Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma
Delta Ghoshal, Ingrid Petersen, Rachel Ringquist, Liana Kramer, Eshant Bhatia, Thomas Hu, Ariane Richard, Reda Park, Jenna Corbin, Savi Agarwal, Abel Thomas, Sebastián Ramírez, Jacob Tharayil, Emma Downey, Frank Ketchum, Abigail Ochal, Neha Sonthi, Sagar Lonial, James N. Kochenderfer, Reginald Tran, Mandy Zhu, Wilbur A. Lam, Ahmet F. Coskun, Krishnendu Roy
Abstract
Multiple myeloma (MM), a cancer of bone marrow plasma cells, is the second-most common hematological malignancy. However, despite immunotherapies like chimeric antigen receptor (CAR)-T cells, relapse is nearly universal. The bone marrow (BM) microenvironment influences how MM cells survive, proliferate, and resist treatment. Yet, it is unclear which BM niches give rise to MM pathophysiology. Here, we present a 3D microvascularized culture system, which models the endosteal and perivascular bone marrow niches, allowing us to study MM-stroma interactions in the BM niche and model responses to therapeutic CAR-T cells. We demonstrated the prolonged survival of cell line-based and patient-derived multiple myeloma cells within our in vitro system and successfully perfused in donor-matched CAR-T cells. We then measured T cell survival, differentiation, and cytotoxicity against MM cells using a variety of analysis techniques. Our MM-on-a-chip system could elucidate the role of the BM microenvironment in MM survival and therapeutic evasion and inform the rational design of next-generation therapeutics.