Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma

Delta Ghoshal¹, Ingrid Petersen¹, Rachel Ringquist², Liana Kramer¹, Eshant Bhatia³, Thomas Hu⁴, Ariane Richard⁵, Reda Park⁵, Jenna Corbin⁵, Savi Agarwal¹, Abel Thomas⁶, Sebastian Ramirez⁵, Jacob Tharayil⁵, Emma Downey⁵, Frank Ketchum⁷, Abigail Ochal⁵, Neha Sonthi⁸, Sagar Lonial⁹, James N Kochenderfer¹⁰, Reginald Tran¹¹, Mandy Zhu⁵, Wilbur A Lam¹¹, Ahmet F Coskun¹, Krishnendu Roy¹²

Affiliations

¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
² The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
³ The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; The George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁴ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁵ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
⁶ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; Department of Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁷ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA.
⁸ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁹ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
¹⁰ Surgery Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
¹¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA.
¹² School of Engineering, Vanderbilt University, Nashville, TN, 37235, USA. Electronic address: krish.roy@vanderbilt.edu.

PMID: 39709851
DOI: 10.1016/j.biomaterials.2024.123016

Free article

Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma

Delta Ghoshal et al. Biomaterials. 2025 May.

Free article

. 2025 May:316:123016.

doi: 10.1016/j.biomaterials.2024.123016. Epub 2024 Dec 15.

Authors

Affiliations

¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
² The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
³ The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; The George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁴ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁵ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
⁶ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; Department of Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁷ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA.
⁸ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁹ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
¹⁰ Surgery Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
¹¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA.
¹² School of Engineering, Vanderbilt University, Nashville, TN, 37235, USA. Electronic address: krish.roy@vanderbilt.edu.

PMID: 39709851
DOI: 10.1016/j.biomaterials.2024.123016

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.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James N. Kochenderfer reports a relationship with Kite Pharma Inc that includes: funding grants. James N. Kochenderfer reports a relationship with Bristol Myers Squibb Co that includes: funding grants. James N. Kochenderfer reports a relationship with Kyverna Therapeutics that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Update of

Multi-Niche Human Bone Marrow On-A-Chip for Studying the Interactions of Adoptive CAR-T Cell Therapies with Multiple Myeloma.
Ghoshal D, Petersen I, Ringquist R, Kramer L, Bhatia E, Hu T, Richard A, Park R, Corbin J, Agarwal S, Thomas A, Ramirez S, Tharayil J, Downey E, Ketchum F, Ochal A, Sonthi N, Lonial S, Kochenderfer JN, Tran R, Zhu M, Lam WA, Coskun AF, Roy K. Ghoshal D, et al. bioRxiv [Preprint]. 2024 Apr 12:2024.04.08.588601. doi: 10.1101/2024.04.08.588601. bioRxiv. 2024. Update in: Biomaterials. 2025 May;316:123016. doi: 10.1016/j.biomaterials.2024.123016. PMID: 38644993 Free PMC article. Updated. Preprint.

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Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma

Affiliations

Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

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Medical