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

脑室内 (ICV) 施用靶向 CD19 的嵌合抗原受体 (CAR) T 细胞治疗原发性中枢神经系统淋巴瘤

• 批准号: 10700973
• 负责人: Stephen J Forman
• 金额: $ 70.52万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700973
• 关键词: Address; Angiopoietins; Animal Model; Autologous; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; CAR T cell therapy; CD19 gene; Cell physiology; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Lymphoma; Cerebral Ventricles; Cerebrospinal Fluid; Characteristics; Cities; Clinical; Clinical Trials; Cognitive; Correlative Study; Data; Development; Disease; Distal; Dose; Endothelial Growth Factors; Endothelium; Environment; Evaluable Disease; Exclusion; FDA approved; Funding; Future; Glioblastoma; Goals; Hematologic Neoplasms; Hematology; Human Resources; Immune; Immunologics; Immunotherapy; Infusion procedures; Injections; Intravenous; Kinetics; Lymphoma; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Metabolic; Methotrexate; Monitor; Neuron-Specific Enolase; Non-Hodgkin' s Lymphoma; Outcome; Participant; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phase I Clinical Trials; Phenotype; Prognosis; Radiation therapy; Recommendation; Refractory; Regimen; Relapse; Reporting; Research Design; Resistance; Role; Safety; Series; Serum; Survival Rate; Systemic disease; Testing; Therapeutic; Toxic effect; Vascular Endothelial Growth Factors; Xenograft procedure; cell motility; chimeric antigen receptor T cells; cytokine; design; follow-up; improved; improved outcome; in vivo; innovation; intravenous administration; manufacture; migration; mouse model; neurotoxicity; non-Hodgkin' s lymphoma patients; peripheral blood; phase 1 study; phase I trial; pre-clinical; response; safety assessment; side effect; standard of care; targeted treatment; timeline; trafficking; tumor; von Willebrand Factor

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.

项目摘要 原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的血液疾病，其中非霍奇金 淋巴瘤（NHL）最初出现在中枢神经系统（CNS）中。 PCNSL的治疗选择是 有限的;护理标准的高剂量甲氨蝶呤方案已经不变了40多年， 并且在大多数患者中都不是治愈性的。靶向CD19的嵌合抗原受体（CAR）T细胞疗法（CD19- CAR T细胞）是一种强大的免疫疗法形式，在交付时具有确定的安全性 静脉内（IV）治疗NHL患者。我们在City of City的CD19卡车T细胞生产的临床平台 HOPE（COH）已在一系列的1期临床试验中评估了B细胞急性淋巴细胞白血病 （全部）和NHL。迄今为止，所有先前和正在进行的CD19卡车T细胞试验都注入了CAR T细胞产品 iv。我们有初步的证据表明，可以在中枢神经系统中检测到IV级的CD19卡车T细胞，并且具有 治疗PCNSL患者的抗肿瘤活性。但是，IV CAR T细胞疗法对患者的功效 使用PCNSL是有限的，可能是由于从血液到CNS的CAR T细胞运输不善，可能导致 与全身性NHL相比，针对PCNSL的活性降低。在COH的第1阶段试验中，局部递送 CAR T细胞治疗中枢神经系统恶性肿瘤（如胶质母细胞瘤）已导致预后改善。我们的研究 动物模型显示了使用使用的疾病反应，耐用性和对肿瘤补偿的抵抗力 CNS淋巴瘤的异种移植小鼠模型中的脑室内（ICV） - vs IV-递送的CD19卡车T细胞。 因此，为了优化CD19卡车T细胞的功效并改善PCNSL患者的结局，我们 建议通过ICV输送来管理CD19卡车T细胞。我们假设ICV交付的CD19卡车T 细胞将是安全的，并显示出高抗PCNSL活性。在特定目标1中，我们将进行1期临床 试验以评估安全性和活动，并确定已交付的ICV的建议2阶段剂量（RP2D） PCNSL参与者中的CD19型T细胞。在特定目标2中，我们将进行一系列相关研究 评估毒性，汽车T细胞持久性，贩运到周围血液，免疫细胞的机制 表型和对肿瘤的影响。我们计划检查ICV分配的CAR T细胞对正常CD19+的影响 正如我们预期的 基于我们PCNSL的临床前动物模型。对血液中正常B细胞​​的活性表明 对于次级中枢神经系统淋巴瘤的患者，ICV输送可能是可行的治疗选择 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 扩展PCNSL患者的治疗选择，并可以为潜在的随后临床设计提供信息 试验以评估治疗继发性中枢神经系统淋巴瘤患者的安全性和功效。