Enhancing T cell persistence of CAR-redirected T cells in solid tumors

Abstract

T cell persistence is likely to promote long-term anti-tumor effects after adoptive T cell transfer. We have recently shown that incorporation of the ICOS intracellu-lar domain into chimeric antigen receptors (CARs) signifi-cantly increased Th17 cell persistence in vivo, compared to CARs with CD28 or 4-1BB intracellular domains [1]. Here, we hypothesized that CD4 + and CD8 + T cells require distinct cytokine and costimulation signals for optimal persistence. To test this hypothesis, we compared the in vivo antitumor effects and persistence of combined CD4 + T cells (bulk or Th17-polarized) and CD8 + T cells redirected with CARs containing CD28, 4-1BB or ICOS-based costimulatory domains. Using multiple mouse tumor models, we demonstrate that the ICOS intracellular domain significantly enhanced the in vivo persistence of CAR-expressing CD4 + T cells, and that both persistence and tumor infiltration were further enhanced by culturing these cells under Th17-polarizing conditions. Importantly, Th17-polarized CD4 + T cells expressing an ICOS-based CAR significantly increased the circulatory persistence of bulk CD8 + T cells expressing either CD28-or 4-1BB-based CARs. We further demonstrate that the antitumor effect of CAR-expressing CD8 + T cells was enhanced when co-injected with ICOS-redirected Th17 cells. Collec-tively, our data suggest that combining Th17 CD4 + T cells redirected with an ICOS-based CAR with CD8 + CAR-T cells will enhance their persistence and antitumor efficacy.