Next generation T cell therapies for mutant KRAS solid tumors

项目摘要 该提案“KRAS突变实体瘤的下一代T细胞疗法”是为了响应 RFA-CA-22-028，并实现癌症免疫细胞治疗网络（Can-ACT）的目标。的焦点 我们的建议是通过早期临床试验靶向突变KRAS，一种克隆驱动癌蛋白， TCR 1020，一种对mKRAS G12 V具有特异性的T细胞受体，局限于HLA-A*11：01。如果成功的话，这个新的国家- 在美国，最先进的细胞疗法（ACT）每年可用于约5，000名新的实体瘤患者。 基因编辑的进展以及与T细胞耗竭机制相关的新见解提供了 为实体瘤中下一代T细胞疗法的开发提供科学依据。我们的核心假设 通过TCR 1020-T细胞的作用靶向突变的KRAS， 耗尽和抵消细胞外在骨髓检查点以克服TME抗性的机制，将 促进实体瘤的持久肿瘤消退。本文有三个假设驱动的具体目标 提议在目标1中，我们将开发表达靶向mKRAS的TCR 1020的遗传修饰的T细胞 G12 V/HLA-A*11：01来克服抗性的外在和内在机制。在目标2中，我们计划评估 TCR 1020-T CD 4+细胞，以改善mKRAS特异性CD 8+效应细胞的持久性和效力。在Aim中 3、工程化TCR 1020-T细胞产品的安全性和临床活性将在剂量递增中确定 多中心I期研究。我们已经召集了一个特殊的调查小组， 在人类免疫学、免疫肿瘤学、细胞治疗、T 细胞工程和基因编辑。此外，分子病理学和生物标志物发现专家将 有助于尖端的相关研究，以帮助生物标志物的开发和TME表征， 描述潜在的反应和抵抗机制。细胞免疫治疗中心（CCI） 宾夕法尼亚大学在ACT疗法的开发方面拥有广泛的专业知识， 超过2，500种细胞产品用于成人和儿童患者。CCI长期以来一直致力于 向大型制药公司（诺华、Kymriah）转让与细胞疗法有关的技术， 生物技术公司在过去的十年里。作为一个多站点的试用应用程序， 我们建议的一个组成部分是通过利用免疫细胞网络（ICN）核心来利用NCI资源 在FNLCR生产、测试、放行和分销工程化TCR 1020-T细胞产品。总的来说， 我们的提案结合了多项针对周期性克隆驱动的科学和技术创新， 癌蛋白与工程化T细胞修饰，以抵抗T细胞耗竭和克服免疫抑制 TME。

Project Summary This proposal “Next generation T cell therapies for KRAS mutated solid tumors” was developed in response to RFA-CA-22-028 and to fulfill the Cancer Adoptive Cellular Therapy Network (Can-ACT) objectives. The focus of our proposal is targeting mutant KRAS, a clonal driver oncoprotein, by the early-stage clinical testing of TCR1020, a T cell receptor specific for mKRAS G12V restricted to HLA-A*11:01. If successful, this novel-state- of-the-art Adoptive Cell Therapy (ACT) could be available to ~5,000 new solid tumor patients per year in the US. Advances in gene editing together with new insights related to mechanisms of T cell exhaustion provide the scientific basis for development of the next generation T cell therapies in solid tumors. Our central hypothesis is that targeting mutant KRAS through the action of TCR1020-T cells, engineered to overcome cell intrinsic mechanisms of exhaustion and counteract a cell extrinsic myeloid checkpoint to overcome TME resistance, will promote durable tumor regression in solid tumors. There are three hypothesis-driven specific Aims in this proposal. In Aim 1, we will develop genetically modified T cells expressing TCR1020 targeting mKRAS G12V/HLA-A*11:01 to overcome extrinsic and intrinsic mechanisms of resistance. In Aim 2, we plan to evaluate TCR1020-T CD4+ cells to improve the persistence and potency of mKRAS specific CD8+ effector cells. In Aim 3, the safety and clinical activity of engineered TCR1020-T cell products will be determined in a dose escalation multi-site phase 1 study. We have assembled an exceptional group of investigators with an extensive track record of collaboration and productivity with expertise in human immunology, immuno-oncology, cell therapy, T cell engineering and gene editing. Additionally, experts in molecular pathology and biomarker discovery will contribute to cutting-edge correlative studies to aid in biomarker development and TME characterization to delineate potential mechanisms of response and resistance. The Center for Cellular Immunotherapies (CCI) at the University of Pennsylvania has extensive expertise in the development of ACT therapies producing more than 2,500 cell products for administration to adult and pediatric patients. CCI has a long track record of technology transfer related to cell therapies to both large pharmaceutical companies (Novartis, Kymriah) and biotechnology companies over the past decade. As a multi-site trial application, an important programmatic component of our proposal is to leverage NCI resources thru utilization of the Immune Cell Network (ICN) Core at FNLCR to manufacture, test, release and distribute the engineered TCR1020-T cell products. In summary, our proposal incorporates multiple scientific and technological innovations that targets a recurrent clonal driver oncoprotein with engineered T cells modified to resist T cell exhaustion and overcome the immunosuppressive TME.