Driving Systemic Antitumor Immune Responses Against Breast Cancer Through Precision Medicine
Abstract
Background and Vision: Of the treatment options for patients with breast cancer, immunotherapies have the unique ability to provide long-term protection from tumor recurrence by acting as a living drug. When immune cells called T cells are properly activated, they can selectively recognize cancer cells and kill them. In addition, a subset of immune cells called memory cells can persist for a patient’s lifetime and prevent cancer cells from growing back again. Therefore, it would be ideal for all patients to benefit from these unique benefits of immunotherapies. However, only a small fraction of patients with breast cancer respond to currently available immunotherapies, which are called immune checkpoint inhibitors (ICIs). ICIs block inhibitory signals that shut off immune cells. They are currently approved by the U.S. Food and Drug Administration for a subset of patients with breast cancer. Patients who have already mounted a substantial immune response to their tumor are more likely to respond to ICIs. In contrast, patients with cold tumors, which do not have many T cells in the tumor prior to treatment, are unlikely to benefit. In contrast to the status quo, I envision a future where each and every patient with breast cancer will receive an immunotherapy that is effective for them. An optimal immunotherapy should drive an anti-tumor immune response capable of clearing a patient’s tumor with minimal toxicity and should also create immune memory that protects from cancer recurrence. Transforming this vision into reality requires two fundamental advances: (1) We must be able to predict which patients will benefit from ICIs and who will require a different type of immunotherapy. We have developed methods to measure the types of immune cells circulating in a patient’s blood and to measure how those cells are activated. We will apply these methods to predict response to ICIs in patients with breast cancer. (2) We must develop immunotherapy strategies that are more effective at driving new anti-tumor immune responses, particularly for women with cold tumors that do not respond to ICIs. Research Goals and Approach: My proposed studies address the Breast Cancer Research Program challenge to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. In our first aim, we will measure the types and activation of immune cells in the peripheral blood of patients with breast cancer before and after treatment with immunotherapy. We hypothesize that a detailed analysis of immune cells in peripheral blood can guide immunotherapy treatment selection for patients with breast cancer to identify patients who will benefit from ICIs and those who will not. We will test this hypothesis using research methods we have developed for immune monitoring technology in collaboration with the I-SPY 2 clinical trial. Activated immune cells circulating in the blood often come from lymph nodes, where they receive the signals that promote their activation. Sentinel lymph nodes are often removed from patients with breast cancer to determine if cancer cells have spread into these lymph nodes, but the immune response in these lymph nodes is not typically measured to guide treatment decisions. We will use innovative imaging technologies to measure immune responses in these lymph nodes to determine which patients are currently benefiting from immunotherapy. Aim 2: Develop new immunotherapies that drive strong systemic anti-tumor immune responses. The main cells responsible for activating T cells are called dendritic cells. Our prior studies revealed that dendritic cells are not activated properly in mice with breast cancer, resulting in poor activation of T cell responses. Here, we will understand the underlying mechanism(s) and target them to develop a new generation of cancer immunotherapy that can drive new immune responses against breast cancers. Impact: We will tackle two fundam
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310161
Entities
People
- Matthew H Spitzer
Organizations
- United States Army
- University of California, San Francisco