I am a surgical oncologist dedicated to caring for patients with advanced malignancies and to developing novel therapeutic approaches for metastatic colon cancer. This project describes a 5-year training program for a career as a surgeon-scientist with the long-term goal of establishing an independently funded research program in gastrointestinal tumor immunology. Early in my education, I was inspired to study new scientific approaches to improve patient outcomes and pursued dedicated research training projects and mentorship opportunities. After graduating with honors in biology from Brown University, I attended Yale School of Medicine where I was awarded the ADA Medical Scholar Grant, Yale research training grants, and the Association for Academic Surgeons (AAS)/Novartis Award for meritorious research. I then trained in general surgery at Harvard University's Brigham and Women's Hospital and chose to devote two additional years to receive tumor immunology and surgical oncology training in the laboratory of Dr. Steven A. Rosenberg in the Tumor Immunology section of the NIH/NCI Surgery Branch where we published multiple reports including """"""""the most cited article of the year"""""""" in the Annals of Surgical Oncology and a mechanism paper in the Journal of Immunology. During my clinical surgical oncology fellowship at Memorial Sloan-Kettering Cancer Center, I studied immunologic biomarkers of dysplasia, and immune infiltrates in liver metastases, which were published in Clinical Cancer Research and the Annals of Surgical Oncology. I was recruited back to my hometown at the University of Illinois at Chicago (UIC) to join a strong immunology program and to build a research effort focused on enhancing anti-tumor immune responses in colon cancer liver metastases, my clinical and research interests. This K08 proposal is a critical step in my career development as the project represents a fusion of my passion for tumor immunology with my clinical and surgical interests. We have created a well-developed training plan to insure educational opportunities that will facilitate my transition toward independent funding. I have also included immunology and translational science coursework at UIC to expand my knowledge base in critical are- as. UIC is an ideal environment for my academic growth and development. Given a desire for increased translational science at UIC and the Cancer Center, my laboratory and career development are top priorities and I receive a tremendous level of support from the administration and Department of Surgery. I have assembled an advisory team of five experts to monitor my progress, support my research, and promote my career development. Each member of the team offers a particular area of expertise that enhances my proposal and development. Dr. Prabhakar is the primary mentor, and his expert knowledge of lymphocyte biology and immunotherapy will be paramount. As head of the Department of Microbiology and Immunology, he has committed his mentorship, lab, facilities, and resources for my development. Dr. Steven Rosenberg will serve as secondary mentor and will provide critical insight and critique from the perspective of a world's expert in tumor immuno- therapy. Dr. Benedetti, Chairman of the Department of Surgery and an authority on transplant immunology and liver surgery, will insure that the research and publications preserve a translational hub and that my time is protected for research. Dr. Hay and Dr. Raychaudhuri, both established experts in tumorigenesis and animal models of human liver cancers, will also serve as co-mentors. All mentors are tenured professors with a long record of supported research and combined successful mentorship of hundreds of trainees. Based on my published work and preliminary data, the hypothesis is that the tumor microenvironment of colon cancer metastases can be manipulated using immunostimulatory cytokines to enhance cytotoxic T lymphocyte infiltration and function. Our lab has optimized a murine model of colorectal liver metastases and immunologic assays;and developed a LIGHT expressing mouse colon cancer cell line. My long-term goal is to improve the control of advanced colon cancer by enhancing anti-tumor responses through targeted manipulation of the patient's immune system. The overall objective of this application is to find ways of increasing the infiltration and activation of anti-tumor lymphocytes within colon cancer tumors and metastases. The rationale for the proposed research is that, once it is known how to create an immunostimulatory tumor microenvironment and then also to traffic T-cells to that microenvironment, a new strategy for the management of metastatic colon cancer with the potential for durable anti-tumor responses is possible.
The first aim of this proposal is to increase lymphocyte infiltration and activation within colon cancer tumors and liver metastases by overexpressing the immunostimulatory cytokine LIGHT on tumor cells. In the second specific aim, we will test strategies to traffic host lymphocytes to the tumor microenvironment utilizing a bispecific antibody (BsAb) to the T-cell determinant CD3, and the epidermal growth factor receptor (EGFR), which is overexpressed on colon cancers. In the third aim, we will perform pre-clinical studies combining intratumoral LIGHT overexpression and an anti- EGFR/CD3 BsAb to enhance anti-tumor immune responses using human lymphocytes and human colorectal cancer tumorgrafts in NSG mice. It is possible that the immunologic manipulations will deliver an inventive """"""""one-two"""""""" punch that is universally applicable from patient to patient to incite an anti-tumor immune response that will have direct translational impact on one of the deadliest cancers worldwide.
The majority of patients with colon cancer present with advanced disease, most commonly to the liver, resulting in it being the second leading cause of cancer related deaths in the US and having limited treatment options. Current immunotherapies for solid organ malignancies have shown only limited success, however, both immune manipulation of the tumor microenvironment and the use of targeted antibodies have shown promise. We propose to study mechanisms to increase lymphocyte infiltration and activation within colorectal cancer liver metastases combined with T-cell trafficking using a tumor-specific bispecific antibody in order to incite an anti- tumor response in one of the deadliest cancers worldwide.
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