Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties1. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs2 have induced remarkable responses in patients with refractory leukemia3,4,5 and lymphoma6 and were recently approved by the US Food and Drug Administration7. These CARs program highly performing effector functions that mediate potent tumor elimination4,8 despite the limited persistence they confer on T cells3,4,5,6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion9,10, which may be accentuated by the redundancy of CD28 and CD3ζ signaling11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs2. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.
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The RNA-seq data have been deposited in the Gene Expression Omnibus and are available under accession number GSE121226. Raw data for the figures in the manuscript will be made available upon request to the corresponding author.
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We thank J. Mansilla-Soto, S. van der Stegen, F. Perna, and other Sadelain laboratory members (Memorial Sloan Kettering Cancer Center) for helpful and critical discussions and G. Gunset for excellent technical assistance. We thank the following Memorial Sloan Kettering Cancer Center (MSKCC) core facilities for the excellent support: SKI Flow Cytometry core facility; animal facility; bioinformatics core; and integrated genomics operation core, funded by the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. We thank the Care-for-Rare Foundation (J.F.), the German Research Foundation (DFG) (J.F.), the Edythe Griffinger Fellowship (J.S.), and the Louis V. Gerstner Jr. Graduate School of Biomedical Sciences (A.D.) for their support. This work was in part supported by the Lake Road Foundation, the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Lymphoma and Leukemia Society, and the MSKCC Support Grant/Core Grant (P30 CA008748).
About this article
Nature Reviews Clinical Oncology (2019)