Epigenetic events involved in CAR T cells maturation: new therapeutic combinations for solid tumors

Immunotherapy has revolutionized cancer treatment by enabling the modulation and activation of patient’s immune system, offering significant outcomes for a vast majority of them. CARs are synthetic molecules that can combine the effector functions of T cells with the specificity of antibody binding domains, consisting of the TCR grafted to extracellular variable region of an antibody. They are able to specifically recognize tumor antigens independently from major-histocompatibility-complex (MHC) and from antigen processing mechanisms. CARs are composed by an extracellular antigen-recognition domain linked to an intracellular signaling domain.

The extracellular antigen-recognition domain consists of an antibody single-chain variable (scFv) fragment which allows the CAR to recognize surface tumor-associated antigens. In recent decades, extensive research has focused on the role of epigenetic events in regulating T cell development within the thymus and the differentiation process that occurs after a T cell encounters its cognate antigen in the periphery.

These events include the switching on of specific effector genes and the concurrent naïve-associated genes switching off. A major factor limiting CAR T cell therapy in patients is its poor persistence, which can lead to a less durable antitumor activity and incomplete tumor regression. In this context, T cell memory gene expression programs emerged as core determinants of CAR T function, suggesting that memory reprogramming, via transcription factor activity modulation, may represent a universal strategy to enhance CAR T cell efficacy. This research project will take advantage of two novel CAR T cell products raised against GloboH tumor antigen, characterized by different phenotypic features, recently developed in our laboratory. Our aim will be to investigate the activity of EZH2, a factor whose role in CD8+ T cell differentiation is only beginning to be understood, focusing on its impact on the expression of genes directly associated with CAR T cell persistence and with memory phenotypes. The data collected will finally allow us to draw a therapy where CAR T cells will be combined to an epigenetic drug with the aim of improving and enhancing their persistence and, consequently, the anti-tumor activity.