A preclinical organotypic model for evaluating immunotherapy-related toxicities

Immunotherapy has revolutionized cancer treatment by enhancing the immune system's ability to target malignant cells. Despite its success, significant challenges remain, particularly treatment-induced toxicities such as "on-target, off-tumor" (OTOT) effects and immune-related adverse events (irAEs). CAR-T cells, bispecific T-cell engagers (BiTEs), and monoclonal antibodies can target antigens shared by both tumors and normal tissues, leading to severe organ-specific toxicities. Similarly, immune checkpoint inhibitors (ICIs) disrupt immune self-tolerance, causing autoimmune-like complications in various organs. Current preclinical models fail to fully predict these toxicities due to their limited ability to replicate human immune-tissue interactions. To address this, we developed an ex vivo human tissue slice model that preserves native immune microenvironments and enables the study of T-cell-mediated toxicity. Using a superantigen to induce broad T-cell activation, our model assesses immunotherapy-induced cytotoxicity through cytokine secretion assays and apoptosis detection (cleaved caspase-3). This approach provides a powerful tool for predicting immunotherapy-induced toxicities and optimizing treatment strategies.