UCLA

Despite recent successes in cancer immunotherapies, challenges including insufficient activation and suppression of effector T cells in the tumor microenvironment, and inadequate ability to expand tumor-specific T cell ex vivo hinder their therapeutic potentials, especially in solid tumors. Some of the common strategies include blocking inhibitory receptors while others include evoking cytotoxic T lymphocyte responses such as chimeric antigen receptor (CAR)-T cell therapies and adoptive cell transfer (ACT) approaches. Despite their revolutionary approaches for hematopoietic cancers, their potency and the need for expanding tumor-specific T cells is a need not yet satisfactorily met for solid tumors. One of the major flaws is their administration route and all the immune-related adverse events associated with it. We have shown that the rate at which cytokines are delivered to CD8+ T cells impacts their differentiation and functionality. To improve ex vivo activation and expansion of tumor-reactive T cells, we studied the impact of particle design and mechanical forces. We designed a series of biocompatible artificial APCs (aAPCs) of various sizes and signal intensities. We confirmed that that absolute amounts of antigen engaged by the T cell are more important for activation than the density of antigen. Moreover, we show that T cells can recognize forces arising from the mechanical rigidity of the microenvironment. We fabricated 3D microporous scaffolds with a broad range of mechanical stiffness. We found that there was an augmentation of T cell activation, proliferation, and migration speed in the context of mechanically stiffer 3D matrices as compared to softer materials. Another major challenge that solid tumors face is the abundance of T regulatory cells (Tregs). Here we developed a platform that offers a solution to the above-mentioned challenges; a “synthetic lymph node” niche implanted proximally to the tumor for supporting locally transferred T cells while enhancing their infiltration and cytotoxic capabilities. Our porous synthetic lymph node serves as a home for the recruitment of endogenous T cells and serves them with the activation clues while providing the sustained release of necessary cytokines. We believe the provided niche offers a home to T cells either for ACT purposes or for localized immunomodulation.