Developing novel CAR T cell designs using combinatorial antigen detection

项目总结/摘要 候选人：申请人，格雷格艾伦，医学博士/博士，是一个在加州大学旧金山分校的医学肿瘤学家与长期目标，以领导 一个独立的基于实验室的转化研究计划，专注于细胞疗法。K08 申请是他职业发展的关键，为他提供了（1）来自不同科学家团队的指导 （2）正式的教学法，以扩大他在临床试验设计和肿瘤方面的知识 免疫学，（3）在新开发的细胞疗法的翻译，以早期广泛的实践培训 阶段临床试验和（4）R 01申请的数据收集。 研究：CAR T细胞是B细胞恶性肿瘤的一种改变游戏规则的治疗方法-基因重编程 患者的细胞毒性T细胞使它们能够识别和清除肿瘤细胞。不幸的是，对于实体癌， 当前一代的CAR T细胞已经无效-没有简单的单一抗原靶向CAR能够 准确识别并安全清除实体瘤细胞。有一个明确的未满足的需求的设计和 下一代工程细胞疗法的实施，以克服这些挑战。核心 该建议假设是组合抗原免疫-肿瘤细胞和肿瘤的检测 使用来自多个抗原的信息的微环境（具有AND/OR/NOT门）可以提供强大的 解决了精确识别的问题，并允许构建更有效的疗法。 在这个项目中，第一个目标是研究使用与门安全地靶向胰腺癌， 认识并克服这种疾病中的抑制性肿瘤微环境。第二个目的 将应用新开发的提供非门功能的受体，以避免CAR T观察到的CNS毒性 专门针对神经母细胞瘤的细胞 指导和培训：艾伦博士的培训将通过正式的课程和直接指导下完成。 导师的世界领导人，包括温德尔林博士，系主任的分子和细胞 他在模块化信号平台、合成生物学和生物学领域拥有丰富的专业知识， 细胞疗法林教授在加州大学旧金山分校工作了20多年，指导了约50名博士后研究员， 临床研究员艾伦博士将由医学博士Larry Fong共同指导，Larry Fong博士是转化免疫学专家， 免疫疗法谁领导癌症免疫治疗计划在加州大学旧金山分校，并有丰富的经验， 帮助翻译免疫学研究人员实现独立。 环境：候选人的培训和研究将在加州大学旧金山分校进行。 弗朗西斯科，它提供了一个特殊的研究环境与国家的最先进的设施和世界知名的 教师。UCSF致力于开发下一代细胞疗法，艾伦博士将成为UCSF的一员 细胞设计研究所（专注于细胞工程），UCSF合成免疫学中心和UCSF 海伦·迪勒综合癌症中心。

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.