A novel discovery platform that establishes stable terminal dysfunction in human CAR T cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B159
Abstract ID: 4374

Presenting Author:
Abbey A Saadey , Graduate Fellow at Ohio State Univ. Col. of Med.

Abstract:

Chimeric antigen receptor (CAR) T cells have been a successful therapeutic approach to treat human blood cancers. However, several challenges remain that limit the efficacy of CAR T cell therapy. Among these challenges are the development of terminal exhaustion in CAR T cells and limited in vivo persistence. Both pre-clinical and clinical studies have shown that exhausted T cells acquire stable epigenetic scars that limit their cytotoxic function and memory potential. Thus, there is a critical need to develop a tractable model that induces terminal exhaustion in human CAR T cells to investigate the molecular mechanisms that drive stable dysfunction. In contrast to a recently described in vitro model of transient CAR T cell dysfunction, we developed a novel model system using human B cell cancer-specific CAR T cells, in which chronic exposure to tumor antigens plus a fundamental microenvironmental signal establishes stable, terminal dysfunction. We also identify a novel molecular switch that can regulate anti-tumor activity of human CAR T cells. Overall, our model establishes stable dysfunctional programming in human CAR T cells that mimics terminally exhausted CAR T cells in vivo. These findings pave the way for developing an efficient platform to identify new therapeutic approaches that prevent terminal exhaustion programming in human CAR T cells.