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：
10689805
负责人：
Hideho Okada
金额：
$ 25.35万
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/10689805
关键词：
Adolescent Adopted Adult Antigens B lymphoid malignancy Biodistribution Blood Brain Brain Neoplasms Cell Therapy Cells Central Nervous System Clinical Clinical Trials Collaborations Data Development Dose Engraftment Enrollment Epidermal Growth Factor Receptor Funding Glioblastoma Goals Good Manufacturing Process Grant Heterogeneity Homing Human Immunologic Monitoring Immunotherapy In Vitro Infiltration Inflammation Intravenous Intravenous infusion procedures Investigational Drugs Investigational New Drug Application Lentivirus Lentivirus Vector Malignant Neoplasms Maximum Tolerated Dose Medical Memory Methods Nervous System 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 Tissues Toxic effect Toxicology Translation Process Tumor Tissue United States National Institutes of Health 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 invention manufacture manufacturing process mutant 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.

开发安全有效的（CAR）转导的T细胞（CART）治疗胶质母细胞瘤（GBM）需要克服多个挑战，包括靶向非肿瘤毒性，抗原表达的异质性和手推车细胞的耗尽。肿瘤中没有均匀存在的GBM特异性表面抗原组织。例如，突变表皮生长因子受体（EGFRVIII）是GBM特异的，但其表达是肿瘤内的异质。另一方面，虽然非突变GBM相关抗原（GAA），但由于Epha2和IL-13Rα2在GBM中更均匀地表达，它们在外面的其他器官中的表达中枢神经系统（CNS）引起了人们对肿瘤毒性的关注。作为安全有效的定位方式 GAAS，我们采用了一种新型的合成缺口“同步”受体系统，并开发了创新的T细胞。在该系统中，第一种抗原仅以大脑或GBM细胞表示（例如Egfrviii），Primes T细胞诱导识别IL-13Rα2和EPHA2的汽车表达，从而消除GBM细胞表达EPHA2或IL-13α2。我们的数据表明，EGFRVIII合成的IL-13Rα2/Epha2 Car是有效但被EGFRVIII限制为GBM特异性信号，导致完全放射具有异质eGfrVIII表达的患者衍生的Xenographictic，但没有攻击IL-13Rα2/epha2- 中枢神经系统外的阳性细胞。此外，这些同步型式T细胞效率更高比常规的，始终表达的IL-13Rα2/epha2 Car T细胞，并且与优秀相关持久性（体内> 100天）。综上所述，我们的数据表明同步汽车T细胞可以革新通过克服非肿瘤毒性，抗原异质性和缺乏的固体癌症治疗持久性。我们的目标是建立发展良好制造实践的过程 EGFRVIII-PRAIRED IL-13Rα2/EPHA2 CAR T细胞的产物，以获得研究新药（IND）批准，并在复发性GBM患者中开发和进行I期试验。在AIM 1中，我们将生成GMP级慢病毒载体，并建立用于GMP级制造的标准程序 EGFRVIII-PRAIRED IL-13Rα2/ EPHA2 CAR T细胞。在AIM 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启动，特异性的细胞毒性和缺乏复制能力的慢病毒。在体内，我们将确认临床前效率，毒理学，组织生物分布和植入以及同步推车细胞的持久性。在AIM 3中第一个人类的第一阶段临床试验，我们将确定同步推车细胞中的安全性和毒性复发性EGFRVIII+ GBM的患者。在随后的扩张队列中，在复发EGFRVIII+的患者中 GBM，我们将在手术前静脉内注入同源性手推车细胞，然后评估浸润，启动被切除的GBM中感染细胞的功能。这些研究将使我们能够确定最佳剂量不仅基于耐受性，还基于药物代谢评估。