van Amerongen Rosa A, Morton Laura T, Chaudhari Umesh G, Remst Dennis F G, Hagedoorn Renate S, van den Berg Cathelijne W, Freund Christian, Falkenburg J H Frederik, Heemskerk Mirjam H M
Department of Hematology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
LUMC hiPSC Hotel, Department of Anatomy and Embryology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
Mol Ther Methods Clin Dev. 2023 Jan 20;28:249-261. doi: 10.1016/j.omtm.2023.01.005. eCollection 2023 Mar 9.
The balance between safety and efficacy of T cell therapies remains challenging and T cell mediated toxicities have occurred. The stringent selection of tumor-specific targets and careful selection of tumor-specific T cells using T cell toxicity screenings are essential. screening options against vital organs or specialized cell subsets would be preferably included in preclinical pipelines, but options remain limited. Here, we set up preclinical models with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, epicardial cells, and kidney organoids to investigate toxicity risks of tumor-specific T cells more thoroughly. CD8+T cells reactive against PRAME, HA-1H, CD20, or WT1, currently used or planned to be used in phase I/II clinical studies, were included. Using these hiPSC-derived preclinical models, we demonstrated that WT1-specific T cells caused on-target toxicity that correlated with target gene expression. Multiple measures of T cell reactivity demonstrated this toxicity on the level of T cells and hiPSC-derived target cells. In addition, phenotypic analysis illustrated interaction and crosstalk between infiltrated T cells and kidney organoids. In summary, we demonstrated the benefit of hiPSC-derived models in determining toxicity risks of tumor-specific T cells. Furthermore, our data emphasizes the additional value of other measures of T cell reactivity on top of the commonly used cytokine levels.
T细胞疗法在安全性和有效性之间的平衡仍然具有挑战性，并且已经出现了T细胞介导的毒性反应。严格筛选肿瘤特异性靶点，并通过T细胞毒性筛查仔细挑选肿瘤特异性T细胞至关重要。针对重要器官或特定细胞亚群的筛查方法最好纳入临床前研究流程，但目前可用的方法仍然有限。在此，我们建立了包含人诱导多能干细胞（hiPSC）衍生的心肌细胞、心外膜细胞和肾类器官的临床前模型，以更全面地研究肿瘤特异性T细胞的毒性风险。其中纳入了对PRAME、HA-1H、CD20或WT1有反应的CD8+T细胞，这些细胞目前已在I/II期临床研究中使用或计划使用。利用这些hiPSC衍生的临床前模型，我们证明WT1特异性T细胞会导致与靶基因表达相关的靶向毒性。多种T细胞反应性检测方法在T细胞和hiPSC衍生的靶细胞水平上证实了这种毒性。此外，表型分析显示了浸润T细胞与肾类器官之间的相互作用和串扰。总之，我们证明了hiPSC衍生模型在确定肿瘤特异性T细胞毒性风险方面的益处。此外，我们的数据强调了除常用的细胞因子水平外，其他T细胞反应性检测方法的附加价值。
