Modeling immunotherapies in live 3D human cancer tissue bioreactors and implications for functional precision medicine

Abstract

Despite the clinical success of cancer immunotherapies in advanced malignancies, patient response remains highly variable, necessitating better predictive platforms to optimize outcomes, mitigate adverse events, and reduce healthcare costs. Addressing the limitations of traditional models that fail to replicate the complex human tumor microenvironment (TME), this study introduces an innovative ex vivo 3D human tissue culture model utilizing optimized perfusion bioreactors to preserve native immune-tumor interactions. Serving as a robust functional precision medicine platform, fresh, intact human lymph node (LN) tissues were cultured for three days to evaluate individual therapeutic responses to novel CAR T-cell therapies and pembrolizumab via flow cytometry, histology, and multiplexed fluorescence microscopy. The bioreactor system demonstrated superior tissue viability compared to static plate cultures, revealing that novel CAR T cells with enhanced PI3K signaling achieved deeper tissue infiltration than conventional variants. Furthermore, pembrolizumab significantly reduced lymphoma and melanoma cell viability while leaving benign LN architectures unaffected, validating the platform's capacity for rapid, patient-specific drug sensitivity testing. Ultimately, this short-term culture system bridges the gap between laboratory evaluation and clinical decision-making, offering a powerful tool to advance functional precision medicine, decode immunotherapy mechanisms, and personalize cancer care.