Evaluation of Short- and Long-Term Systemic Anti-Tumor Immunity Following Combined Radiation and Immunotherapy in Triple-Negative Breast Cancer
Abstract
This project addresses two overarching challenges of the fiscal year 2022 (FY22) Breast Cancer Research Program (BCRP): (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and (2) Eliminate the mortality associated with metastatic breast cancer. While we have made many advances in the treatment of breast cancer, many women still develop metastatic disease after standard of care treatment, particularly women with aggressive subtypes such as triple-negative breast cancers (TNBCs) and those with locally advanced disease. One of the most promising new avenues of therapy over the last several years has been immunotherapy, which uses agents to unleash the body s own immune system to fight cancer. One such immunotherapy that has shown particular promise in melanoma and lung cancer, and has recently been approved in both early-stage and metastatic TNBC, is a class of agents known as immune checkpoint inhibitors. These drugs target pathways including programmed death 1 (PD-1) that are known to suppress immune responses and, by blocking these suppressive checkpoints, these drugs allow an immune response against a tumor to develop. Unfortunately, while responses to immunotherapy combinations can be remarkable, two-thirds of metastatic patients and one-third of early-stage TNBC patients have limited to no response to immune checkpoint inhibitors. Interestingly, there has been emerging data showing that radiation causes inflammation in tumors which can prime a tumor, making it more responsive to immunotherapies like immune checkpoint inhibitors. This project focuses on extending our understanding of how using radiation in combination with a checkpoint inhibitor can enhance the antitumor immune response against breast cancers. The mechanisms by which radiation of tumors produces an inflammatory response have been explored previously, however with the advent of single-cell sequencing, we can now characterize the immune changes in tumors following radiation therapy (RT) with unprecedented detail. Historically, radiation-induced injury to the cells has been viewed as the primary mechanism by which radiation mediates its antitumor effects. However, more recent studies have begun to implicate our own immune cells, and the response to the cell death induced by radiation, as key factors driving the efficacy of radiation. In fact, preclinical studies in mice have shown significant synergy between radiation and immunotherapy in several histologies, though none have addressed the mechanism of this synergy using single-cell sequencing, which will provide unique and powerful new information about the types and activity of the immune cells in the tumor following treatment. The experiments proposed in this application will examine the relationships between radiation-induced inflammation and the systemic response to checkpoint inhibitors in breast cancer, using and collecting additional samples from a recently completed clinical trial of pre-surgical radiation and anti-PD-1 therapy in early-stage TNBC. We have developed novel laboratory and computational approaches for defining the immune populations in this unique setting of combined radiation and checkpoint inhibitor treatment. We will: (1) Extend follow-up for patients enrolled in our previous trial to understand long-term outcomes and collect long-term blood samples; (2) Evaluate the specific immune cells involved in the response to radiation and checkpoint inhibition by using single-cell sequencing; and (3) Investigate the functional activity of immune cells, during and in the long term, following radiation; and an immune checkpoint inhibitor in the neoadjuvant setting for TNBCs. We believe that the proposed studies will provide an experimental foundation from which to optimize and develop combinations of radiation and immunotherapy using a unique clinical dataset and novel genomic approaches. Further
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311044
Entities
People
- Simon Knott
Organizations
- Cedars-Sinai Medical Center
- United States Army