Unraveling the Pathophysiology of Neurotoxicity Induced by CAR T-cells

揭示 CAR T 细胞引起的神经毒性的病理生理学

基本信息

批准号：
10453491
负责人：
CHRISTOPHER A PENNELL
金额：
$ 54.23万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453491
关键词：
Adverse effects Adverse event Affect Area Astrocytosis Autologous B lymphoid malignancy B-Cell Leukemia B-Cell Neoplasm B-Lymphocytes Basic Science Behavior Blood - brain barrier anatomy Brain CAR T cell therapy CD19 Antigens CD19 gene Cell surface Cells Cerebrovascular system Cessation of life Clinical Differentiation Antigens Disorientation Elements Engineering Etiology Functional disorder Gene Expression Genetic Genetic Engineering Hospitalization Human Immunocompetent Immunologics Immunotherapy In Situ In complete remission Infusion procedures Learning Leukocytes Liquid substance Methods Microglia Modeling Morbidity - disease rate Mus Myeloid Cell Activation Myeloid Cells Neuraxis Neurologic Patients Peripheral Pharmacology Refractory Reporting Sampling Specificity Suggestion Symptoms T-Lymphocyte Testing Toxic effect Transgenes Translational Research Tumor Burden blood-brain barrier disruption blood-brain barrier function brain parenchyma cancer immunotherapy cancer type chimeric antigen receptor chimeric antigen receptor T cells cost cytokine experience experimental study genetically modified cells humanized mouse improved leukemia/lymphoma mouse model neoplastic cell neuroinflammation neuropathology neurotoxicity novel prevent protein expression side effect tumor

项目摘要

ABSTRACT We wish to understand how immunotherapy-induced neurotoxicity occurs. Neurotoxicity is the most pernicious side effect of several immunotherapies for B-cell leukemias and lymphomas, including CAR T-cell therapy. In the latter approach, a sample of the patient’s own T-cells are removed, genetically engineered to recognize B- cell tumors, expanded to large numbers, and then reinfused into the patient. The genetically engineered tumor- recognition component is a chimeric antigen receptor (CAR). CARs reprogram T-cells to recognize and kill tumor cells, regardless of the T-cell’s innate specificity. CAR T-cells specific for the B-cell-associated antigen CD19 can induce durable complete remissions in patients with otherwise terminal B-cell malignancies. Like any therapy, though, it has side-effects. CD19-specific CAR T-cells frequently cause a spectrum of neurological adverse effects (NAE) ranging from disorientation to death. They cannot be prevented or treated adequately because their pathophysiology is poorly understood. To that end, we developed a novel, immune- competent humanized mouse model that replicates the anti-tumor efficacy and toxicities (including NAE) caused clinically by CD19-specific CAR T-cells. In our model, mouse B-cells express a human CD19 transgene (hCD19Tg). Transfer of mouse T-cells – called CART19 cells - that express a hCD19-specific CAR into hCD19Tg mice cause NAEs that are very similar to those experienced clinically. Because our findings mirror clinical reports, we suggest the causes of CART19-induced murine NAE will extrapolate to patients treated with CD19-specific CAR T-cells. Our central hypothesis is that blood brain barrier (BBB) disruption following CART19 infusion permits leukocytes, fluids, and systemic cytokines to enter the central nervous system (CNS). Here these systemic cytokines, and to a greater extent cytokines produced in the CNS by CART19 cells, activate resident microglial cells and extravasated myeloid cells. The differentiation of both into proinflammatory cells ultimately causes NAE. We propose two aims to test these hypotheses. The first aim will reveal what causes BBB dysfunction while the second aim will determine what drives NAE. We will learn how CART19 cells cross the BBB and if their persistent activation in the CNS contributes to or drives NAE. Using genetic, immunological, and pharmacological methods, we also will assess the contributions of resident and extravasated peripheral myeloid cells and specific cytokines to NAE. Finally, we will assess how NAE affects gene and protein expression by brain parenchymal cells using single cell approaches. Our proposed project will significantly impact two areas: 1) basic research in CNS pathobiology as it relates to NAE and 2) translational research as it relates to improving CD19-specific CAR T-cell therapy for human B-cell malignancies.

抽象的我们希望了解免疫治疗引起的神经毒性是最有害的。多种 B 细胞白血病和淋巴瘤免疫疗法（包括 CAR T 细胞疗法）的副作用。后一种方法是取出患者自身的 T 细胞样本，并进行基因改造以识别 B- 细胞肿瘤，扩大到大量，然后回输到患者体内。识别组件是嵌合抗原受体 (CAR)，它可对 T 细胞进行重新编程以识别并杀死细胞。 B 细胞相关抗原特异性的 CAR T 细胞 CD19 可以诱导患有其他晚期 B 细胞恶性肿瘤的患者持久完全缓解。然而，任何疗法都有副作用，CD19 特异性 CAR T 细胞经常会引起一系列副作用。神经不良反应（NAE），从迷失方向到死亡，这些都是无法预防或治疗的。因为我们对它们的病理生理学知之甚少，为此，我们开发了一种新型的免疫- 复制抗肿瘤功效和毒性（包括 NAE）的能力人源化小鼠模型临床上由 CD19 特异性 CAR T 细胞引起。在我们的模型中，小鼠 B 细胞表达人类 CD19。转基因 (hCD19Tg) 的小鼠 T 细胞（称为 CART19 细胞）的转移，表达 hCD19 特异性 CAR hCD19Tg 小鼠引起的 NAE 与临床经历的非常相似，因为我们的发现。镜像临床报告，我们建议将 CART19 诱导的小鼠 NAE 的原因外推至患者我们的中心假设是血脑屏障 (BBB) 破坏。 CART19输注后允许白细胞、液体和全身细胞因子进入中枢神经系统此处，这些系统性细胞因子，在更大程度上是由中枢神经系统产生的细胞因子。 CART19细胞，激活驻留的小胶质细胞和外渗的骨髓细胞，将两者分化为细胞。我们提出两个目标来检验这些假设。揭示导致 BBB 功能障碍的原因，而第二个目标将确定驱动 NAE 的原因。 CART19 细胞穿过 BBB，并且它们在 CNS 中的持续激活是否有助于或驱动 NAE。遗传、免疫学和药理学方法，我们还将评估居民和外渗的外周骨髓细胞和 NAE 的特异性细胞因子最后，我们将评估 NAE 如何影响。我们提出的项目通过脑实质细胞表达基因和蛋白质。将显着影响两个领域：1）与 NAE 相关的中枢神经系统病理学基础研究；2）与改善人类 B 细胞的 CD19 特异性 CAR T 细胞疗法相关的转化研究恶性肿瘤。