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

• 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
• 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

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.

项目摘要 遗传工程化以表达CD 19特异性嵌合抗原受体（汽车）的T细胞的连续转移 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CD 19 CAR-T细胞以来， 该领域已经呈指数增长，范围从黑色素瘤和实体瘤的治疗， 移植耐受治疗自身免疫性疾病。尽管取得了这些成功， 由于过度的免疫反应而具有严重的毒性。细胞因子释放综合征（CRS），表现为 如血清细胞因子过度产生、发热、低血压和多器官功能障碍/衰竭，是 严重副作用，如果不进行适当的临床干预，可能会对患者造成永久性损害。 虽然已经开发了临床方案来减轻临床中CRS的病理生理学，但潜在的 导致细胞因子过度分泌的机制仍不完全清楚。的一个主要 障碍是缺乏可以完全概括CAR-T细胞介导的免疫反应的临床前模型。 交互. 造血人源化（hu）小鼠模型是一个强大的平台， 研究和临床CRS，并已在开发新的疗法，以减轻CRS- 药物毒性然而，在这些小鼠中重建复杂的人类免疫系统是具有挑战性的， 它们没有人类胸腺，胸腺是负责产生和选择T细胞的主要淋巴器官。 细胞虽然内源性小鼠胸腺可以为人类T细胞发育提供有限的支持， 在小鼠胸腺中产生的人T细胞不能适当地与其他人免疫细胞接合以调节 有效的免疫反应。我们最近开发了一种组织工程方法， 诱导性多能干细胞（iPSC）的胸腺。iPSC衍生的人胸腺可以支持从头 在hu小鼠中产生可介导细胞和体液免疫的功能性人T细胞区室 免疫反应。基于这些发现，我们假设移植iPSC-胸腺的hu小鼠可以 概述了CAR-T下人类免疫系统与癌细胞之间的复杂相互作用 治疗，并作为一个强大的模型，研究CRS的病理生理学的新疗法的发现。 在这个探索性项目中，我们将建立和表征CD 19 CAR-T/B淋巴母细胞癌， 用iPSC-胸腺移植的hu小鼠建立模型以概括CRS及其相关毒性。如果成功， 该项目将在免疫治疗领域产生广泛影响。