Overcoming Metabolic CAR T Suppression via Nanotechnology-Based Metabolite Feeding in Cancer Immunotherapy

T cell starvation and nutrient competition at the tumor microenvironment is considered a major limiting factor in cancer immunotherapy. This metabolic suppression leads to T cell anergy and apoptosis, resulting in tumor escape and immunotherapy failure. In order to overcome metabolic suppression of T cells, we propose a novel nanotechnology based approach to selectively feed T cells with essential metabolic nutrients: nano-metric sized essential metabolites are encapsulated in a nano-meter silica shell enabling their controlled release. These core-shell nano-particles are fed to T cells during the ex-vivo phase of adoptive CAR T or TIL therapy, creating an internal cellular reservoir of nutrients that will support their metabolic requirements upon reaching the nutrient depleted tumor microenvironment. Our preliminary work focused on providing T cells with L-arginine as model system - an important amino acid for T cell activation depleted at the tumor microenvironment. We generated arginine-loaded nano-particles and demonstrated arginine-controlled release kinetics and T cells uptake following anti-CD3 conjugation to nano-particles surface. Finally, we demonstrate that arginine starvation leads to inhibition of T cell proliferation, reduced activation markers expression, and impaired survival; while prior feeding of the T cells with arginine-encapsulating nanoparticles partially rescues activation phenotypes. We suggest that metabolic enhancement of adoptive cell therapies using metabolite encapsulating nano-particles can result in superior CAR T and TIL immunotherapies.