Preclinical Rationale and Clinical Considerations for Radiotherapy Plus Immunotherapy: Going Beyond Local Control.

Abstract The use of radiation for cancer therapy has expanded and sparked interest in possible synergistic effects by combining it with current immunotherapies. In this review, we present a case of a patient who responded to programmed cell death 1 (PD1) blockade and radiation therapy and discuss possible mechanisms. We provide background on the blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD1 checkpoints and highlight future immune-based therapies that may synergize with radiation, including cytosine-phosphate-guanine vaccines, OX40 agonists, CD40 agonists, regulatory T-cell depletion, and metabolic "rewiring" of cancer cells. Clinical considerations are noted for combining radiation with immunotherapies to extend the benefit of immunotherapy to more patients. New trials are needed to appropriately investigate the best sequencing and radiation dose to prime an immune response and to identify predictive biomarkers of such responses.