CD28 Costimulation Provided through a CD19-Specific Chimeric Antigen Receptor EnhancesIn vivoPersistence and Antitumor Efficacy of Adoptively Transferred T Cells

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Abstract
Chimeric antigen receptors (CAR) combine an antigen-binding domain with a CD3-ζ signaling motif to redirect T-cell specificity to clinically important targets. First-generation CAR, such as the CD19-specific CAR (designated CD19R), may fail to fully engage genetically modified T cells because activation is initiated by antigen-dependent signaling through chimeric CD3-ζ, independent of costimulation through accessory molecules. We show that enforced expression of the full-length costimulatory molecule CD28 in CD8+CD19R+CD28− T cells can restore fully competent antigen-dependent T-cell activation upon binding CD19+ targets expressing CD80/CD86. Thus, to provide costimulation to T cells through a CD19-specific CAR, independent of binding to CD80/CD86, we developed a second-generation CAR (designated CD19RCD28), which includes a modified chimeric CD28 signaling domain fused to chimeric CD3-ζ. CD19R+ and CD19RCD28+ CD8+ T cells specifically lyse CD19+ tumor cells. However, the CD19RCD28+ CD8+ T cells proliferate in absence of exogenous recombinant human interleukin-2, produce interleukin-2, propagate, and up-regulate antiapoptotic Bcl-XL after stimulation by CD19+ tumor cells. For the first time, we show in vivo that adoptively transferred CD19RCD28+ T cells show an improved persistence and antitumor effect compared with CD19R+ T cells. These data imply that modifications to the CAR can result in improved therapeutic potential of CD19-specific T cells expressing this second-generation CAR. (Cancer Res 2006; 66(22): 10995-1004)