Investigating Interactions Between Adaptive Immune Cells and Dormant Disseminated Tumor Cells
Abstract
A significant proportion of breast cancer patients will experience metastatic recurrence, or distant spread of disease to organs such as bone, lung, liver, and/or brain, years or even decades after their initial treatment. It is thought that these metastases arise from tumor cells that spread to distant organs prior to the initial diagnosis, but lay dormant for years or even decades, and were subsequently triggered to re-awaken. These metastases ultimately kill the patient. Currently, there are no treatments available to target dormant tumor cells. Immunotherapy with T cells, which have demonstrated potent tumor killing capacity, may be one means by which to eliminate dormant tumor cells and prevent breast cancer metastases. However, very little is known regarding whether dormant tumor cells employ tactics to evade T cell killing such as reducing expression of major histocompatibility complex (MHC), important for T cell recognition and killing. It is also unknown whether T cells traffic through tissues in a way that allows them to find these rare dormant DTCs and kill them. For these reasons, we aim to define the relationship between dormant breast cancer cells and T cells in the bone marrow and other metastasis-prone tissues. Our ultimate goal is to leverage what we learn about dormant disseminated breast cancer cells and T cell interactions in the bone marrow to develop T cell-based immunotherapies for the elimination of dormant disease in preclinical trials. We propose to test two unique T cell immunotherapies, T cell receptor (TCR) and chimeric antigen receptor (CAR) T cell therapies. Importantly, both TCR and CAR T cells have been tested and/or approved for use in the treatment of human cancer, often with outstanding clinical responses. The translation of these T cell immunotherapies to breast cancer, and specifically to the window of breast cancer dormancy, has the potential to impact tens of thousands of breast cancer patients annually. Minimally, this research will greatly expand our understanding of how dormant tumor cells escape immune killing. The studies described in this proposal will also lay the foundation for future studies that may bring TCR and CAR T cells into the clinic for breast cancer survivors. Because dormant tumor cell-specific antigens in breast cancer patients are currently unknown, the immunotherapeutic targets we propose in this application serve to prove a principle. If this work identifies effective T cell-based immunotherapies that eliminate dormant tumor cells and prevent metastasis in preclinical models, it will motivate essential studies to identify dormant tumor cell-specific antigens in patients and to ensure safety and efficacy of the immunotherapies in breast cancer patients. A therapy that might eliminate risk of lethal metastatic disease, even in a subset of breast cancer patients, will represent a major breakthrough. This proposal will address three of the Breast Cancer Research Program?s overarching challenges: it will (i) reveal mechanisms by which breast cancer cells lie dormant for years and then re-emerge, and will determine ways of preventing lethal recurrence; (ii) identify effective adoptive immunotherapies that will revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and benefit patient survival; and (iii) contribute to the elimination of mortality associated with metastatic breast cancer. After my postdoctoral training, I aim to establish my independent research program at a major biomedical research institute. I am dedicated to studying breast cancer dormancy, developing immunotherapies to target dormant tumor cells, and working to prevent breast cancer metastasis. I have developed an individualized development plan with my mentor, Dr. Cyrus Ghajar, and my co-mentor, Dr. Stanley Riddell, both at the Fred Hutchinson Cancer Research Center. This development plan and the research environment at the Fred Hut
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910076
Entities
People
- Erica T Goddard
Organizations
- Fred Hutchinson Cancer Center
- United States Army