Abstract 6771: Tumor-microenvironment-on-chip: an ex vivo drug screening platform enabling real-time observation of regional tumor responses during drug development and clinical treatments

Abstract

Abstract Background: Current tumor models face challenges in accurately replicating the intricate and dynamic conditions of the tumor microenvironment (TME), limiting predictions of drug efficacy in drug development and personalized treatment. Furthermore, the continuous and real-time observation of drug responses variations resulting from tumor heterogeneity poses challenges in existing models, including patient-derived organoids and animal models. To address these limitations, our study introduces a novel approach through a tumor-microenvironment-on-chip (TMoC) that combines 3D tissue cultivation and a circulation system, incorporating physiological gradients of oxygen and nutrients. Serving as a tool to faithfully replicate the intricate TME, TMoC facilitates highly accurate drug screening for enhanced therapeutic precision. Method: Based on organ-on-chip and microfluidic systems, our platform reconstructs the cellular heterogeneity of the TME using tumor tissue-dissociated cells in collagen I or Matrigel within a strip-shaped 3D cultivation space, enabling simple analysis of regional responses. A circulation system, powered by a peristaltic pump, aids medication and immune cell entry for combination immunotherapy assessment. Real-time apoptosis analysis via fluorescence microscopy and sample retrieval for in-depth analysis are enabled. In drug screening, TMoC results are compared with mouse model outcomes and medication records for various cancers and treatments. Result: TMoC reconstructed physiological-like gradients, including oxygen levels, and facilitated the infiltration of cytotoxic CD8+ T cells, providing a distinctive model for assessing the synergistic impact of immune checkpoint inhibitors and chemotherapy drugs. Additionally, tissues cultured in TMoC retained their original cellular composition. TMoC demonstrated efficacy in drug screening across various cancer models, including breast, pancreatic, and colorectal cancers. In clinical studies, tumor tissue-derived cells from patients were cultivated on the TMoC, and the treating results are subsequently compared with clinical outcomes. Whether in animal models or clinical cases, the drug screening outcomes of TMoC consistently aligned with in vivo drug responses. Conclusion: The TMoC offering a platform that modeling some complex characteristics of TME. With applications in drug screening and clinical studies, it shows promising correlations between TMoC and in vivo responses. Citation Format: Chiao-Min Lin, Hsaun-Yu Mu, Li-An Chu, Ya-Hui Lin, Ji Li, Chao-Yu Liu, Hsi-Chien Huang, Sheng-Liang Cheng, Tsung-Ying Lee, Hsin Mei Lee, Hsin-Min Chen, Yun-Jen Tsai, Tzu-Hung Hsiao, Kee-Ming Man, Yunching Chen, Jen-Huang Huang. Tumor-microenvironment-on-chip: an ex vivo drug screening platform enabling real-time observation of regional tumor responses during drug development and clinical treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6771.