Understanding how the immune system responds to tumor may lead to development of novel treatment strategies for cancer. The candidate is a physician-scientist currently pursuing fellowship training in medical oncology who is proposing a 5-year mentored research experience with Irving Weissman at Stanford University. Tumor-reactive cytotoxic T cells represent a promising approach to cancer therapy, but is limited by difficulty isolating and expanding pure populations of these cells for each patient. An alternate approach is to transduce hematopoetic stem cells with genes encoding anti-tumor T cell receptors (TCRs) under control of an inducible T cell-specific promoter. The important benefit achieved is that a single inoculum of gene-modified stem cells could provide cancer patients with a continuously renewing and expanding pure population of effective tumor-reactive cytotoxic T cells. Moreover, as TCRs are cloned that recognize common tumor epitopes (eg. HER-2/neu, p53), a significant number of malignancies potentially could be targeted by this approach, referred to as Stem Cell-Derived Immunotherapy (SDI). The long term goal of the candidate, and thus the proposal, is to understand mechanisms of T cell interaction with tumor and apply this knowledge to develop new therapeutic strategies against cancer. To this end, a transgenic (TG) mouse model system will be generated that will allow study of cytotoxic T cell response to breast cancer while exploring the feasibility of SDI. First, we will create two lines of TG mice: a tumor model line in which mammary tumors will arise that express immunogenic viral nucleoprotein (NP); and, a TCR line in which activated cytotoxic cells will express TCR specific to NP. Second, we will determine if activated TCR-expressing cytotoxic cells can develop, expand and migrate to sites of immune stimulus and endogenous tumor. Third, we will test if activated TCR-expressing cytotoxic cells can mediate significant regression of endogenous tumor, or prevent de novo tumor development. Lastly, we will define the homing receptors and ligands involved in tumor localization, and the identity of cytotoxic cell subsets mediating tumor cytolysis. The experiments will be performed at Stanford University Beckman Center, a facility with high quality labs, state of the art equipment, and a stimulating academic environment. Ancillary training activities include courses in immunology, signal transduction, and biomedical ethics, as well as weekly seminars offered by the Departments of Medical Oncology, Immunology, and Developmental Biology. The proposed training program is designed with the goal of preparing this applicant to establish an independent laboratory in an academic oncology department.
