Engineering synthetic helper cells that autonomously deliver orthogonal IL-2 to selectively promote therapeutic T cell proliferation in tumors

工程合成辅助细胞可自主递送正交 IL-2 以选择性促进肿瘤中治疗性 T 细胞增殖

• 批准号: 10285941
• 负责人: WENDELL A LIM
• 金额: $ 25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285941
• 关键词: Acute; Address; Adoptive Transfer; Antigens; Area; Automobile Driving; Bioinformatics; Bypass; Cell Proliferation; Cell Therapy; Cells; Cellular immunotherapy; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Communities; Computer Models; Consumption; Cytokine Receptors; Development; Discrimination; Disease; Education and Outreach; Engineering; Exhibits; Gene Expression Profiling; Goals; Grant; Helper-Inducer T-Lymphocyte; Hematopoietic Neoplasms; Human Engineering; IL2 gene; Immune; Immunotherapeutic agent; Individual; Instruction; Interleukin 2 Receptor; Interleukin-2; Killer Cells; Malignant Neoplasms; Microscopic; Modeling; Molecular; Mus; Museums; Normal tissue morphology; Pattern Recognition; Process; Protein Engineering; Receptor Signaling; Regulatory T-Lymphocyte; Research; Resources; Safety; San Francisco; Scheme; Science; Signal Transduction; Solid; Solid Neoplasm; Specialist; Suppressor-Effector T-Lymphocytes; Synthetic immunology; System; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Variant; blood treatment; cell transformation; cellular engineering; chimeric antigen receptor T cells; cytokine; database design; design; engineered T cells; exhaust; exhaustion; immunoengineering; improved; in vitro testing; in vivo; nano; neoplastic cell; next generation; novel; novel strategies; paracrine; parent project; programs; prototype; receptor; response; small molecule; success; symposium; synergism; tool; trafficking; tumor; tumor microenvironment; tumor xenograft; tumor-immune system interactions

Project Summary/Abstract The goal of this collaboration between the Lim/UCSF and June/UPenn IOTN centers is to develop a novel approach to autonomously and selectively drive proliferation of CAR T cells within a solid tumor. Current clinical data indicates that strong proliferation is critical for therapeutic success of adoptively transferred T cells1,2. In solid tumors this is a particularly acute challenge as tumor cells are surrounded by an immunosuppressive microenvironment that presents multiple barriers to T cell expansion and activity, including suppressive regulatory T cells that act as sinks for pro-proliferation cytokines3, as well as other suppressor cells and factors that promote terminal T cell differentiation into an exhausted state4,5. To address these problems, we will combine the expertise of our two groups: the Garcia Lab (June/UPenn center) has expertise in engineering orthogonal cytokine/receptor systems, while the Lim Lab (Lim/UCSF center) has expertise in engineering synthetic helper cells that can autonomously recognize and remodel the tumor microenvironment in a targeted way using synthetic paracrine cytokine circuits. In this collaboration, we propose to engineer synthetic helper cells that autonomously produce orthogonal IL-26 in tumors, thereby selectively driving CAR T cell expansion locally. This collaboration merges approaches from both centers in a synergistic way. If successful, this approach will yield a way to promote CAR T cell expansion in tumors more effectively, selectively and autonomously than approaches within the original individual center aims. Our specific aims are to: Aim 1. Engineer synthetic helper T cells that deliver ortho-IL2 to the tumor micro-environment Aim 1.1: Engineer mouse ortho-IL-2 helper/killer cell system; test in vitro and in syngeneic tumor models Aim 1.2: Engineer human ortho-IL-2 helper/killer cell system; test in vitro and in NSG xenograft tumor models Aim 2: Modulate orthogonal IL-2 receptor signaling to improve and tune cell responses to ortho-IL2. Systematically alter the signaling domains in the ortho-IL-2 receptor intracellular domain to identify and deploy variants that increase T cell proliferation and/or minimize exhaustion.

项目概要/摘要 Lim/UCSF 和 June/UPenn IOTN 中心之间的合作目标是开发一种新颖的 一种自主、选择性驱动实体瘤内 CAR T 细胞增殖的方法。目前临床 数据表明，强劲的增殖对于过继转移 T 细胞的治疗成功至关重要1,2。在 实体瘤这是一个特别严峻的挑战，因为肿瘤细胞被免疫抑制物质包围 微环境对 T 细胞扩增和活性存在多重障碍，包括抑制 充当促增殖细胞因子3以及其他抑制细胞和因子的接收器的调节性T细胞 促进终末 T 细胞分化为耗尽状态 4,5。为了解决这些问题，我们将结合 我们两个团队的专业知识：加西亚实验室（六月/宾夕法尼亚大学中心）拥有正交工程方面的专业知识 细胞因子/受体系统，而 Lim 实验室（Lim/UCSF 中心）拥有工程合成辅助因子的专业知识 能够有针对性地自主识别和重塑肿瘤微环境的细胞 合成旁分泌细胞因子回路。在这次合作中，我们建议设计合成辅助细胞 在肿瘤中自主产生正交 IL-26，从而选择性地驱动 CAR T 细胞局部扩增。这 协作以协同方式融合两个中心的方法。如果成功的话，这种方法将产生 一种比 在最初的个人中心目标范围内采取的方法。我们的具体目标是： 目标 1. 设计合成辅助 T 细胞，将邻 IL2 递送至肿瘤微环境 目标 1.1：改造小鼠 ortho-IL-2 辅助细胞/杀伤细胞系统；体外和同基因肿瘤模型中的测试 目标 1.2：设计人类 ortho-IL-2 辅助/杀伤细胞系统；体外测试和 NSG 异种移植肿瘤模型 目标 2：调节正交 IL-2 受体信号传导以改善和调节细胞对邻 IL-2 的反应。 系统地改变邻位 IL-2 受体胞内结构域中的信号传导结构域以识别和部署 增加 T 细胞增殖和/或最大限度减少耗竭的变异。