Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

摘要

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-21-083. In our Cancer Moonshot IOTN U01 award, we are developing a combined modality therapeutic approach to eradicating metastatic cancers that are immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). To advance the objectives of that award and to broadly define the radiosensitivity and immuno-radiobiology of immune cell lineages, we will use advanced immune assays to determine the effects of radiation dose, dose rate, and fractionation on the survival and phenotype of immune cell lineages from blood, bone marrow, and tumor infiltrating immune cells. We hypothesize that diverse immunologic effects of radiation will have distinct dose-response profiles, such that no single dose of radiotherapy can be defined as “optimal” but rather that a heterogeneous dose of radiation will be best able to activate a potent anti-tumor immune response by optimally engaging distinct mechanisms within a single tumor microenvironment. The insights and treatment regimens developed in these studies should enable more effective clinical translation of therapeutic approaches that combine radiation and immunotherapies in patients with metastatic cancer.