T Cell Engineering Laboratory, Mayo Clinic, Rochester; Division of Hematology, Mayo Clinic, Rochester; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester; Department of Molecular Medicine, Mayo Clinic, Rochester; Regenerative Sciences PhD Program, Mayo Clinic, Rochester.
T Cell Engineering Laboratory, Mayo Clinic, Rochester; Division of Hematology, Mayo Clinic, Rochester.
J Vis Exp. 2023 Feb 10(192). doi: 10.3791/64535.
Chimeric antigen receptor T (CART) cell therapy has emerged as a powerful tool for the treatment of multiple types of CD19 malignancies, which has led to the recent FDA approval of several CD19-targeted CART (CART19) cell therapies. However, CART cell therapy is associated with a unique set of toxicities that carry their own morbidity and mortality. This includes cytokine release syndrome (CRS) and neuroinflammation (NI). The use of preclinical mouse models has been crucial in the research and development of CART technology for assessing both CART efficacy and CART toxicity. The available preclinical models to test this adoptive cellular immunotherapy include syngeneic, xenograft, transgenic, and humanized mouse models. There is no single model that seamlessly mirrors the human immune system, and each model has strengths and weaknesses. This methods paper aims to describe a patient-derived xenograft model using leukemic blasts from patients with acute lymphoblastic leukemia as a strategy to assess CART19-associated toxicities, CRS, and NI. This model has been shown to recapitulate CART19-associated toxicities as well as therapeutic efficacy as seen in the clinic.
嵌合抗原受体 T (CART) 细胞疗法已成为治疗多种 CD19 恶性肿瘤的有力工具，这导致了最近 FDA 批准了几种针对 CD19 的 CART（CART19）细胞疗法。然而，CART 细胞疗法与一组独特的毒性相关，这些毒性具有自身的发病率和死亡率。这包括细胞因子释放综合征 (CRS) 和神经炎症 (NI)。临床前小鼠模型的使用对于评估 CART 技术的疗效和 CART 毒性的研究和开发至关重要。可用于测试这种过继细胞免疫疗法的现有临床前模型包括同基因、异种移植、转基因和人源化小鼠模型。没有一个单一的模型能够完美地模拟人类免疫系统，每个模型都有其优点和缺点。本方法论文旨在描述一种使用急性淋巴细胞白血病患者的白血病细胞作为策略来评估 CART19 相关毒性、CRS 和 NI 的患者衍生异种移植模型。该模型已被证明可重现 CART19 相关毒性以及临床所见的治疗效果。
