Our proposal addresses an unmet clinical need to treat and eradicate metastatic breast cancer (MBC). An estimated 90% of deaths attributable to breast cancer (BC) are a consequence of metastases, with more than 40,000 deaths caused by MBC each year in the United States alone. Despite notable therapeutic innovations for BC, patients with metastatic disease have a median survival of only 2-3 years. Triple-negative breast cancer (TNBC), which is clinically defined as a lack of estrogen, progesterone, and HER2 receptor expression, affects approximately 180,000 women worldwide and is a challenge to manage. TNBC accounts for 15%-20% of newly diagnosed BCs, is overrepresented among cases of metastatic disease, and is responsible for a disproportionately high number of deaths from BC.

Although the recent literature has identified BC-specific immune factors as biomarkers of therapy response and prognosis, the role of immune responses in the cause and outcomes of metastatic TNBC have not been studied. The primary goal of this proposal is to promote the eradication of MBC by using a patient's own immune cells, T lymphocytes, which are genetically engineered and redirected to target the tumor antigen. Our laboratory has pioneered technology to generate tumor-specific T cells by the transfer of genes that encode chimeric antigen receptors (CARs), the engineered receptors useful in the generation of cancer-targeted T cells. Although our recently published results on obtaining complete remissions in leukemia patients with relapsed, chemorefractory disease are impressive, this approach is untested in BC. On the basis of our clinical observations that mesothelin, a cancer cell-surface antigen, is overexpressed in TNBC, and that this overexpression correlates with decreased overall and disease-specific survival, along with decreased time to metastases, we have developed extensive preclinical data that support the use of mesothelin-targeted T-cell therapy for MBC. We propose to conduct Phase I/II clinical trials using our CARs (which have received approval by requisite National Institutes of Health groups) in patients with MBC. Our proposed first-in-human clinical studies of mesothelin-targeted T-cell therapy, combined with immune monitoring, will provide knowledge that may ultimately lead to better outcomes in patients with MBC.

Within 6 months of the start date of the award, we will initiate a Phase I clinical trial of cancer-targeted T cells in patients with metastatic TNBC. On the basis of the data obtained from this Phase I study and from other studies of antibody-based immunotherapy in TNBC patients that are currently underway at our center, we will initiate a prospective clinical trial to validate the immune responses in all TNBC tumors from patients, as well as serially collected blood specimens, over the course of 4 years. The observations from the above clinical trials will direct the laboratory studies in Aim 3 (0-42 months), wherein we will fine-tune the T-cell treatment regimen with other synergistic agents by the use of clinically relevant mouse models of metastatic TNBC. Our ultimate goal is to develop a rational strategy to initiate a Phase II study (Aim 4, Year 4) of combination immunotherapy for patients with TNBC.

Impact: Our proposed first-in-human clinical studies of MSLN-targeted T cell therapy will provide knowledge that may lead to better outcomes in patients with MBC. While the knowledge gained from our prospective systematic analysis of TNBC may identify the factors that drive BC metastases and aggressiveness, immune cell therapies tailored specifically to the individual patient may ultimately result in the eradication of metastatic disease. The knowledge gained from these clinical trials will not only inform the treatment of MBC, it may also advance the treatment of patients with operable TNBC that could prevent the development of MBC. This proposal address an unmet clinical need for prevention and targeted treatment of MBC that is based on a patient's personalized immune profile and that could lead to the eradication of MBC altogether.