Developing novel CAR T cell designs using combinatorial antigen detection

项目摘要/摘要 应聘者：格雷格·艾伦，医学博士，加州大学旧金山分校的肿瘤内科医生，他的长期目标是领导 一个以实验室为基础的独立转化研究项目，专注于细胞疗法。K08 应用是他职业发展的关键，为他提供了来自不同科学家团队的指导 和内科科学家，(2)正式的教学，以扩大他在临床试验设计和肿瘤方面的知识 免疫学，(3)广泛的实践培训，将新开发的细胞疗法转化为早期 阶段临床试验和(4)R01应用的数据收集。 研究：CAR T细胞是一种改变B细胞恶性肿瘤游戏规则的治疗方法--对A细胞进行基因重组 患者的细胞毒性T细胞使他们能够识别和清除肿瘤细胞。不幸的是，对于实体癌症来说 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肿瘤细胞。对设计和设计有明显的未满足的需求 实施下一代工程细胞疗法以克服这些挑战。其核心是 这一建议的假设是组合抗原识别-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 解决准确识别的问题，并允许建立更有效的治疗方法。 在这个项目中，第一个目标将研究与门的使用，通过以下方式安全地靶向胰腺癌 认识和克服这种疾病中出现的抑制性肿瘤微环境。第二个目标 将应用新开发的受体，提供NOT门功能，以避免在CAR T中看到的CNS毒性 专为神经母细胞瘤设计的细胞。 指导和培训：艾伦博士的培训将通过正式课程完成，并在 世界领导人的导师，包括分子和细胞系主任温德尔·林博士 在加州大学旧金山分校的药理学，他在模块化信号平台、合成生物学和 细胞疗法。林教授在加州大学旧金山分校工作了20年，指导了约50名博士后研究员和4名博士后 临床研究员。艾伦博士将由拉里·方博士共同指导，他是翻译免疫学和 他是加州大学旧金山分校癌症免疫治疗项目的负责人，拥有丰富的 帮助翻译免疫学研究人员实现独立性。 环境：候选人的培训和研究将在加州大学旧金山分校进行 旧金山，提供卓越的研究环境，拥有最先进的设施和世界知名的 教职员工。加州大学旧金山分校致力于开发下一代细胞疗法，艾伦博士将成为加州大学旧金山分校的一员 细胞设计研究所(专注于细胞工程)、加州大学旧金山分校合成免疫学中心和加州大学旧金山分校 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.