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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要候选人：申请人Greg Allen，MD/PhD是UCSF的医学肿瘤学家，长期目标一个独立的基于实验室的转化研究计划，重点是细胞疗法。 K08 应用是他职业发展的关键（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转换为早期的翻译中的大量动手培训 R01应用程序的阶段临床试验和（4）数据收集。研究：CAR T细胞是B细胞恶性肿瘤的改变游戏规则的治疗方法 - 基因重编程A 患者的细胞毒性T细胞使他们能够识别并清除肿瘤细胞。不幸的是，对于固体癌症当前一代的汽车T细胞无效 - 没有简单的单一抗原靶向汽车能够精确识别，安全清除实体瘤细胞。设计明显未满足设计和实施下一代工程细胞疗法以克服这些挑战。核心该提议的假设是组合抗原识别 - 检测肿瘤细胞和肿瘤使用来自多种抗原（和/或/不门）的信息的微环境可以提供强大的解决精确识别问题的方法，并允许建立更有效的疗法。在这个项目中，第一个目标将调查使用和门的使用，以安全地针对胰腺腺癌。认识并克服了这种疾病中看到的抑制性肿瘤微环境。第二个目标将应用新开发的接收器，这些接收器不提供栅极功能以避免CNS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和直接完成分子和蜂窝部主席Wendell Lim在内的世界领导人的遗产 UCSF的药理学，在模块化信号平台，合成生物学和细胞疗法。 Lim教授在UCSF的20年中指导了约50个博士后研究员，以及4个临床研究员。艾伦博士将由翻译免疫学专家Larry Fong博士和在UCSF领导癌症免疫疗法计划的免疫疗法，并具有丰富的经验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利福尼亚大学SAN进行弗朗西斯科（Francisco），提供了一个特殊的研究环境，并具有最先进的设施和世界知名度学院。 UCSF致力于开发下一代细胞疗法，艾伦博士将成为UCSF的一部分细胞设计学院（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。