Overcoming Immunotherapy Resistance in Breast Cancer Using RT-Mediated Immunomodulation
Abstract
This project addresses the Fiscal Year 2018 Breast Cancer Research Program Overarching Challenge of Breast Cancer Treatments. While science has made many advances in the treatment of breast cancer, many women and men still develop metastatic disease after standard of care treatment, particularly those with aggressive subtypes such as triple-negative breast cancers 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 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, not all types of cancer are responsive to immune checkpoint inhibitors, and breast cancers are among those with limited responses to single-agent immune checkpoint inhibitors. Interestingly, there has been emerging data showing that radiation causes inflammation in tumors that can prime a tumor, making it more responsive to immunotherapies like immune checkpoint inhibitors. This project focuses on using radiation in combination with a checkpoint inhibitor to 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 anti-tumor 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 response to checkpoint inhibitors in breast cancer using novel mouse models and a paired clinical trial. We have developed an approach for focally irradiating a mouse breast tumor to more closely mimic clinical therapy. 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) evaluate the optimal radiation dose and schedule to combine with checkpoint inhibitor to get optimal immune cell activation both in the original tumor as well as throughout the body; (2) evaluate the specific immune cells involved in the response to radiation and checkpoint inhibition by using agents that allow us to specifically target different immune populations; and (3) investigate our findings in an early-phase trial to look at the safety and efficacy of combining radiation and an immune checkpoint inhibitor in the neoadjuvant setting for triple-negative breast cancers. We believe that the proposed studies will provide an experimental foundation from which to optimize and develop combinations of radiation and immunotherapy using a set of unique models and novel genomic approaches. Further, the trial to be conducted in this project will establish a trial platform and pipeline to interrogate the novel findings from our preclinical models and more rapidly translate them into cli
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910600
Entities
People
- Simon Knott
Organizations
- Cedars-Sinai Medical Center
- United States Army