The long term goal of this clinical career development award is to establish the candidate, Dr. Alberto J. Montero, as an independent clinical researcher in the field of cancer immunotherapy. To achieve this goal, the candidate, concurrently with his mentors, has designed a comprehensive training plan that includes research and extramural funding mentoring, formal didactic training in advanced immunologic techniques, biostatistics and clinical trial design. These four areas have been identified by candidate and mentors as areas of deficiency, which the candidate needs to further develop relevant to his career goals, and are essential to help the candidate successfully make the transition to independence. The candidate's research interests focus on the clinical development of immunomodulatory agents that can potentiate immune-mediated cancer cell death. Consistent with this interest the candidate has designed and written an ongoing neoadjuvant phase II trial with the glutathione mimetic NOV-002 plus cytotoxic chemotherapy in breast cancer patients. The candidate has also made several novel observations that NOV-002 was associated with significantly higher circulating CD8+ and CD3+ T-cells in those patients who achieved a complete pathologic response. He has also shown that NOV-002 reverses the suppressive effect of myeloid suppressor cells (MDSC) on T-cells and potentiates the effect of adoptive immunotherapy in vivo. Based on these observations, it is hypothesized that NOV-002 potentiates chemotherapy by enhancing tumor specific T-cell responses. To test this hypothesis the following specific aims are being proposed: 1) Assess the impact of NOV-002 on T cells, and its effect on the generation of long lasting immunologic memory;2) Evaluate whether enhancement of T-dependent immune responses by NOV-002 is due to decreased suppressive ability of MDSC;3) Determine if circulating and tumor-infiltrating cytotoxic lymphocyte levels and/or activity correlate with pathologic complete responses in patients enrolled in the NEO-NOVO trial. The candidate's laboratory mentor, Dr. Krishna Komanduri is a nationally recognized leader in human T-cell immunology. His clinical mentor Dr. Mark Pegram has been at the forefront of clinical research in breast medical oncology and has been involved with the development of novel targeted therapies for the treatment of HER-2 positive breast cancer and the development of novel drugs that target angiogenesis. Dr. Montero was recruited to the University of Miami as part of the Dodson Interdisciplinary Immunotherapy Institute initiative to develop high-impact and broadly useful immune-based treatments for breast cancer and other solid tumors. His recruitment package included start up funds and laboratory space. In summary, this award will provide the candidate the necessary protected time to conduct his proposed studies and to fully exploit the outstanding institutional environment available at the University of Miami Sylvester Comprehensive Cancer Center with the ultimate goal of becoming an independent clinical researcher in the field of tumor immunology.
A better understanding of the immunomodulatory effects of NOV-002, and their relationship to potentiating the anti-tumor effect of chemotherapy, would be important to develop novel strategies that utilize other immunomodulatory drugs as chemotherapy adjuvants. Results of these studies would also provide further evidence to develop novel clinical strategies with drugs that target glutathione pathways to enhance the effectiveness of T-cell directed therapies in treating not only breast cancer, but would be applicable to the treatment of other solid malignancies.
