Abstract 6763: A human-relevant vascularized organ-on-a chip platform for anti-tumor drug efficacy and liver injury assessment

Abstract

Abstract Cancer global burden accounts for 19.3 million new cases and 10 million deaths in 2020. Despite advances on the understanding of disease progression and efforts to find successful therapeutic strategies, most drugs fail in clinical stages. Lack of models with clinical mimicry recapitulating the in vivo pathophysiology and the organ microenvironment where the tumor forms is a key driver reducing the success rate of anti-cancer drugs. Animal models remain the gold standard for preclinical research but fail to recapitulate the complex human tumor microenvironment, a critical component determining tumor development, progression, and response to treatments. Organ-on-a-chip models allow to control the environment and organization of cells in an in vivo-like arrangement by culturing multiple cell types to better replicate human conditions, and by implementing different biochemical and physical stimuli, such as fluid shear stress, chemical/nutrient gradients, and perfusion/flow to recapitulate the human vascular system physiology. We leverage our 3D bioprinting technologies to develop complex vascularized organ-on-a-chip models aimed to recapitulate the tumor and liver niche. Both organ-systems are interconnected by our h-VIOS™ platform, allowing dynamic perfusion for 21 days and enabling the simultaneous assessment of anti-tumor therapeutic efficacy and drug-induced liver injury. Our hydrogels feature a complex perfusable vasculature that interfaces with an interstitial chamber where tissues of interest are grown. The vasculature allows for continued and controlled delivery of nutrients, oxygen, and small molecule drugs. Dextran diffusion studies revealed diffusion coefficients ranging from 43.2 μm2/s (4kDa) to 8 μm2/s (70kDa). Vascular architectures are lined with endothelial cells forming a functional barrier expressing the junctional markers ZO-1 and PECAM-1. Moreover, we can modulate the permeability of our vasculature architecture, allowing the extravasation of immune and cancer cells. PBMC-derived T cells and Jurkat cells undergo transendothelial migration in response to a CXCL12 gradient, highlighting the applicability of our model for immunotherapeutic efficacy studies. The tumor interstitial chamber incorporates co-culture of cancer spheroids or tumoroids, fibroblasts, endothelial and immune cells. Colon carcinoma spheroids effectively integrate into the tumor niche with no growth arrest. The liver model consists of an interstitial chamber with a lobular microstructure supporting the monoculture of primary human hepatocytes, and sustaining their viability and function for 9 days as demonstrated by high albumin production, urea synthesis and CYP activity. Our organ-on-a-chip models are fully customizable and anticipated to contribute to advance personalized medicine and improve clinical translation rates. Citation Format: Juliana Navarro-Yepes, Queeny Dasgupta, Purboja Purkayastha, Kevin Janson, Cassio Mello, Ameya Narkar, Soon Seng Ng, Taci Pereira. A human-relevant vascularized organ-on-a chip platform for anti-tumor drug efficacy and liver injury assessment [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 6763.