The costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T cell function, expansion and survival in vitro and in vivo. Human T cells transduced to express an antigen-specific chimeric antigen receptor (CAR-T) containing an intracellular CD3 zeta (CD3ζ) chain signaling module with the CD27 costimulatory motif in tandem exerted increased antigen-stimulated effector functions in vitro, including cytokine secretion and cytotoxicity, compared to CAR-T with CD3ζ alone. After antigen stimulation in vitro, CD27 bearing CAR-T cells also proliferated, upregulated Bcl-XL protein expression, resisted apoptosis and underwent increased numerical expansion. The greatest impact of CD27 was noted in vivo where transferred CAR-T cells with CD27 demonstrated heightened persistence after infusion, facilitating improved regression of human cancer in a xenogeneic allograft model. This tumor regression was similar to that achieved with CD28 or 4-1BB costimulated CARs, and heightened persistence was similar to 4-1BB, but higher than CD28. Thus, CD27 costimulation enhances expansion, effector function and survival of human CAR-T cells in vitro and augments human T cell persistence and anti-tumor activity in vivo.
- Submitted March 24, 2011.
- Accepted November 18, 2011.
- Copyright © 2005 American Society of Hematology