Strategies to Counteract Resistance Mechanisms in CAR+ T-Cell-Based Immunotherapy for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that disproportionally affects younger African American women. No effective therapy is at present available for metastatic TNBC. These clinical findings have prompted us to develop a novel effective immunotherapeutic strategy that can reduce, if not eliminate, mortality associated with metastatic TNBC. The development of this strategy has been facilitated by a productive collaborative program between Dr. Dotti and Dr. Ferrone. Their expertise in distinct, but complementary research areas has provided the opportunity to develop, in an efficient and timely fashion, a novel therapeutic strategy that can have a major impact on the treatment of TNBC. A critical evaluation of the information in the literature has shown that chemotherapy, targeted therapy, and treatment with antibodies that enhance the anti-tumor activity of a patient's immune system are poorly effective for the treatment of metastatic TNBC. Therefore, Dr. Dotti and Dr. Ferrone plan to utilize T cells genetically engineered so that they specifically recognize tumor cells and kill them. The T cells are referred to as tumor antigen-specific chimeric antigen receptor T cells (CAR+ T cells, for short). Immunotherapy with CAR+ T cells has been shown to be very effective for the treatment of leukemia, but to be poorly effective for the treatment of solid tumors such as TNBC. The studies outlined in this proposal aim to show that the therapeutic efficacy of CAR+ T cell based immunotherapy of TNBC can be markedly improved by combination with strategies that counteract the escape mechanisms utilized by TNBC cells to avoid recognition and destruction by the host immune system. The escape mechanisms we have identified are caused by changes induced in TNBC cells and in CAR+ T cells by hypoxia, the hallmark of tumor microenvironment. These changes reduce the susceptibility of TNBC cells to destruction by T cells and the anti-tumor activity of CAR T cells. This information has been used for a rational design of strategies to restore the susceptibility of TNBC cells to destruction by CAR+ T cells and to markedly enhance their anti-tumor activity. The patients who will initially benefit from the strategy we have developed and will test in an animal model that mimics the clinical setting are those with metastatic TNBC. We expect that this type of therapy will induce regression of metastases and will prevent or block disease recurrence. If the results are positive as we expect, this type of therapy can be extended to other types of breast cancer and eventually to other types of solid tumors for which tumor antigens to be used as targets of CAR+ T cell based immunotherapy have been identified. Side effects are not expected in patients treated with this type of therapy. Should they occur, approaches are available to treat them. Dr. Dotti has extensive experience in this area. We expect that 3 years will be needed to perform the studies outlined in this grant proposal and to prove the validity of our working hypothesis that the combinatorial immunotherapeutic strategy we have designed can eradicate TNBC in an animal model that mimics the clinical setting. The information derived from these studies will be used to design a Phase I clinical trial, which we expect to implement in the second year following the completion of the studies outlined in this proposal. The rapid translation of the results obtained in an animal model system to the clinical setting is facilitated by the involvement in our research program of Dr. S. Isakoff, a clinical oncologist with a large background in TNBC and by the availability of infrastructures to produce CAR+ T cells clinical grade. If the results obtained in an animal model can be translated to a clinical setting without unexpected problems, the immunotherapeutic strategy we have designed is expected to greatly contribute to reduce patients' mortality cau