Research Focus: Microfluidic Tumor Models for Adoptive Cell Therapy Testing.

Multiple myeloma is the 2nd-most common hematological malignancy, affecting plasma cells in the bone marrow (BM). A functional model of human MM would allow for detailed studies on its pathological effects in a
small-scale, tunable culture system. Limitations of animal models, especially with regards to precisely-controlled manipulations and dynamic evaluation inside the marrow, have limited our ability to come to a consensus regarding the roles and character of the niche environments, their crosstalk, specific cell types, and signaling pathways. Understanding the pathophysiology of MM in a physiologically-relevant human model that utilizes primary patient samples to ensure diversity within the BM microenvironment could could also potentially lead to a better understanding of chimeric antigen receptor (CAR)-T cell toxicity, especially how stromal and immune cells in the MM microenvironment interact with and respond to the infused CAR-T cell. This could aid us in enhancing CAR-T cell migration into the MM niche, increase memory T cell development and proliferation, and enhance response- durability through increased persistence and decreased T cell attrition.

Our human bone marrow on-a-chip (hBM-chip) and subsequent human multiple myeloma on-a-chip (hMM-chip) are compatible with laboratory- and industry-standard equipment and techniques. To further support its robustness, the hMM-chip is fabricated from only 3 components, 2 of which are commercially available for better reproducibility. Next, the perfusable microvascularized network within the device closely resembles the highly-vascularized reality of human bone marrow, particularly the perivascular niche. This would enable the modeling of more physiologically-relevant phenomena, such as T cell trafficking through vessels to encounter and activate against target cells. Finally, there is a significant gap in knowledge about the phenotypic changes undergone by adoptively-transferred T cells, which is difficult to study in human subjects. Our model is based on human cells and enables the systematic inclusion or removal of any cell type of interest. Therefore, we will be able to harvest and study T cells pre- and post-implantation” within the system in order to better understand the immunomodulation that occurs in the immunosuppressive microenvironment of MM.

Relevant Publications:

• Nelson, M. R.*, Ghoshal, D.*, Mejías, J. C., Rubio, D. F., Keith, E. & K. Roy 2021. A Multi-Niche Microvascularized Human Bone Marrow (hBM) On-A-Chip Elucidates Key Roles Of The Endosteal Niche In hBM Physiology. Biomaterials, 270, 120683.
• Ghoshal, D.*, Ringquist, R.*, Jain, R., & K. Roy 2021. Understanding and improving cellular immunotherapies against cancer: From cell-manufacturing to tumor-immune models. Advanced Drug Delivery Reviews, 2021. 179.