Abstract 5481: A 3D bioprinted vascularized human tumor-on-a-Chip model for simultaneous evaluation of immunotherapeutic efficacy and safety

Abstract Immuno-oncology has revolutionized cancer treatment by harnessing the immune system to target tumors. However, developing effective therapies is challenging due to the complexity of the tumor microenvironment (TME), which influences therapy response, and toxicity risks like vascular injury and off-tumor effects. Traditional preclinical models fail to replicate human-specific immune responses and TME complexities, such as immune cell trafficking and tumor immune evasion. Additionally, current safety assessments for immunotherapies are inadequate in predicting systemic risks. These limitations highlight the need for more accurate, human-relevant tumor models. To address these challenges, we developed a 3D vascularized tumor-on-a-chip platform that incorporates key TME features for enhanced clinical relevance. Using 3D bioprinting, we integrated vascular structures with our human vascularized integrated organ system (h-VIOS™), enabling dynamic perfusion and simulating immune cell flow. The vasculature, endothelialized with primary human endothelial cells, forms a functional barrier expressing junctional markers and adhesion molecules, supporting immune cell interactions during T cell trafficking and tumor infiltration, while facilitating immunotherapy safety evaluation. Our model also integrates patient-derived tumor organoids that replicate key tumor characteristics, including heterogeneity and genetic diversity, and simulates TME interactions through co-culture with endothelial and immune cells. In a colorectal cancer model, we demonstrated chemokine-driven T cell infiltration from the endothelialized vasculature into the tumor, confirmed by confocal imaging and flow cytometry. We also modeled T cell responses to immune checkpoint inhibition with pembrolizumab, showing increased tumor killing, evidenced by elevated markers such as IFN-γ, Granzyme B, and cleaved-caspase 3. These results validate anti-PD-1 therapy in our model, highlighting its ability to capture T cell reactivation and tumor killing. In a TROP-2-expressing lung cancer model, we recapitulated the efficacy of the TROP-2 antibody-drug conjugate Sacituzumab govitecan, shown by increased cleaved-caspase 3 and reduced tumoroid viability. We also observed drug-induced vascular injury (DIVI) and off-tumor toxicity, evidenced by upregulation of inflammatory markers (ICAM-1, PECAM, P-selectin, IL-6, TNF-α) in endothelial cells. In conclusion, our 3D vascularized tumor-on-a-chip model outperforms traditional models by accurately replicating the TME and enabling the simultaneous assessment of drug-induced toxicities. This customizable platform facilitates mechanism-of-action studies and holds significant potential for personalized medicine, offering a powerful tool for advancing immuno-oncology research and improving therapeutic outcomes. Citation Format: Juliana Navarro-Yepes, Queeny Dasgupta, Purboja Purkayastha, Clara Erice, Carly Truong, Kim Phan, YongDuk Han, Michael Doerfert, Cassio Mello, Kevin Janson, Alma Antonio, Tracy Lin, Ameya Narkar, Sammy Datwani, SoonSeng Ng, Taci Pereira. A 3D bioprinted vascularized human tumor-on-a-Chip model for simultaneous evaluation of immunotherapeutic efficacy and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5481.