Seminars

Tcell starvation and nutrient competition at the tumor micro environment is considered a major limiting factor in cancer immunotherapy. Metabolic suppression hampers T cell activation, differentiation, and effector functions, leading to T cell anergy and apoptosis, resulting in tumor escape and immunotherapy failure. We propose a novel nanotechnology-based approach to overcome metabolic T cell suppression: specific feeding of T cells with nanoparticles encapsulating essential metabolites during the ex-vivo phase of adoptive CAR Tor TIL therapy. This creates an internal cellular reservoir of controlled release nutrients that will support T cell metabolic requirements upon reaching the nutrient-depleted tumor microenvironment. In order to achieve high metabolite loading, we use a core-shell architecture in which we polymerize a nano-meter silica shell on a nano-sized core of the desired metabolite obtained by grinding. By controlling the sol-gel synthesis parameters we can tailor shell thickness and porosity and determine metabolite release rate and encapsulation efficiency. Our preliminary work focuses on L-arginine as a model system – one of the keys most important amino acids for T cell activation depleted at the tumor microenvironment of many cancers. We generate arginine-loaded nanoparticles and demonstrated arginine-controlled release kinetics. In order to enable T cell uptake, we conjugate anti-CD3 antibodies to the nanoparticle 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 the activation phenotype. Based on these preliminary results we propose that feeding T cells with metabolite encapsulating nanoparticles may potentially relieve metabolic immune suppression in adoptive cell therapies and result in superior CAR T andTIL cancer immunotherapies.