Aurora kinase inhibitors regulate T memory stem cell phenotype in T cell receptor-engineered T cells with prolonged persistence

Abstract

Background Adoptive T cell therapies including T cell receptor-engineered T (TCR-T) cell therapy are limited by poor in-vivo persistence. According to literature, aurora kinase inhibitors elicit glycolysis suppression and fatty acid oxidation enhancement. Less differentiated memory T cells rely more on fatty acid oxidation with better proliferative potency. Therefore, this study aims to determine whether aurora kinase inhibition during TCR-T cell preparation and expansion promote a more long-lived phenotype leading to T cells with increased in vivo persistence and efficacy. Methods The study involves preparing TCR-T cells with aurora kinase inhibitors for 7 days with anti-CD3/CD28 beads and IL-2. And the antitumor effects of these TCR-T cells were investigated in vitro and in subcutaneous and metastatic melanoma models. Results TCR-T cells cultured with aurora kinase A and B inhibitor generated more effector T cells (~ 79% and ~ 77%) when compared to cells with beads alone (~ 36%) after in-vitro re-stimulation. And aurora kinase B inhibitor-treatment benefits in vivo persistence of TCR-T cells and extends survival in both subcutaneous and metastatic melanoma model. Phenotypic analysis shows an increased percentage of T cells stem cell-like memory properties in terms of aurora kinase inhibition. The stemness of T cells is maintained by delaying proliferation mediated by limitation of mTOR activity. Conclusion Taken together, these data suggest that incorporation of aurora kinase inhibitor in TCR-T cells preparation might be a potential method to generate long-live TCR-T cells with potent therapeutic characteristics.