Human iPSC-derived preclinical models to identify toxicity of tumor-specific T cells with clinical potential

• Published in: Molecular therapy. Methods & clinical development 2023-03, Vol.28, p.249-261
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: adoptive T cell therapy; human iPSCs; Original; preclinical screening; TCR gene transfer; toxicity
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2023.01.005

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. In vitro 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. [Display omitted] Preclinical pipelines of T cell based therapies lack toxicity screening options against vital organs or specialized cell subsets. This work demonstrates the benefit of human induced pluripotent stem cell (hiPSC)-derived heart cell subsets and kidney organoids in determining toxicity risks for preclinical evaluation of tumor-specific T cells.