Novel hematopoietic humanized mouse model to study CAR-T therapy-associated cytokine release syndrome

研究CAR-T疗法相关细胞因子释放综合征的新型造血人源化小鼠模型

基本信息

批准号：
10648862
负责人：
YONG FAN
金额：
$ 24.96万
依托单位：
ALLEGHENY-SINGER RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648862
关键词：
Adrenal Cortex Hormones Allogenic Animal Model Autoimmune Diseases Autologous B lymphoid malignancy B-Cell Leukemia B-Lymphocytes Blocking Antibodies Blood Cells Body Temperature Body Weight CD19 gene CD28 gene CD3 Antigens Cancer Model Cell Compartmentation Cells Clinic Clinical Clinical Protocols Complex Development Disease Engraftment Ethics Failure Fever Functional disorder Generations Growth Harvest Hematopoietic Hematopoietic stem cells Histopathology Human Hypotension IL1R1 gene Immune Immune response Immune system Immunodeficient Mouse Immunoglobulin Class Switching Immunotherapeutic agent Immunotherapy Incubated Inflammatory Inflammatory Response Interleukin-1 Interleukin-6 Intervention Left Life Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator Methods Modeling Molecular Monitor Monoclonal Antibodies Muromonab-CD3 Mus Organ Organoids Outcome Pathway interactions Patients Physiology Pre-Clinical Model Precursor B-Lymphoblast Production Proteome Proteomics Refractory Relapse Research Role Serum Solid Neoplasm Source Splenocyte Stimulus T cell therapy T-Cell Development T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Thymus Gland Tissue Engineering Tissues Toxic effect Transplantation Transplantation Tolerance Treatment-related toxicity Tumor Antigens Tumor Burden United States Food and Drug Administration Work anakinra antagonist anti-tumor immune response antitumor effect cancer cell cancer therapy cell mediated immune response cell type chimeric antigen receptor chimeric antigen receptor T cells cohort cytokine cytokine release syndrome drug discovery genetically modified cells human fetal thymus humanized mouse induced pluripotent stem cell melanoma monocyte mouse model multiplex assay neurotoxicity novel novel therapeutics particle preclinical study prevent primary lymphoid organ reconstitution side effect single-cell RNA sequencing success tocilizumab transcriptome tumor

项目摘要

Project Summary Adoptive transfer of T cells genetically engineered to express CD19-specific chimeric antigen receptors (CARs) have achieved tremendous clinical success in treating patients with refractory and relapsed B-cell leukemia. Since the approval of CD19 CAR-T cells in 2017 by the US Food and Drug Administration (FDA), research in the field has grown exponentially, ranging from therapies for melanoma and solid tumors, induction of transplantation tolerance to treatment of autoimmune diseases. Despite these successes, the treatment also has severe toxicities due to the excessive immune responses. Cytokine release syndrome (CRS), manifesting as serum cytokine over-production, fever, hypotension, and multiple organ dysfunction/failure, is one of the major side effects that can cause permanent damage to patients if left without proper clinical intervention. While clinical protocols have been developed to mitigate the pathophysiology of CRS in clinic, the underlying mechanisms responsible for the excessive cytokine secretion remains not fully understood. One of the major hurdles is the lack of preclinical models that can fully recapitulate the CAR-T cell-mediated immune interactions. Hematopoietic humanized (hu) mouse models are a powerful platform to bridge the gap between preclinical studies and clinical CRS, and have been instrumental in developing novel therapies to mitigate CRS- medicated toxicities. However, recreating the complex human immune system in these mice is challenging, as they don’t have a human thymus, the primary lymphoid organ responsible for the generation and selection of T cells. Although the endogenous mouse thymus can provide limited support for human T cell development, human T cells generated in mouse thymus cannot properly engage with other human immune cells to regulate effective immune responses. We have recently developed a tissue-engineering method to generate human thymus from inducible pluripotent stem cells (iPSCs). iPSC-derived human thymus can support the de novo generation of a functional human T cell compartment in hu mice that can mediate both cellular and humoral immune responses. Based on these findings, we hypothesize that hu mice engrafted with iPSC-thymus can recapitulate the complex interactions between the human immune system and cancer cells under CAR-T therapy, and serve as a powerful model to study CRS pathophysiologies for the discovery of novel therapies. In this exploratory project, we are going to establish and characterize a CD19 CAR-T/B-lymphoblastic cancer model with the iPSC-thymus engrafted hu mice to recapitulate CRS and its associated toxicities. If successful, the project will have broad impacts in the field of immunotherapy.

项目概要经过基因工程改造的 T 细胞过继转移，表达 CD19 特异性嵌合抗原受体 (CAR) 在治疗难治性和复发性 B 细胞白血病患者方面取得了巨大的临床成功。自2017年美国食品药品监督管理局（FDA）批准CD19 CAR-T细胞以来，该领域呈指数级增长，涵盖黑色素瘤和实体瘤的治疗、诱导移植对自身免疫性疾病治疗的耐受性尽管取得了这些成功，但该治疗还不够。由于过度的细胞因子释放（CRS）而表现出严重的毒性。血清细胞因子过度产生、发烧、低血压和多器官功能障碍/衰竭是其中之一如果没有适当的临床干预，可能会对患者造成永久性损害的主要副作用。虽然已经制定了临床方案来减轻临床中 CRS 的病理生理学，但潜在的造成细胞因子过度分泌的主要机制之一仍不完全清楚。障碍是缺乏能够完全重现 CAR-T 细胞介导的免疫的临床前模型互动。造血人源化 (hu) 小鼠模型是一个强大的平台，可弥合临床前模型与模型之间的差距。研究和临床 CRS，并在开发减轻 CRS 的新疗法方面发挥了重要作用然而，在这些小鼠中重建复杂的人类免疫系统具有挑战性，因为它们没有人类胸腺，而人类胸腺是负责 T 细胞生成和选择的主要淋巴器官尽管内源性小鼠胸腺可以为人类 T 细胞发育提供有限的支持，小鼠胸腺中产生的人类 T 细胞不能正确地与其他人类免疫细胞结合来调节我们最近开发了一种组织工程方法来产生人类免疫反应。来自诱导性多能干细胞 (iPSC) 的胸腺可以支持从头开始。在 hu 小鼠中产生功能性人类 T 细胞区室，可介导细胞和体液基于这些发现，我们发现移植了 iPSC-胸腺的 hu 小鼠可以产生免疫反应。概括 CAR-T 下人体免疫系统与癌细胞之间复杂的相互作用疗法，并作为研究 CRS 病理生理学以发现新疗法的强大模型。在这个探索性项目中，我们将建立并表征 CD19 CAR-T/B 淋巴母细胞癌如果成功的话，用 iPSC 胸腺移植的 hu 小鼠模型来重现 CRS 及其相关毒性。该项目将在免疫治疗领域产生广泛影响。