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 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并履行癌症收养细胞治疗网络（CAN-ACT）目标。重点 我们的建议是针对克隆驱动器癌蛋白的突变体Kras，通过早期临床测试 TCR1020，一种针对MKRAS G12V的T细胞受体，仅限于HLA-A*11：01。如果成功，这个新颖的国家 - 在美国，每年约有5,000名新的实体瘤患者可以使用The-Art养管疗法（ACT）。 基因编辑的进步以及与T细胞耗尽机制有关的新见解提供了 在实体瘤中开发下一代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kras，设计为克服细胞的固有 疲惫的机制和抵消细胞外部髓样检查点以克服TME耐药性，将会 促进实体瘤的耐用肿瘤消退。在此中有三个以假设为驱动的特定目标 提议。在AIM 1中，我们将开发一般修饰的T细胞，表达TCR1020靶向MKRA G12V/HLA-A*11：01克服抗性的外在和内在机制。在AIM 2中，我们计划评估 TCR1020-T CD4+细胞可改善MKRAS特异性CD8+效应细胞的持久性和效力。目标 3，工程TCR1020-T细胞产品的安全性和临床活动将以剂量升级确定 多站点1期研究。我们已经组建了一组杰出的调查员 与人类免疫学，免疫肿瘤学，细胞治疗，T的协作和生产力的记录 细胞工程和基因编辑。此外，分子病理学和生物标志物发现专家将 有助于尖端的纠正研究，以帮助生物标志物的发展和TME表征 描述反应和抗性的潜在机制。细胞免疫疗法中心（CCI） 宾夕法尼亚大学在开发ACT疗法方面拥有广泛的专业知识，产生更多 超过2,500个细胞产品用于成人和儿科患者。 CCI有很长的记录 技术转移到大型制药公司（诺华，Kymriah）和 生物技术公司在过去十年中。作为多站点的试用应用程序，是一个重要的程序化 我们建议的组成部分是通过免疫细胞网络（ICN）核心利用NCI资源来利用NCI资源 在FNLCR，生产，测试，释放和分发工程的TCR1020-T细胞产品。总之， 我们的提案结合了针对经常性克隆驱动程序的多种科学和技术创新 癌蛋白具有修饰的工程T细胞，以抵抗T细胞耗尽并克服免疫抑制 TME。