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

Madhuri Dey; Myoung Hwan Kim; Mikail Dogan; Momoka Nagamine; Lina Kozhaya; Nazmiye Celik; Derya Unutmaz; Ibrahim T Ozbolat

doi:10.1002/adfm.202203966

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

Adv Funct Mater. 2022 Dec 22;32(52):2203966. doi: 10.1002/adfm.202203966. Epub 2022 Oct 3.

Authors

Madhuri Dey¹, Myoung Hwan Kim², Mikail Dogan³, Momoka Nagamine¹, Lina Kozhaya³, Nazmiye Celik⁴, Derya Unutmaz⁵, Ibrahim T Ozbolat⁶

Affiliations

¹ Department of Chemistry, Penn State University, University Park, PA 16802, USA; The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA.
² The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Biomedical Engineering Department, Penn State University, University Park, PA 16802, USA.
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
⁴ The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, USA.
⁵ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; University of Connecticut Health Center, Farmington, CT 06032, USA.
⁶ The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Biomedical Engineering Department, Penn State University, University Park, PA 16802, USA; Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, USA; Materials Research Institute, Penn State University, University Park, PA 16802, USA; Cancer Institute, Penn State University, Hershey, PA 17033, USA; Neurosurgery Department, Penn State University, Hershey, PA 17033, USA; Department of Medical Oncology, Cukurova University, Adana 01330, Turkey.

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.

Keywords: CAR-T immunotherapy; bioprinting; cancer; tumor models.

Abstract

Grants and funding