Dinh-Le Thuvan, Escobar John, Poisson Louis, Adkins Karissa, Jornet Culubret Maria, Scheller Lukas, van den Brulle Jan, Hudecek Michael, Drake Iii Donald R, Alb Miriam, Luna Ernesto
Sanofi, Global Human Immunology, Orlando, FL, USA.
Sanofi, Pre-Clinical Safety, Cambridge, MA, USA.
J Immunotoxicol. 2024 Oct;21(sup1):S29-S37. doi: 10.1080/1547691X.2024.2378729. Epub 2024 Dec 10.
CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells have shown success in clinical studies, with several CD19 CAR-T cell products now having been approved for market use. However, this cell therapy can be associated with side effects such as cytokine release syndrome (CRS). Therefore, pre-clinical test systems are highly desired to permit the evaluation of these unwanted effects before clinical trials begin. In this study, we evaluated cytokine secretion and cell phenotype changes induced by human CD4 and CD8 CD19-targeted CAR-T cells in the cytokine release assay (CRA) module of a pre-clinical human 3D co-culture platform. The CRA data showed that CD19-targeted CAR-T cells induced a diverse and concentration-dependent cytokine response led by a T1-profile (IFNγ, IL-2) and pro-inflammatory cytokines (IL-6, TNFα, MCP-1, IL-8, MIP-1b). It was also shown that different cellular components in this 3D co-culture system contributed to the CAR-T cell cytokine response. In particular, whole blood-derived cell populations were necessary to drive the production of T cell cytokines, and endothelial cells were required to generate pro-inflammatory cytokines. CD19-targeted CAR-T cells also triggered cell phenotype changes, including the activation of whole blood-derived CD4 and CD8 T-cells and activation/maturation of antigen-presenting cells, during treatment of the CRA platform. Additionally, the observation of a CD19-targeted CAR-T cell concentration-dependent reduction in the B-cell compartment in this study is aligned with the expected pharmacology and clinical profile of this compound. Overall, this dataset shows the utility of an CRA model as a pre-clinical platform for evaluating cytokine release potential and analysis of mechanisms of action of CD19-targeted CAR-T cells.
靶向CD19的嵌合抗原受体修饰T（CAR-T）细胞在临床研究中已取得成功，目前已有数种CD19 CAR-T细胞产品获批上市。然而，这种细胞疗法可能会伴有诸如细胞因子释放综合征（CRS）等副作用。因此，在临床试验开始前，非常需要临床前测试系统来评估这些不良影响。在本研究中，我们在临床前人类3D共培养平台的细胞因子释放试验（CRA）模块中，评估了靶向人类CD4和CD8 CD19的CAR-T细胞诱导的细胞因子分泌和细胞表型变化。CRA数据表明，靶向CD19的CAR-T细胞诱导了以T1型谱（IFNγ、IL-2）和促炎细胞因子（IL-6、TNFα、MCP-1、IL-8、MIP-1b）为主导的多样且浓度依赖性的细胞因子反应。还表明，该3D共培养系统中的不同细胞成分对CAR-T细胞的细胞因子反应有贡献。特别是，全血来源的细胞群体是驱动T细胞细胞因子产生所必需的，而内皮细胞是产生促炎细胞因子所必需的。在CRA平台处理过程中，靶向CD19的CAR-T细胞还引发了细胞表型变化，包括全血来源的CD4和CD8 T细胞的激活以及抗原呈递细胞的激活/成熟。此外，本研究中观察到靶向CD19的CAR-T细胞在B细胞区室中呈浓度依赖性减少，这与该化合物预期的药理学和临床特征相符。总体而言，该数据集显示了CRA模型作为评估靶向CD19的CAR-T细胞细胞因子释放潜力和作用机制分析的临床前平台的实用性。
