissect such strategies. Recent evidence suggest a new role for focal radiotherapy, to partnering and synergize with immune checkpoint blockade (ICB). Evidence is emerging both preclinically and in the clinical setting that optimal integration of radiotherapy with the available immune modifiers might require changes in standard radiation oncology practices. Variables like the type of treatment fields, the inclusion of draining nodal stations, the degree of exposure of circulating immune cells, the type of dose-fractionation and the timing of radiotherapy during ICB all can affect the success of immunoradiotherapy combinations. Hence, defining the parameters for adapting classic radiation therapy to best integrate with ICB remains a fundamental area of investigation, as it is integral to a successful partnership with immunotherapy. Citation Format: Silvia C. Formenti. Adapting clinical radiation therapy to immune checkpoint blockade [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 SY43-02.