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

项目概要/摘要 Lim/UCSF和June/UPenn IOTN中心之间合作的目标是开发一种新颖的 这是一种自主和选择性地驱动实体瘤内CAR T细胞增殖的方法。当前临床 数据表明，强增殖对于过继转移的T细胞的治疗成功是关键的1，2。在 这是一个特别严重的挑战，因为肿瘤细胞被免疫抑制剂包围， 微环境对T细胞扩增和活性呈现多重障碍，包括抑制性 作为促增殖细胞因子3以及其他抑制细胞和因子的汇的调节性T细胞 其促进终末T细胞分化为耗尽状态4，5。为了解决这些问题，我们将联合收割机 我们两个小组的专业知识：加西亚实验室（六月/宾夕法尼亚大学中心）具有工程正交的专业知识， 细胞因子/受体系统，而Lim实验室（Lim/UCSF中心）在工程合成辅助细胞方面具有专业知识， 这些细胞可以自主识别并以靶向方式重塑肿瘤微环境， 合成的旁分泌细胞因子回路。在这项合作中，我们建议设计合成辅助细胞， 在肿瘤中自主产生正交IL-26，从而选择性地局部驱动CAR T细胞扩增。这 协作以协同方式合并了两个中心的方法。如果成功，这种方法将产生 一种更有效、选择性和自主地促进肿瘤中CAR T细胞扩增的方法， 在最初的个人中心目标内的方法。我们的具体目标是： 目标1。设计合成辅助T细胞，将ortho-IL 2递送到肿瘤微环境 目的1.1：改造小鼠ortho-IL-2辅助/杀伤细胞系统;在体外和同基因肿瘤模型中进行测试 目的1.2：工程改造人ortho-IL-2辅助/杀伤细胞系统;在体外和NSG异种移植肿瘤模型中进行测试 目的2：调节正交IL-2受体信号以改善和调节细胞对ortho-IL-2的应答。 系统地改变邻-IL-2受体胞内结构域中的信号传导结构域，以鉴定和部署 增加T细胞增殖和/或使耗竭最小化的变体。

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.