PROJECT SUMMARY/ABSTRACT Candidate: The applicant, Greg Allen, MD/PhD, is a medical oncologist at UCSF with a long-term goal to lead an independent laboratory-based translational research program focused on cellular therapies. The K08 application is key for his career development, providing him with (1) mentorship from a diverse team of scientists and physician-scientists, (2) formal didactics to expand his knowledge in clinical trial design and tumor immunology, (3) extensive hands-on training in the translation of newly developed cellular therapies to early phase clinical trials and (4) data collection for an R01 application. Research: CAR T cells are a game-changing treatment for B cell malignancies — genetically reprogramming a patient's cytotoxic T cells allows them to recognize and clear tumor cells. Unfortunately for solid cancers the current generation of CAR T cells have been ineffective – no simple single antigen targeted CAR is able to precisely recognize and safely clear solid tumor cells. There is a clear unmet need for the design and implementation of the next-generation of engineered cell therapies to overcome these challenges. The core hypothesis of this proposal is that combinatorial antigen recognition—the detection of tumor cells and tumor microenvironments using information from multiple antigens (with AND/OR/NOT gates) can provide a powerful solution to the problem of precise recognition and allow the construction of more effective therapies. In this project the first aim will investigate the use of AND gates to safely target pancreatic adenocarcinoma by recognizing and overcoming the suppressive tumor-microenvironment seen in this disease. The second aim will apply newly developed receptors that provide NOT gate functionality to avoid CNS toxicity seen with CAR T cells designed to target neuroblastoma. Mentorship and Training: Dr. Allen's training will be accomplished through formal coursework and under direct mentorship of world leaders including Wendell Lim, PhD, chair of the Department of Molecular and Cellular Pharmacology at UCSF who has extensive expertise in modular signaling platforms, synthetic biology and cellular therapy. Professor Lim has over his 20 years at UCSF mentored ~50 postdoctoral fellow as well as 4 clinical fellows. Dr. Allen will be co-mentored by Dr. Larry Fong, MD, an expert in translational immunology and immunotherapy who leads the Cancer Immunotherapy Program at UCSF and has extensive experience in helping translational immunology researchers achieve independence. Environment: The candidate's training and research will be performed at the University of California, San Francisco, which provides an exceptional research environment with state-of-art facilities and world-renowned faculty. UCSF is dedicated to developing next-generation cell therapies and Dr. Allen will be part of the UCSF Cell Design Institute (focused on cell engineering), the UCSF Center for Synthetic Immunology and the UCSF Helen Diller Comprehensive Cancer Center.

PROJECT NARRATIVE Cellular therapy has made a dramatic impact on the treatment of B cell lymphoma and leukemia. However, attempts to apply cellular therapy to solid tumors have largely been unsuccessful. This project seeks to both develop and apply next-generation synthetic biology tools to tackle the twin challenges of safely targeting and improving the efficacy of therapeutic cells for solid tumors.