Developing novel CAR T cell designs using combinatorial antigen detection

使用组合抗原检测开发新型 CAR T 细胞设计

• 批准号: 10597967
• 负责人: Greg Maness Allen
• 金额: $ 28.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597967
• 关键词: Antigen Targeting; Antigens; B lymphoid malignancy; B-Cell Lymphomas; Bioinformatics; Biometry; California; Cell Therapy; Cells; Clinical; Clinical Trials Design; Comprehensive Cancer Center; Cross Reactions; Cytotoxic T-Lymphocytes; Data Collection; Dedications; Department chair; Detection; Disease; Doctor of Philosophy; Ecosystem; Engineering; Environment; Faculty; Fibroblasts; Foundations; Generations; Genetic Engineering; Goals; Immune system; Immunocompetent; Immunotherapy; Knowledge; Laboratories; Lead; Logic; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Medical Oncologist; Medical Oncology; Mentors; Mentorship; Molecular; Mus; Neuroblastoma; Neurons; Normal Cell; Normal tissue morphology; Organ; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patients; Pharmacology; Physicians; Positioning Attribute; Postdoctoral Fellow; Production; Proteins; Research; Research Personnel; Safety; San Francisco; Scientist; Signal Transduction; Solid; Solid Neoplasm; Surface Antigens; Synthetic immunology; System; Testing; Therapeutic; Toxic effect; Training; Translations; Treatment Efficacy; Tumor Antigens; Tumor Tissue; Twin Multiple Birth; Universities; Work; antigen detection; cancer immunotherapy; career development; cell type; cellular engineering; chimeric antigen receptor; chimeric antigen receptor T cells; clinical practice; combinatorial; cross reactivity; cytokine; design; early phase clinical trial; early phase trial; effective therapy; engineered T cells; experience; gene repression; improved; leukemia/lymphoma; mesothelin; mouse model; neoplastic cell; neurotoxicity; next generation; novel; novel therapeutics; pancreatic cancer model; prevent; professor; programs; receptor; receptor expression; success; synthetic biology; tool; translational immunology; translational research program; tumor; tumor immunology; tumor microenvironment

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.

项目概要/摘要 候选人：申请人 Greg Allen，医学博士/博士，是 UCSF 的肿瘤内科医生，其长期目标是领导 一个基于独立实验室的转化研究项目，专注于细胞疗法。 K08 应用程序是他职业发展的关键，为他提供了（1）来自多元化科学家团队的指导 和医师科学家，(2) 正式的教学，以扩展他在临床试验设计和肿瘤方面的知识 免疫学，（3）将新开发的细胞疗法转化为早期的广泛实践培训 阶段临床试验和 (4) R01 应用的数据收集。 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——对 B 细胞进行基因重编程 患者的细胞毒性 T 细胞使它们能够识别并清除肿瘤细胞。不幸的是，对于实体癌来说 当前一代 CAR T 细胞已经无效——没有简单的单一抗原靶向 CAR 能够 精确识别并安全清除实体瘤细胞。设计和设计方面存在明显未满足的需求 实施下一代工程细胞疗法来克服这些挑战。核心 该提案的假设是组合抗原识别——肿瘤细胞和肿瘤的检测 使用来自多种抗原的信息（带有 AND/OR/NOT 门）的微环境可以提供强大的 解决精确识别的问题并允许构建更有效的疗法。 在该项目中，第一个目标将研究使用 AND 门来安全地靶向胰腺腺癌 认识并克服这种疾病中的抑制性肿瘤微环境。第二个目标 将应用新开发的受体，提供 NOT 门功能，以避免 CAR T 出现的中枢神经系统毒性 旨在靶向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课程并在直接指导下完成 世界领导人的指导，包括分子和细胞系主任 Wendell Lim 博士 加州大学旧金山分校药理学博士，在模块化信号平台、合成生物学和 细胞疗法。 Lim 教授在 UCSF 工作了 20 多年，指导了约 50 名博士后研究员以及 4 名博士后研究员。 临床研究员。 Allen 博士将由转化免疫学专家 Larry Fong 博士（医学博士）共同指导。 领导加州大学旧金山分校癌症免疫治疗项目，并在以下方面拥有丰富的经验： 帮助转化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圣何塞分校进行 弗朗西斯科提供了卓越的研究环境，拥有最先进的设施和世界知名的 学院。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。