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

Area of Science:

• Immunology
• Stem Cell Biology
• Toxicology

Background:

• T cell therapies show promise but face challenges balancing efficacy with safety, as T cell-mediated toxicities can occur.
• Current preclinical pipelines have limited options for in vitro screening against vital organs or specialized cell subsets to assess T cell toxicity.
• Stringent selection of tumor-specific targets and T cells is crucial for mitigating adverse events.

Purpose of the Study:

• To establish and validate human induced pluripotent stem cell (hiPSC)-derived preclinical models for thorough investigation of tumor-specific T cell toxicity.
• To assess the toxicity risks associated with CD8+ T cells targeting PRAME, HA-1H, CD20, or WT1 using these novel models.
• To evaluate the correlation between target gene expression and observed on-target toxicity.

Main Methods:

• Development of hiPSC-derived preclinical models including cardiomyocytes, epicardial cells, and kidney organoids.
• Co-culture of these hiPSC-derived models with CD8+ T cells specific for tumor antigens (PRAME, HA-1H, CD20, WT1).
• Assessment of T cell reactivity using multiple measures, including cytokine levels and phenotypic analysis, alongside target cell viability.

Main Results:

• WT1-specific T cells demonstrated on-target toxicity in hiPSC-derived models, directly correlating with WT1 gene expression.
• Multiple measures of T cell reactivity confirmed toxicity at both the T cell and hiPSC-derived target cell levels.
• Phenotypic analysis revealed interactions and crosstalk between infiltrating T cells and kidney organoids, providing deeper insights into toxicity mechanisms.

Conclusions:

• hiPSC-derived organoid models are beneficial for determining the toxicity risks of tumor-specific T cells in a preclinical setting.
• These models offer a more comprehensive evaluation of T cell toxicity compared to traditional methods.
• The study highlights the added value of employing diverse measures of T cell reactivity beyond standard cytokine analysis for robust safety assessments.