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如何发生免疫疗法诱导的神经毒性。神经毒性是最有害的几种免疫疗法对B细胞白血病和淋巴瘤的副作用，包括CAR T细胞疗法。在后一种方法，除去了患者自己的T细胞的样本，通常设计为识别B- 细胞肿瘤，扩展到大量，然后重新融入患者。基因工程肿瘤 - 识别成分是嵌合抗原受体（CAR）。汽车重新编程T细胞以识别和杀死肿瘤细胞，无论T细胞的先天特异性如何。针对B细胞相关的抗原特异的汽车T细胞 CD19可以诱导其他终末B细胞恶性肿瘤患者的持久完全缓解。喜欢但是，任何疗法都具有副作用。 CD19特异性汽车T细胞经常引起频谱神经不良反应（NAE）从迷失方向到死亡。他们不能预防或治疗足够的是因为他们的病理生理学知之甚少。为此，我们开发了一种新颖的免疫力 - 复制抗肿瘤效率和毒性（包括NAE）的合理人性化小鼠模型（包括NAE）由CD19特异性汽车T细胞在临床上引起。在我们的模型中，鼠标B细胞表达人类CD19 转基因（HCD19TG）。表示HCD19特异性汽车的小鼠T细胞的转移（称为CART19细胞）进入HCD19TG小鼠，导致NAE与临床上经历的小鼠非常相似。因为我们的发现镜像临床报道，我们建议CART19诱导的鼠NAE的原因将推断为患者用CD19特异性汽车T细胞处理。我们的中心假设是血脑屏障（BBB）破坏 CART19输注允许白细胞，液体和全身细胞因子进入中枢神经系统（CNS）。在这里，这些系统性细胞因子以及在CNS中产生的细胞因子在更大程度上由 Cart19细胞，激活居民小胶质细胞并渗入髓样细胞。两者之间的分化促炎细胞最终导致NAE。我们提出了两个目的，以检验这些假设。第一个目标揭示导致BBB功能障碍的原因，而第二个目标将决定驱动NAE的原因。我们将学习如何 CART19细胞越过BBB，如果中枢神经系统中的持续激活有助于或驱动NAE。使用遗传，免疫学和药物方法，我们还将评估居民的贡献外周的髓样细胞和NAE的特异性细胞因子。最后，我们将评估NAE如何影响脑实质细胞的基因和蛋白质表达使用单细胞方法。我们提出的项目将显着影响两个领域：1）与NAE相关的CNS病理生物学基础研究和2）转化研究与改进人类B细胞的CD19特异性CAR T细胞疗法有关恶性肿瘤。