3D Bioprinted perfusable and vascularized breast tumor model for dynamic screening of chemotherapeutics and CAR-T cells

Dey, M.; Kim, M. H.; Nagamine, M.; Dogan, M.; Kozhaya, L.; Unutmaz, D.; Ozbolat, I. T.

doi:10.1101/2022.03.15.484485

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bioRxiv · 10.1101/2022.03.15.484485

3D Bioprinted perfusable and vascularized breast tumor model for dynamic screening of chemotherapeutics and CAR-T cells

Dey, M.·Kim, M. H.·Nagamine, M.·Dogan, M.·Kozhaya, L.·Unutmaz, D.·Ozbolat, I. T.

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Abstract

Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically-relevant in vitro testing platforms limit the rapid and early screening of anti-cancer agents. A major barrier in this endeavor, is the complex interplay between the tumor microenvironment and host immune response and lack of predictive biomarkers for clinical benefit. To tackle this challenge, we have developed a dynamic-flow based three-dimensionally (3D) bioprinted vascularized breast tumor model, responding to chemo and immunotherapeutic treatments. Heterotypic tumor spheroids, comprising metastatic breast cancer cells (MDA-MB-231), human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs), precisely bioprinted at pre-defined distances from a perfused vasculature, exhibited tumor angiogenesis and cancer invasion. Proximally bioprinted tumors ([~]100 m) exhibited enhanced capillary sprouting, anastomosis to perfused vasculature and increased cancer cell migration as compared to distally bioprinted spheroids ([~]500 m). Proximally bioprinted tumors treated with varying dosages of doxorubicin for 72 h enabled functional analysis of drug response, wherein, tumors portrayed a dose-dependent drug response behavior with [~]70% decrease in tumor volume for 1 M dose. Additionally, a cell based immune therapy approach was explored by perfusing HER2-targeting chimeric antigen receptor (CAR) modified CD8+ T cells for 24 or 72 h through the central vasculature. Extensive CAR-T cell recruitment to the endothelium and substantial T cell activation and infiltration in the tumor site, resulted in [~]70% reduction in tumor growth for high CAR treatment densities, after 72 h of treatment. The presented 3D model paves the way for a robust, precisely fabricated and physiologically-relevant 3D tumor microenvironment platform for future translation of anti-cancer therapies to personalized medicine for cancer patients. One Sentence SummaryA physiologically-relevant 3D bioprinted perfusable vascularized tumor model capable of dynamic screening of chemo and immunotherapeutics.

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Dey, M., Kim, M. H., Nagamine, M., Dogan, M., Kozhaya, L., Unutmaz, D., Ozbolat, I. T.. 2022-03-18. 3D Bioprinted perfusable and vascularized breast tumor model for dynamic screening of chemotherapeutics and CAR-T cells. https://doi.org/10.1101/2022.03.15.484485

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