Elucidating resistance mechanisms and enhancing response to immune checkpoint blockade in central nervous system metastases from breast cancer

PROJECT SUMMARY Metastases to the central nervous system (CNS) are a common complication of breast cancer. Prognosis is typically on the order of a few months. Immunotherapies have revolutionized the management of many types of cancers. However, these agents have not been systematically studied in the management of CNS metastases from breast cancer. We are conducting several Phase II trials to explore the role of newly developed immunotherapies in CNS metastases. Three of our trials have already met primary endpoint, with a subset of patients with breast cancer showing responses to immunotherapy. We propose to study cancer genetic and immune phenotypic changes in samples collected from patients before, during and after immunotherapy. Our overarching objective is to characterize mechanisms of resistance to immunotherapy in CNS metastases. To achieve this, we will chart the co-evolution of cancer and the immune system over time and anatomical location during immunotherapy by profiling DNA and RNA from cancer tissues, peripheral blood, and cerebrospinal fluid (CSF). Notably, using cutting edge single-cell technologies, we will examine alterations to the cancer genome and immune cell behaviors at unprecedented resolution. Furthermore, in our innovative mouse models of brain metastases, we will study novel combination therapies, including CDK inhibition with immune-checkpoint blockade, to augment the efficacy of immunotherapy. We believe that this work has the potential to uncover basic mechanisms of treatment-failure in these patients and that these discoveries will have tremendous translational potential as a basis on which to refine existing immunotherapy protocols and develop novel treatment strategies.