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.

项目概要 该提案“针对 KRAS 突变实体瘤的下一代 T 细胞疗法”是针对 RFA-CA-22-028 并实现癌症过继细胞治疗网络 (Can-ACT) 的目标。重点是 我们的建议是通过早期临床测试来针对突变型 KRAS（一种克隆驱动癌蛋白） TCR1020，一种针对 HLA-A*11:01 的 mKRAS G12V 特异性 T 细胞受体。如果成功的话，这部小说-状态- 在美国，每年约有 5,000 名新实体瘤患者可以使用最先进的过继细胞疗法 (ACT)。 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 开发下一代实体瘤 T 细胞疗法的科学基础。我们的中心假设 是通过 TCR1020-T 细胞的作用靶向突变的 KRAS，该细胞经过改造以克服细胞内在的 耗尽机制并抵消细胞外源性骨髓检查点以克服 TME 耐药性，将 促进实体瘤的持久肿瘤消退。本研究中有三个由假设驱动的具体目标 提议。在目标 1 中，我们将开发表达 TCR1020 的转基因 T 细胞，靶向 mKRAS G12V/HLA-A*11:01 克服外在和内在的耐药机制。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。瞄准 3、工程TCR1020-T细胞产品的安全性和临床活性将在剂量递增中确定 多地点第一阶段研究。我们组建了一支杰出的调查人员小组，拥有广泛的跟踪记录 在人类免疫学、免疫肿瘤学、细胞治疗、T细胞治疗等领域的专业知识的协作和生产力记录 细胞工程和基因编辑。此外，分子病理学和生物标志物发现方面的专家将 为尖端相关研究做出贡献，以帮助生物标志物开发和 TME 表征 描述潜在的反应和抵抗机制。细胞免疫治疗中心 (CCI) 宾夕法尼亚大学在 ACT 疗法开发方面拥有丰富的专业知识，可产生更多 超过 2,500 种细胞产品可供成人和儿童患者使用。 CCI 拥有长期的记录 向大型制药公司（Novartis、Kymriah）和 过去十年的生物技术公司。作为多站点试用应用程序，一个重要的程序化 我们提案的一部分是通过利用免疫细胞网络 (ICN) 核心来利用 NCI 资源 FNLCR 负责制造、测试、发布和分销工程 TCR1020-T 细胞产品。总之， 我们的提案结合了针对反复出现的克隆驱动因素的多项科技创新 含有经过改造的 T 细胞的癌蛋白可抵抗 T 细胞耗竭并克服免疫抑制 TME。