Intracerebroventricular (ICV) Administration of CD19-Targeting Chimeric Antigen Receptor (CAR) T cells for Treatment of Primary Central Nervous System Lymphoma

项目总结 摘要原发性中枢神经系统淋巴瘤(PCNSL)是一种罕见的非霍奇金淋巴瘤。 淋巴瘤(NHL)最初出现在中枢神经系统(CNS)。PCNSL的治疗选择是 有限；护理标准大剂量甲氨蝶呤方案40多年来一直没有变化， 对大多数患者来说是不能治愈的。CD19(CD19-)嵌合抗原受体(CAR)T细胞治疗 Car T细胞)是一种强大的免疫疗法，在提供时具有既定的安全性 静脉(IV)治疗非霍奇金淋巴瘤。我们生产CD19-CAR T细胞的临床平台 HOPE(COH)已在一系列B细胞急性淋巴细胞白血病的1期临床试验中得到评估 (所有)和NHL。到目前为止，所有之前和正在进行的CD19-CAR T细胞试验都注入了CAR T细胞产品 我们有初步证据表明，静脉注射的CD19-CAR T细胞可以在中枢神经系统中检测到，并具有 抗肿瘤活性在PCNSL患者治疗中的应用然而，静脉注射CAR T细胞疗法对患者的疗效 PCNSL是有限的，可能是由于CAR T细胞从血液到中枢神经系统的运输不畅，这可能导致 与系统性非霍奇金淋巴瘤相比，针对PCNSL的活性降低。在COH的第一阶段试验中，局部区域交付 CAR T细胞治疗中枢神经系统恶性肿瘤，如胶质母细胞瘤，结果有所改善。在我们的研究中 动物模型显示改善的疾病反应，耐受性和对肿瘤再攻击的抵抗力 脑室内(ICV)与静脉注射CD19-CAR T细胞在CNS淋巴瘤异种移植小鼠模型中的比较。 因此，为了优化CD19-CAR T细胞的疗效并改善PCNSL患者的预后，我们 建议通过ICV传递给CD19-CAR T细胞。我们假设ICV交付的CD19-CAR T 细胞将是安全的，并表现出高抗PCNSL活性。在具体目标1中，我们将进行阶段1临床 评估安全性和活性的试验，并确定推荐的ICV第二阶段剂量(RP2D) PCNSL患者CD19-CAR T细胞的检测在具体目标2中，我们将进行一系列相关研究 评估毒性、CAR T细胞持久性、外周血转运和免疫细胞的机制 表型，以及对肿瘤的影响。我们计划检测ICV传递的CAR T细胞对正常CD19的影响 外周血中的B细胞来确定CAR T细胞是否像我们预期的那样从中枢神经系统流向血液 基于我们的PCNSL临床前动物模型。血液中正常B细胞的活性表明 对于既有这两种疾病的继发性中枢神经系统淋巴瘤患者来说，脑室注射可能是一种可行的治疗选择 中枢神经系统和全身性疾病。成功完成拟议的临床试验和相关研究将 扩大PCNSL患者的治疗选择，并可能为潜在的后续临床设计提供信息 评价继发性中枢神经系统淋巴瘤患者治疗的安全性和有效性。

PROJECT SUMMARY Primary central nervous system lymphoma (PCNSL) is a rare hematologic maligancy in which non-Hodgkin lymphoma (NHL) initially presents in the central nervous system (CNS). Therapeutic options for PCNSL are limited; standard of care high-dose methotrexate-containing regimens have been unchanged for over 40 years, and are not curative in most patients. Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CD19- CAR T cells) is a powerful form of immunotherapy that has an established safety profile when delivered intravenously (IV) to treat patients with NHL. Our clinical platform for manufacturing CD19-CAR T cells at City of Hope (COH) has been evaluated in a series of phase 1 clinical trials for B cell acute lymphoblastic leukemia (ALL) and for NHL. To date, all previous and ongoing CD19-CAR T cell trials have infused the CAR T cell product IV. We have preliminary evidence that IV-administered CD19-CAR T cells can be detected in the CNS and have anti-tumor activity in treating patients with PCNSL. However, the efficacy of IV CAR T cell therapies for patients with PCNSL is limited, possibly due to poor trafficking of CAR T cells from blood to CNS that may result in reduced activity against PCNSL compared to systemic NHL. In phase 1 trials at COH, locoregional delivery of CAR T cells to treat CNS malignancies such as glioblastoma has led to improved outcomes. Studies in our animal models show improved disease response, durability and resistence to tumor rechallenge using intracerebroventricular (ICV)- vs IV- delivered CD19-CAR T cells in xenograft mouse models of CNS lymphoma. Thus, to optimize the efficacy of CD19-CAR T cells and improve the outcomes of patients with PCNSL, we propose to administer CD19-CAR T cells via ICV delivery. We hypothesize that ICV-delivered CD19-CAR T cells will be safe and demonstrate high anti-PCNSL activity. In Specific Aim 1, we will conduct a phase 1 clinical trial to assess the safety and activity, and determine the recommended phase 2 dose (RP2D) of ICV delivered CD19-CAR T cells in participants with PCNSL. In Specific Aim 2, we will conduct a series of correlative studies to assess mechanisms of toxicity, CAR T cell persistance, trafficking to the peripheral blood, immune cell phenotype, and effect on tumor. We plan to examine the effects of ICV-delivered CAR T cells on normal CD19+ B cells in the peripheral blood to determine whether CAR T cells traffic from the CNS to the blood, as we expect based on our preclinical animal models of PCNSL. Activity against normal B cells in the blood would indicate that ICV delivery could be a viable treatment option for patients with secondary CNS lymphoma, who have both CNS and systemic disease. Successful completion of the proposed clinical trial and correlative studies will expand therapeutic options for patients with PCNSL and could inform the design of a potential subsequent clinical trial to evaluate the safety and efficacy of treating patients with secondary CNS lymphoma.