课题基金 / 基金详情

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

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
批准号:
10305133
负责人:
Hideho Okada
金额:
$29.09万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-10 至 2026-08-31

项目摘要

项目成果

Hideho Okada的其他基金

相似基金

相关文献

中文摘要
翻译
开发安全有效的 (CAR) 转导 T 细胞 (CART) 治疗胶质母细胞瘤 (GBM) 需要 克服多重挑战,包括靶向肿瘤外毒性、抗原表达的异质性,以及 CART 细胞耗尽。肿瘤中不存在均匀存在的 GBM 特异性表面抗原 组织。例如,突变型表皮生长因子受体 (EGFRvIII) 是 GBM 特异性的,但其表达是 肿瘤内异质。另一方面,虽然非突变 GBM 相关抗原(GAA),例如 EphA2 和 IL-13Rα2 在 GBM 中表达更为一致,它们在 GBM 以外的其他器官中表达 中枢神经系统(CNS)引发了对肿瘤外毒性的担忧。作为一种安全有效地瞄准目标的方法 GAAs,我们采用了新型合成Notch“synNotch”受体系统并开发了创新的T细胞。 在该系统中,仅在脑或 GBM 细胞(例如 EGFRvIII)上表达的第一个抗原引发 T细胞诱导识别IL-13Rα2和EphA2的CAR表达,从而根除GBM细胞 表达 EphA2 或 IL-13α2。我们的数据显示,EGFRvIII-synNotch 引发的 IL-13Rα2/EphA2 CAR 是 EGFRvIII 作为 GBM 特异性信号有效但有限地激活,从而彻底根除 患者来源的异种移植物具有异质 EGFRvIII 表达,但不攻击 IL-13Rα2/EphA2- CNS 以外的阳性细胞。此外,这些 synNotch-CAR T 细胞显着更有效 与传统的、组成型表达的 IL-13Rα2/EphA2 CAR T 细胞相比,并且与优异的 持久性(体内 >100 天)。总而言之,我们的数据表明 synNotch CAR T 细胞可以彻底改变 CAR T疗法通过克服肿瘤外毒性、抗原异质性和缺乏 坚持。我们的目标是建立良好生产规范的开发流程 EGFRvIII 引发的 IL-13Rα2/EphA2 CAR T 细胞的产品,以获得研究性新药 (IND) 批准,并针对复发性 GBM 患者开发和进行 I 期试验。在目标 1 中,我们将 生成 GMP 级慢病毒载体并建立 GMP 级生产的标准程序 EGFRvIII 引发的 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引发、特异性 细胞毒性和缺乏复制能力的慢病毒。在体内,我们将确认临床前疗效, synNotch CART 细胞的毒理学、组织生物分布、植入以及持久性。在目标 3 中, 这是一项首次人体 1 期临床试验,我们将确定 synNotch CART 细胞在 复发性 EGFRvIII GBM 患者。在随后的扩展队列中,在复发 EGFRvIII 患者中 GBM,我们会在术前静脉注射synNotch CART细胞,然后评估浸润、启动 以及切除的 GBM 中输注细胞的功能。这些研究将使我们能够确定最佳剂量 不仅基于耐受性,还基于药效学评估。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
海外基金