Designing a Hydrogel Micropatch for Phosphatase-Exclusion-Driven Stimulation of CD8+ T Cells for Clinical Applicability

Abstract

Adoptive T cell therapies have emerged as a promising approach for targeting tumors. They involve reintroducing tumor-specific cytotoxic T cells into cancer patients, thus enabling the recognition, targeting, and destruction of tumor cells. Sustained activity of these cells is required for these adoptive cell therapies to be effective. However, re-introduced cells lose their function rapidly with time after injection into patients. Commercially available products, such as Dynabeads that are functionalized with αCD3 and αCD28, have been used for ex vivo activation. However, they have numerous drawbacks, creating the need to be physically separated from the cells before re-administration. To address these clinical problems, this project aims to develop a biocompatible hydrogel micropatch (hMP) for phosphatase exclusion that can maintain functional T cells, with the ability to increase their metabolic and cytotoxic potential. This project began by optimizing the fabrication process of hyaluronic acid-based hMPs to increase the binding efficiency, with surface decoration and the inclusion of a monoclonal adhesive layer yielding the highest adhesion rate. In vitro studies to measure the impact that the hMPs had on physiological processes were evaluated. These studies revealed that hMPs are biocompatible and do not affect transendothelial migration. Furthermore, preliminary studies quantifying the stimulatory capabilities of hMPs revealed that hMPs can drive stimulation through phosphatase exclusion and increased metabolic activity. Altogether, this study reports a biocompatible microparticle that can stimulate cytotoxic T cells, thus providing a potential avenue to retain an activated phenotype for adoptive cell therapies post ex vivo activation.