Breaking Through Immune Resistance of HR+ Breast Cancer
Abstract
Background: Hormone receptor (HR)+ breast cancer (BC) is responsible for the majority of BCs and BC-related deaths in the US. Standard treatment includes surgery, endocrine therapy +/- chemotherapy depending on risk assessment. Standard treatments, particularly chemotherapy, are associated with both acute and late toxicities, often with small incremental benefit in survival. While clinicians have made some progress in predicting risk, many women are still being treated with relatively toxic regimens, benefiting only a few. Clearly, there is an unmet need for improved therapeutic approaches to HR+ BC. Unfortunately, the efficacy of immunotherapy has been disappointing so far. Our group originally introduced the concept of targeting radiotherapy to the tumor to enhance the effectiveness of immunotherapy, in an attempt to convert the tumor into a personalized vaccination. Radiotherapy-induced cell death releases tumor antigens and signals that stimulate the immune system and, in the presence of immunotherapy, can recover immune recognition of the tumor and rejection. While this approach has found confirmation in other solid tumors, progress in HR+ BC has been delayed by the lack of a preclinical model of a HR+ BC that would recapitulate tumor insurgence and progression in an immunologically intact host, which is critical to understand resistance to immunotherapy. This gap needs to be addressed to make progress in HR+ BC immunotherapy, in response to the challenge of revolutionizing treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. A good preclinical tumor model needs to consist of mammary carcinomas that occur in immunocompetent mice, ideally in response to carcinogens that also provoke BC, and should recapitulate the key histological, biological, and immunological features of human HR+ BC. It is a precious asset to decipher and verify mechanisms of resistance as well as test intervention to overcome them. The Principal Investigators (PIs) of this proposal are clinical and basic science investigators who have joined forces to address this experimental gap. They have preliminary data demonstrating that slow-release medroxyprogesterone acetate (MPA, M) pellets combined with 7,12-dimethylbenz[a]anthracene (DMBA, D) administered orally to mice with normal immune system enable the development of mammary carcinomas that are histologically, biologically, and immunologically very similar to human HR+ BC. Similar to HR+ BC in patients, M/D-driven tumors in mice escape the immune system of the host through multiple, distinct mechanisms associated with specific immunological profiles that may dictate which therapeutic regimens are most appropriate. The PIs propose to characterize the immunological profiles of untreated M/D-driven tumors, and of M/D-driven tumors subjected to clinically relevant radiation therapy regimens. These data will then be compared to the immunological signatures of HR+ BCs resected from patients that failed to respond to neo-adjuvant radiation, enabling the identification of optimal combinatorial regimens to be implemented in future clinical trials. The specific aims of this proposal are: (1) To characterize the immunological profiles of treatment-naïve M/P-driven mammary carcinomas. (2) To characterize the immunological profiles of HR+ BCs before and after preoperative radiotherapy and to compare them with those of M/P-driven mammary carcinomas receiving a similar treatment. (3) To test a combination of radiotherapy and immunotherapy in mice with M/D-driven mammary carcinomas in preparation for testing the same therapies in patients with HR+ BC. Impact: Defining how to best break through the resistance to immunotherapy in the M/D-driven tumor model will generate the necessary information to direct strategies to overcome resistance to immunotherapy in HR+BC patients, the majority of BC patients. If successful in mice, this approach ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910101
Entities
People
- Silvia C. Formenti
Organizations
- United States Army
- Weill Cornell Medicine