Systems Immunology for Breast Cancer
Abstract
In this proposal, we will identify and deeply characterize new cell subsets in the breast cancer microenvironment that suppress anti-tumor immunity, thereby addressing the challenge to “identify what drives breast cancer growth; determine how to stop it.” We will then identify novel treatment strategies to reactivate the immune system and thereby “revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” Solid cancers are complex cellular “ecosystems” in which the development and drug response of the tumor is controlled by the cellular milieu. Through our recent revolutionary studies on breast cancer using single cell genomics, we have discovered several new types of cells that reside within breast cancers, known as stromal cells. We now have convincing preliminary evidence that these stromal cells suppress anti-tumor immune responses. This project will provide experimental evidence to determine which stromal cell types suppress antitumor immunity, and the mechanism by which they achieve this. Once we understand the cell types responsible and the molecules they use, we can develop methods to block this signal and release the “handbrake” holding back the immune system from attacking breast cancer. This project, if successful, will lead to a major advance in our understanding of the mechanisms governing immune evasion in cancer and the development of new combination immunotherapies to successfully treat breast cancer. Short and Medium Term: Following completion of this project, new drug targets would undergo additional preclinical testing to ensure that they are effective and safe in a number of experimental models. Lead targets arising from this study would be subject to drug discovery or repurposing programs. New drug/s would be tested in early phase clinical trials. Close collaboration with leading clinicians and clinical trial organizations (such as the Australian Breast Cancer Trialists Group) actively running early phase clinical trials provides a path to translation. Our recent published work provides proof of principle for this new project. Using cellular genomics, we recently discovered that stromal cells can promote chemotherapy resistance in triple-negative breast cancer (TNBC) cancer cells. After preclinical testing in cell culture and mouse models, we ran a Phase I clinical trial and showed that patients with metastatic TNBC derived clinical benefit from a combination of stromal- and chemotherapy, with one patient experiencing a complete response. A Phase II clinical trial to pursue this therapy is being developed. Long Term: If successful through early-phase clinical trials, this treatment would undergo Phase II/III testing in TNBC and perhaps other cancers. This new treatment strategy could become standard of care, bringing the promise of long-term survival for these patients, as we have seen for melanoma patients. Further trials could also test its effectiveness for (i) earlier treatment for high-risk patients, (ii) other cancers, both breast and other. Agents with a clear path to commercialization have the best chance of success, and we have already had interest in this program from Astra Zeneca (UK); 5AM Ventures, a Boston-based venture capital firm; and Celsius Therapeutics, a drug discovery company. These commercial partnerships will provide additional funds to accelerate this work and increase its chance of becoming a widely available treatment. Barriers: (i) Small molecules or antibodies may not be available for repurposing to block our candidate genes/pathways. In this case, we or others will develop antibodies through the advanced Antibody Development Laboratory at our Institute or partner with a drug discovery team to discover new drugs to block these pathways. (ii) It is likely that only a subset of patients will respond to any new drug, thus a companion biomarker that can predict response needs to be developed. At the completi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110770
Entities
People
- Alexander Swarbrick
Organizations
- Garvan Institute of Medical Research
- United States Army