BioE PhD Proposal Presentation- Abir Muhuri

Advisor: Susan N. Thomas, Ph.D. (Woodruff School of Mechanical Engineering, Georgia Institute of Technology) 

Committee:

Yunus Alapan, Ph.D. (Department of Mechanical Engineering, University of Wisconsin-Madison)

Andrés J. García, Ph.D. (Woodruff School of Mechanical Engineering, Georgia Institute of Technology)

Sarwish Rafiq, Ph.D. (Department of Hematology and Medical Oncology, Emory University School of Medicine)

Levi Wood, Ph.D. (Woodruff School of Mechanical Engineering, Georgia Institute of Technology)

Microfluidic-Enabled Adhesion Analysis of Therapeutic T cells for Lymph Node Homing PotentialAdoptive T cell therapy (ACT) remains a promising class of cancer therapy, where patient-extracted T cells are engineered or expanded ex vivo before re-infusion. Importantly, treatment efficacy is strongly dependent on transferred cell engraftment within target tissues. These targets include the tumor, where transferred T cells mediate direct cancer cell killing, and lymphoid tissues, including lymph nodes (LNs), which serve as specialized niches for T cell survival and priming. However, current patient responses to ACT are severely limited by poor engraftment within these target sites. To this end, the objective of this thesis is to engineer microfluidic devices to isolate T cell subsets with improved LN engraftment potential and evaluate the phenotype and therapeutic potential of isolated populations. My central hypothesis is that in vitro recapitulation of both physiological fluid flow and different adhesive motifs of the LN vascular microenvironment (termed high endothelial venules, HEVs) will result in capture of T cell subsets with enhanced LN homing capacity and therapeutic potency. Using these devices, I will evaluate the adhesion profiles of two distinct T cell products and their homing efficacy and therapeutic potency in in vivo adoptive transfer studies. These include 1) human CAR-T cell adhesion to homeostatic vs. inflamed LN HEV motifs associated with lymphoma and 2) murine CD8+ T cell adhesion to a tumor-draining LN HEV motif in the context of breast cancer. Lastly, I will interrogate the adhesive phenotypes of murine T cell subsets using engineered microfluidic devices that mimic anatomically distinct LN HEVs. Specifically, these will include peripheral versus mesenteric LNs, due to their specialized immune functions. Overall, these studies will demonstrate a scalable in-vitro methodology to relate different adhesion ligand/receptor profiles among heterogenous T cell products to their phenotypes and predict resulting therapeutic potency, based on homing capacity.