<i>In Vitro</i> Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness <i>In Vivo</i>

Abstract

Adoptive T-cell transfer therapy is an FDA- approved treatment for leukemia that relies on the <i>ex vivo</i> expansion and reinfusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during <i>ex vivo</i> expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, <i>ex vivo</i> use of this agonist bolstered the antitumor properties of murine tumor-specific CD4⁺ and CD8⁺ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion <i>in vitro</i><i>In vivo</i>, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that <i>in vitro</i> treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells <i>in vivo</i><b>Significance:</b> RORγ agonists can be used <i>in vitro</i> during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/14/3888/F1.large.jpg <i>Cancer Res; 78(14); 3888-98. ©2018 AACR</i>.