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: 10522948
• 负责人: Stephen J Forman
• 金额: $ 71.96万
• 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/10522948
• 关键词: Address; Angiopoietins; Animal Model; Animals; 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 Diseases; Central Nervous System Lymphoma; Cerebral Ventricles; Cerebrospinal Fluid; Characteristics; Cities; Clinical; Clinical Trials; Cognitive; Correlative Study; Data; Development; Disease; Distal; Dose; Endothelium; Environment; Evaluable Disease; FDA approved; Funding; Future; Glioblastoma; Goals; Hematologic Neoplasms; Hematology; Human Resources; Immune; Immunologics; Immunotherapy; Infusion procedures; Injections; Intravenous; Kinetics; Lead; Lymphoma; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Metabolic; Methotrexate; Monitor; Mus; Neuraxis; Neuron-Specific Enolase; Non-Hodgkin' s Lymphoma; Outcome; Participant; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phase I Clinical Trials; Phenotype; Prognosis; Radiation therapy; Refractory; Regimen; Relapse; Reporting; Research Design; Role; Safety; Series; Serum; Survival Rate; Systemic disease; T-Lymphocyte; Testing; Therapeutic; TimeLine; Toxic effect; Vascular Endothelial Growth Factors; Xenograft procedure; base; chimeric antigen receptor T cells; cytokine; design; follow-up; improved; improved outcome; in vivo; innovation; migration; mouse model; neurotoxicity; non-Hodgkin' s lymphoma patients; peripheral blood; phase 1 study; phase I trial; pre-clinical; response; side effect; standard of care; targeted treatment; 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.

项目概要 原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的血液系统恶性肿瘤，其中非霍奇金淋巴瘤 淋巴瘤（NHL）最初出现在中枢神经系统（CNS）中。 PCNSL 的治疗选择有 有限的; 40 多年来，大剂量含甲氨蝶呤治疗方案的护理标准一直没有改变， 并且对大多数患者来说并不能治愈。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，在交付时具有既定的安全性 静脉注射 (IV) 治疗 NHL 患者。我们在纽约市生产 CD19-CAR T 细胞的临床平台 Hope (COH) 已在 B 细胞急性淋巴细胞白血病的一系列 1 期临床试验中进行了评估 （全部）和 NHL。迄今为止，所有先前和正在进行的CD19-CAR T细胞试验均已注入CAR T细胞产品 四．我们有初步证据表明，可以在中枢神经系统中检测到静脉注射的 CD19-CAR T 细胞，并且 治疗 PCNSL 患者的抗肿瘤活性。然而，IV CAR T细胞疗法对患者的疗效 PCNSL 的治疗效果有限，可能是由于 CAR T 细胞从血液到 CNS 的运输不畅，这可能会导致 与系统性 NHL 相比，针对 PCNSL 的活性降低。在 COH 的 1 期试验中，局部区域递送 CAR T 细胞用于治疗胶质母细胞瘤等中枢神经系统恶性肿瘤，改善了治疗效果。我们的研究 动物模型显示出改善的疾病反应、耐久性和对肿瘤再攻击的抵抗力 CNS 淋巴瘤异种移植小鼠模型中脑室内 (ICV) 与 IV 递送的 CD19-CAR T 细胞。 因此，为了优化 CD19-CAR T 细胞的功效并改善 PCNSL 患者的预后，我们 建议通过 ICV 递送来施用 CD19-CAR T 细胞。我们假设 ICV 递送 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 1 期临床 评估安全性和活性的试验，并确定推荐的 ICV 2 期剂量 (RP2D) PCNSL 参与者的 CD19-CAR T 细胞。在具体目标2中，我们将进行一系列的相关研究 评估毒性机制、CAR T 细胞持久性、外周血运输、免疫细胞 表型和对肿瘤的影响。我们计划检查 ICV 递送的 CAR T 细胞对正常 CD19+ 的影响 外周血中的 B 细胞可确定 CAR T 细胞是否如我们预期的那样从 CNS 运输到血液 基于我们的 PCNSL 临床前动物模型。针对血液中正常 B 细胞的活性表明 对于继发性中枢神经系统淋巴瘤患者来说，ICV 输送可能是一种可行的治疗选择，这些患者同时患有继发性中枢神经系统淋巴瘤 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，并可为潜在的后续临床设计提供信息 评估治疗继发性中枢神经系统淋巴瘤患者的安全性和有效性的试验。