(31c) Engineering Hydrogel Coated Membranes to Modulate Activation and Transduction of T-Cells

Biomaterials are a subtype of materials that have been engineered to interact with biological systems. Combined with immune engineering, a relatively new field where engineering tools are used to modulate immune responses, biomaterials offer the opportunity to reprogram immune cells. In recent years, hydrogels have become an important tool to study cells behavior as a more relevant environment since these systems can change composition, stiffness, and biochemical functions, which makes them more biological relevant that common tissue culture plastic for many applications. Furthermore, the versatility of these materials has the potential to impact T-cells phenotype (e.g., by functionalization with different co-stimulatory molecules [1]). In this work, hydrogel coated membranes (HCM) were functionalized with a wide variety of ligands to activate T-cells, leading to distinct modulation of desirable phenotypes, improving T-cell activation and transduction emulating the in vivo microenvironment.

Activation of T cells is a fundamental step to achieve proliferative phenotypes on T cells. Hence, in this in this work, four different co-stimulatory ligands have been functionalized on the surface of HCMs to study their activation potential. Phenotype, activation, and exhaustion markers were used to compare with industry standard TransAct^TM, finding memory phenotype, minimal exhaustion, and similar activation profiles with HCMs. Due to the increase in memory phenotypes and lower exhaustion, transduction experiments with a model lentivirus were performed, where an increase in T cell transduction was observed. Furthermore, the lower exhaustion on the full population was translated to the transduced population. These findings demonstrated how T-cell phenotype can be modulated using functionalized hydrogels, leading to potential applications on the CAR-T (chimeric antigen receptor) manufacturing process. CAR-T cell therapies have become a fundamental treatment for hematological cancers with a remission rate of 60%-90%. However, the cost of the therapy ($350k up to 450k per injection) limits accessibility for patient and is directly related to the activation and transduction steps. Therefore, after proving the potential of functionalized HCMs for T-cell activation and transduction, a CD19 CAR virus was used to transduce T-cells for CAR-T applications. CAR-T efficacy was determined through various killing assays showing remarkable killing potential and demonstrating the importance of biomaterials-based approaches for tuning T-cell phenotype. This work presents significant opportunities to modulate T-cells phenotypes for cell therapy applications by using engineered soft materials.

My long-term goal is to launch a research program focused on improving therapeutic options for female-specific disorders, where my team will apply materials-based approaches to create models and therapeutics targeting autoimmune diseases to advance disease understanding and test new therapeutic modalities [2]. By applying my expertise with T-cells modulation within the autoimmune environment, I aim to engineer new models and therapeutic approaches to modulate autoimmunity and enable new translation options for women facing autoimmune diseases.

Acknowledgements: This project was developed with an award from the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and financial assistance from the U.S. Department of Commerce, National Institute of Standards and Technology (70NANB21H086).

References:

[1] K. Bomb, P.J. Levalley, I.R. Woodward, S.E. Cassel, B.P. Sutherland, A. Bhattacharjee, Z. Yun, J. Steen, E. Kurdzo, J. McCoskey, D. Burris, K. Levine, C. Carbrello, A.M. Lenhoff, C.A. Fromen, A.M. Kloxin, Cell Therapy Biomanufacturing: Integrating Biomaterial and Flow‐Based Membrane Technologies for Production of Engineered T‐Cells, Advanced Materials Technologies, (2023) 2201155.

[2] A. López Ruiz, E.D. Slaughter, A.M. Kloxin, C.A. Fromen, Bridging the gender gap in autoimmunity with T-cell–targeted biomaterials, Current Opinion in Biotechnology, 86 (2024) 103075.