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Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma

开发新型 synNotch CART 细胞疗法治疗复发性 EGFRvIII 胶质母细胞瘤成人患者

基本信息

批准号：
10487528
负责人：
Hideho Okada
金额：
$ 25.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487528
关键词：
Adolescent Adopted Adult Antigens B lymphoid malignancy Biodistribution Blood Brain Brain Neoplasms Cell Therapy Cells Clinical Clinical Trials Data Development Dose Engraftment Enrollment Epidermal Growth Factor Receptor Funding Glioblastoma Goals Grant Heterogeneity Homing Human Immunologic Monitoring Immunotherapy In Vitro Infiltration Inflammation Institutes Intravenous Intravenous infusion procedures Investigational Drugs Investigational New Drug Application Lentivirus Lentivirus Vector Malignant Neoplasms Maximum Tolerated Dose Medical Memory Methods Neuraxis New Drug Approvals Operative Surgical Procedures Organ Patients Pharmacodynamics Phase Phase I Clinical Trials Phenotype Pre-Clinical Model Procedures Process Recurrence Research Personnel Resected Safety Signal Transduction Solid Surface Antigens System T cell therapy T-Lymphocyte Testing Time Tissues Toxic effect Toxicology Tumor Tissue United States National Institutes of Health base blood-brain tumor barrier body system cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells cohort cytotoxicity design epidermal growth factor receptor VIII exhaustion experience first-in-human in vivo innovation manufacturing process mutant neoplasm immunotherapy neoplastic cell notch protein novel patient derived xenograft model phase 1 study phase I trial preclinical efficacy prospective quality assurance receptor stem tumor ultrasound

项目摘要

Development of safe and effective (CAR)-transduced T cell (CART) therapy for glioblastoma (GBM) needs to overcome multiple challenges, including on-target off-tumor toxicity, heterogeneity of antigen expression, and exhaustion of CART cells. There are no GBM-specific surface antigens that are uniformly present in tumor tissue. Mutant epidermal growth factor receptor (EGFRvIII), for example, is GBM-specific but its expression is heterogenous within the tumor. On the other hand, while non-mutant GBM-associated antigens (GAAs), such as EphA2 and IL-13Rα2, are more uniformly expressed in GBM, their expression in other organs outside the central nervous system (CNS) raises concern for off-tumor toxicity. As a way to safely and effectively target GAAs, we have adopted a novel synthetic Notch “synNotch” receptor system and developed innovative T cells. In this system, the first antigen, which is expressed exclusively on brain or GBM cells (e.g. EGFRvIII), primes the T cells to induce expression of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells expressing either EphA2 or IL-13α2. Our data show that EGFRvIII-synNotch primed IL-13Rα2/EphA2 CAR are effectively but restrictedly activated by EGFRvIII as the GBM-specific signal, leading to complete eradication of patient-derived xenografts with heterogeneous EGFRvIII expression but without attacking IL-13Rα2/EphA2- positive cells outside of CNS. Furthermore, these synNotch-CAR T cells were significantly more efficacious than conventional, constitutively expressed IL-13Rα2/EphA2 CAR T cells, and were associated with excellent persistence (>100 days in vivo). Taken together, our data indicate that synNotch CAR T cells can revolutionize the CAR T therapy for solid cancers by overcoming the off-tumor toxicity, antigen heterogeneity and lack of persistence. Our goals are to establish the process for development of Good Manufacturing Practice products of EGFRvIII-primed IL-13Rα2/EphA2 CAR T cells, to obtain an Investigational New Drug (IND) approval, and to develop and conduct a phase I trial in patients with recurrent GBM. In Aim 1, we will generate GMP-grade lentiviral vector and establish standard procedures for GMP-grade manufacturing of the EGFRvIII-primed IL-13Rα2/ EphA2 CAR T cells. In Aim 2, we will complete both in vitro and in vivo studies that are required for submission of an IND. In vitro studies include confirmation of antigen-specific priming, specific cytotoxicity, and absence of replication competent lentivirus. In vivo, we will confirm preclinical efficacy, toxicology, tissue biodistribution, and engraftment as well as persistence of synNotch CART cells. In Aim 3, in a first-in-human phase 1 clinical trial, we will determine safety and toxicity of the synNotch CART cells in patients with recurrent EGFRvIII+ GBM. In a subsequent expansion cohort, in patients with recurrent EGFRvIII+ GBM, we will infuse synNotch CART cells intravenously prior to surgery, and then evaluate infiltration, priming and function of the infused cells in the resected GBM. These studies will allow us to determine optimal dosing based not only on tolerability but also on pharmacodynamic assessments.

开发安全有效(CAR)转导的T细胞(CART)治疗胶质母细胞瘤(GBM)需要克服多重挑战，包括靶点上的肿瘤外毒性、抗原表达的异质性以及 CART细胞耗尽。没有统一存在于肿瘤中的GBM特异性表面抗原。组织。例如，突变的表皮生长因子受体(EGFRvIII)是GBM特异的，但它的表达是肿瘤内部的异质性。另一方面，虽然非突变的GBM相关抗原(GaAs)，如由于EphA2和IL-13Rα2在基底膜中的表达更加均匀，它们在其他器官中的表达中枢神经系统(CNS)引起了人们对非肿瘤毒性的关注。作为一种安全有效地瞄准目标的方式我们采用了一种新的合成Notch“synNotch”受体系统，并开发了创新的T细胞。在这个系统中，第一个抗原，它只在脑或GBM细胞(例如，EGFRvIII)上表达，是质数 T细胞诱导表达识别IL-13Rα2和EphA2的CAR，从而根除基底膜细胞 EphA2或IL-13α2的表达。我们的数据表明，EGFRⅢ-SynNotch诱导的IL-13Rα2/EphA2 CAR 作为GBM特异性信号，由EGFRvIII有效但受限地激活，导致彻底根除异种表达EGFRⅢ但不攻击IL-13Rα2/EphA2的患者来源的异种移植中枢神经系统外的阳性细胞。此外，这些SynNotch-CAR T细胞明显更有效比传统的、有成分地表达IL-13Rα2/EphA2的CAR T细胞，并与优秀的持久性(体内100天)。综上所述，我们的数据表明，SynNotch CAR T细胞可以彻底改变克服瘤外毒性、抗原异质性和肿瘤免疫缺陷的实体癌CAR治疗坚持不懈。我们的目标是建立开发良好制造规范的过程 IL-13Rα_2/EphA_2诱导的IL-13R/EphA_2 CAR T细胞的产物获得研究新药(IND) 批准，并在复发的GBM患者中开发和进行I期试验。在目标1中，我们将产生GMP级慢病毒载体并建立GMP级生产的标准程序 EGFRⅢ免疫的IL-13Rα2/EphA2 CAR T细胞。在目标2中，我们将完成体外和体内研究，是提交IND所必需的。体外研究包括确认抗原特异性的启动，特异性的细胞毒性，以及缺乏复制能力的慢病毒。在体内，我们将确认临床前的疗效，毒理学、组织生物分布、植入以及SynNotch CART细胞的持久性。在目标3中，在作为人类首个1期临床试验，我们将确定SynNotch CART细胞的安全性和毒性复发的EGFRvIII+GBM患者。在随后的扩大队列中，在复发的EGFRvIII+患者中 GBM，我们将在手术前静脉输注SynNotch CART细胞，然后评估渗透、预充以及移植细胞在切除的基底膜中的功能。这些研究将使我们能够确定最佳剂量不仅基于耐受性，还基于药效学评估。