Next generation T cell therapies for mutant KRAS solid tumors

针对突变 KRAS 实体瘤的下一代 T 细胞疗法

• 批准号: 10731929
• 负责人: Beatriz M. Carreno
• 金额: $ 130.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731929
• 关键词: Ablation; Address; Adoptive Cell Transfers; Adult; Aftercare; Alleles; Biotechnology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cancer Patient; Case Study; Cell Proliferation; Cell Therapy; Cells; Cellular immunotherapy; Clinic; Clinical; Clinical Trials; Codon Nucleotides; Collaborations; Correlative Study; DNA Sequence Alteration; Data; Development; Dose; Drug Combinations; Effector Cell; Eligibility Determination; Engineering; Ensure; Epitopes; Genes; Genetic Transcription; Genomics; Goals; HLA-A gene; HLA-C Antigens; Human; Immune; Immune Targeting; Immune system; Immunology; Immunooncology; In Vitro; KRAS2 gene; Laboratories; Lesion; Leukocytes; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Missense Mutation; Mutate; Myelogenous; Myeloid Cells; Neoplasm Circulating Cells; Oncoproteins; Patients; Pennsylvania; Pharmacologic Substance; Phenotype; Population; Productivity; Proteomics; Publishing; Rattus; Reagent; Recurrence; Research; Research Personnel; Resistance; Resources; Safety; Site; Solid Neoplasm; T cell infiltration; T cell therapy; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Technology Transfer; Testing; Translations; Tumor Antigens; Universities; Variant; Vertebral column; Virus; Work; base editing; biomarker development; biomarker discovery; cancer clinical trial; cell growth; clinical translation; cost; design; engineered T cells; exhaustion; improved; in vivo; insight; lead candidate; manufacture; molecular marker; molecular pathology; multi-site trial; mutant; neoantigens; next generation; novel; pediatric patients; peripheral blood; personalized medicine; phase 1 study; premalignant; receptor; research clinical testing; resistance mechanism; response; safety engineering; sarcoma; single cell technology; small molecule inhibitor; success; targeted treatment; technological innovation; tumor; tumor microenvironment

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.

项目摘要 这项名为“下一代T细胞疗法治疗KRAS突变实体瘤”的建议是针对 RFA-CA-22-028和实现癌症采用细胞治疗网络(CAN-ACT)的目标。的关注点 我们的建议是针对突变的KRAS，一种克隆驱动癌蛋白，通过早期临床测试 TCR1020是一种针对mKRAS G12V的T细胞受体，可与人类白细胞抗原A*11：01结合。如果成功，这个新奇的国家-- 在美国，最先进的采用细胞疗法(ACT)每年可以为大约5000名实体肿瘤患者提供服务。 基因编辑的进展和与T细胞耗竭机制相关的新见解提供了 实体瘤下一代T细胞疗法发展的科学基础。我们的中心假设 是通过TCR1020-T细胞的作用来靶向突变的KRAS，这种T细胞被设计成克服细胞固有的 耗尽和抵消细胞外髓系检查点以克服TME耐药的机制，将 促进实体肿瘤的持久肿瘤消退。这其中有三个假设驱动的具体目标 求婚。在目标1中，我们将开发针对mKRAS的表达TCR1020的转基因T细胞 G12V/HLA-A*11：01克服外在和内在耐药机制。在目标2中，我们计划评估 TCR1020-T CD4+细胞可提高mKRAS特异性CD8+效应细胞的持久性和效力。在AIM 3、基因工程TCR1020-T细胞产品的安全性和临床活性将随着剂量的增加而确定 多点1期研究。我们已经召集了一支特殊的调查小组，他们有广泛的线索 在人类免疫学、免疫肿瘤学、细胞疗法、T 细胞工程和基因编辑。此外，分子病理学和生物标记物发现方面的专家将 有助于前沿相关研究，以帮助生物标记物开发和TME表征 描述潜在的反应和抵抗机制。细胞免疫治疗中心，网址： 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，生产更多 超过2500种细胞产品，用于成人和儿童患者。CCI有很长的记录， 向大型制药公司(诺华、Kymriah)和 生物技术公司在过去的十年里。作为多站点试用应用，具有重要的纲领性 我们建议的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制造、测试、发布和分销经过改造的TCR1020-T细胞产品。总而言之， 我们的方案结合了多种科技创新，针对的是一种经常性的克隆驱动器 修饰工程T细胞以抵抗T细胞耗竭和克服免疫抑制的癌蛋白 我也是。