Chemotherapeutics and CAR‐T Cell‐Based Immunotherapeutics Screening on a 3D Bioprinted Vascularized Breast Tumor Model

Abstract

Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically-relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic-flow based 3D bioprinted multi-scale vascularized breast tumor model, responding to chemo and immunotherapeutics is developed. Heterotypic tumors are precisely bioprinted at pre-defined distances from a perfused vasculature, exhibit tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of doxorubicin for 72 h portray a dose-dependent drug response behavior. More importantly, a cell based immune therapy approach is explored by perfusing HER2-targeting chimeric antigen receptor (CAR) modified CD8 + T cells for 24 or 72 h. Extensive CAR-T cell recruitment to the endothelium, substantial T cell activation and infiltration to the tumor site, resulted in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically-relevant tumor model for future translation of anti-cancer therapies to personalized medicine.

Nested biofabrication: Matryoshka-inspired Intra-embedded Bioprinting

“…Finally, into the model and close to the channel (200 to 400 µm), tumor spheroids (composed of MDA-MB-231 and ADSCs) were bioprinted using AAB ( Figures 6C-E, Supporting Movie 4 ). Based on a previous report [22] , we here used a mixture of the two cell types to form stable spheroids as MDA-MB-231 spheroids were structurally weak. Additionally, ADSCs are one of the major stromal cells in the breast cancer microenvironment that promote cancer progression [23] .…”

“…A custom-made AAB system was used to bioprint spheroids inside the hydrogels as reported before [33,34] and characterization of AAB was performed according to the literature [22,33] . To evaluate the bioprinting accuracy and precision of spheroids, first, a support bath was cast into a Petri dish and composite hydrogels (1% XaGMA/ 5% GelMA, 1.5% XaGMA/ 5% GelMA, and 2% XaGMA/ 5% GelMA) were bioprinted inside the support bath in a single layer.…”

Embedded Bioprinting of Breast Tumor Cells and Organoids Using Low‐Concentration Collagen‐Based Bioinks

“…[53,[82][83][84] For example, a bioprinted breast cancer and CAR T-cell model can be used for high-throughput evaluation of cell therapy response in the solid tumor. [85] One feature of the cancer-on-a-chip system is the perfusable vasculature, which can be potentially achieved by embedded printing. [58,86] We conducted a preliminary study by first printing the 15% Pluronic F127 as a sacrificial ink in the SF bath and then infusing the channel with a dye solution (Figure S12, Supporting Information).…”

3D bioprinting tumor models mimic the tumor microenvironment for drug screening

“…Meanwhile, 3D bioprinted in vitro tumor models can also be used for tumor immune-related drug screening, which to a certain extent makes up for the deficiency of human-derived xenograft animal tumor models for drug screening. Recently, Ibrahim T. Ozbolat's team 107 constructed a vascularized breast cancer model using 3D bioprinting. In this study, the authors used this breast cancer tumor model for screening chemotherapeutic agents and CAR-T cell-based immunotherapies, and this work is very interesting to lay the groundwork for translating anti-cancer therapies in the future.…”