Immunoengineering Seminar Series

"Multi-niche Human Bone Marrow on-a-chip for Studying the Interactions of Adoptive Cell Therapies with Multiple Myeloma"

Delta Ghoshal
Graduate Student, Roy Lab
Georgia Institute of Technology
Biomedical Engineering

Multiple myeloma, a cancer of bone marrow-resident plasma cells, is the 2nd-most common hematological malignancy. However, despite the advent of immunotherapies like chimeric antigen receptor T (CAR-T) cells, which gained FDA approval in March 2021, relapse is nearly universally inevitable. The bone marrow (BM) microenvironment influences how MM cells survive, proliferate, and interact with stromal cells and how treatment resistance and relapses arise; yet it is unclear which BM niches (endosteal, central marrow, and perivascular) interact with MM and how various cells of the BM give rise to MM phenotypes and pathophysiology. Therefore, it is important to recapitulate each niche in any in vitro MM model. The overall hypothesis of the proposed work is that a 3D, multi-niche, microvascularized culture system will accurately model primary MM behavior and allow us to study MM interactions with stromal cells in the BM as well as model the responses to therapeutic cells. To that end, we have created a microphysiologic, microvascularized model of human MM to enable the introduction of various agents in order to study MM’s response to external stimuli. The overall objective is to investigate the heterogeneity within and among MM samples and create a physiologically relevant model of MM that accurately models the behavior of adoptively-transferred CAR-T cells. If successful, the proposed work could be used to study the role of the BM microenvironment in multiple myeloma survival and therapeutic evasion and may eventually be used to better-inform the rational design of next-generation MM therapeutics.

"Host Type-2 Immune Response to Xenogeneic Serum Proteins Impairs Biomaterial-Directed Mesenchymal Stem Cell Therapy"

Karen Martin
Graduate Student, García Lab
Georgia Institute of Technology

The transformative potential of cells as therapeutic agents is being realized in a wide range of applications, from regenerative medicine to cancer therapy to autoimmune disorders. The majority of these therapies require ex vivo expansion of the cellular product, often utilizing fetal bovine serum (FBS) in the culture media. While serum-free media formulations do exist for some cell types (e.g. human T cells and human mesenchymal stem cells), these are not readily available for many cell types, especially non-human cells. Many groups utilize mice (and murine cells) as model systems to test the efficacy of their cell product and to understand its mechanism of action. However, it is unclear what the impact of residual FBS is on cell therapy outcomes or how this might obscure the interpretation of immunological responses to these therapies. The overall aim of this project is to characterize the immune response to serum proteins and the impact this has on biomaterial-directed mesenchymal stem cell immunomodulation and bone repair. We show that hydrogels containing FBS induce a robust type-2 immune response upon injection in C57BL/6 mice characterized by increased infiltration of eosinophils, ILC2s, and CD4 T cells. Additionally, we demonstrate that this immune response is specific to xenogeneic serum proteins as murine serum injected in mice does not elicit this response. Finally, we show that serum proteins mask murine mesenchymal stem cell immunomodulatory properties and negatively impact their ability to promote bone repair.