DESCRIPTION (provided by applicant): I am a surgical oncologist dedicated to caring for patients with complex malignancies and to developing novel immunotherapeutic approaches for metastatic liver cancer. Early in my medical training, I developed a passion for immunology and host-tumor interactions. After graduating from the New York University (NYU) School of Medicine with the top academic record in my class, I trained in general surgery at NYU and Bellevue. I spent two years as a research fellow with Dr. Ronald DeMatteo at Memorial Sloan-Kettering (MSK), where I gained valuable experience in immunologic research and published papers on liver immune cells in Hepatology and the Journal of Immunology. During my clinical surgical oncology fellowship at MSK, I studied immune infiltrates in liver metastases, work published in the Annals of Surgical Oncology and featured in Nature Reviews Clinical Oncology. I was recruited to Roger Williams to join a strong immunotherapy program and build a lab focused on investigating how suppressive liver immune cells may contribute to the development and progression of liver metastases. My K08 proposal is a critical step in my career development as the project represents a fusion of my basic liver immunology background with a therapeutic platform, genetically modified or "designer" T cells (dTc), we are presently using in clinical trials at Roger Williams. The associated training plan, as noted below, will provide me with important educational opportunities to facilitate my transition toward independent funding. Environment - The Roger Williams Medical Center (RWMC) is an ideal environment for my academic growth and development. Dr. Richard Junghans, my mentor, is a well established immunologist with a rich experience with immunotherapy trials and dTc. I also work with Dr. Vincent Falanga, the RWMC Chief of Dermatology, as he shares valuable resources obtained through their COBRE grant. As the RWMC is of modest size, my laboratory and career development are top priorities for the institution. I receive a tremendous level of support from th administration and my Division Chief and Cancer Center Director, Dr. N. Joseph Espat. This enables me to have the necessary protected time and maintain a high level of focus on my laboratory work. Development and Training Plan - I have assembled a mentoring team of well respected experts to monitor my progress, support my research, and promote my career development. Each member of the team has successfully competed for NIH funding and offers a particular area of expertise that meshes well with my proposal. Dr. Junghans will be the primary mentor, and his experience with immunotherapy and T cell biology will be invaluable. The three co- mentors will make important contributions as well. Dr. Espat, an authority on liver metastases, will ensure that the work and publications maintain a translational focus. My mentor from MSKCC, Dr. DeMatteo, will provide important insight and critique from the vantage point of an expert in liver immune cell biology. Dr. Alfred Ayala at Brown, with whom I have recently begun to collaborate, is another well respected expert in liver immunobiology. I have also included translational medicine and immunology course-work at Brown to expand my knowledge base in critical areas. Research Plan - Based upon the work I have published to date, I hypothesize that suppressive liver immune cells limit the effectiveness of T cell based therapies for eradicating liver metastases. T regulatory cells (Treg) and myeloid derived suppressor cells (MDSC) are likely contributors to liver tolerance. Our lab has spent over one year optimizing our murine model of CEA+ colorectal liver metastases and the immunologic assays described in the proposal. My first specific aim focuses on elucidating the mechanisms by which Treg and MDSC may limit anti-CEA dTc function in the liver. I have designed the experiments to focus on each component of the model separately, including the Treg or MDSC, dTC, and immune receptor express by dTc. In addition, contact-dependent mechanisms such as the programmed death-1 pathway and secreted factors will be studied. For the second specific aim, specific strategies for blocking the suppressive interactions between Treg or MDSC an dTc will be tested in vivo. We hope some of our immunologic manipulations will be translatable into the clinical arena.

The liver is a frequent site of metastatic cancer and more than 70,000 patients die of liver metastases each year in the United States, as current treatment options are limited. T cell based immunotherapy has shown only limited success, and the genetically modified or "designer" T cell (dTc) approach is promising. As we know little about how dTc interact with host immune cells, particularly in the immunosuppressive environment of the liver, we propose to study the mechanisms by which suppressive immune cells inhibit dTc function in a murine model of liver metastases.