Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency Journal Article


Authors: Feucht, J.; Sun, J.; Eyquem, J.; Ho, Y. J.; Zhao, Z.; Leibold, J.; Dobrin, A.; Cabriolu, A.; Hamieh, M.; Sadelain, M.
Article Title: Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency
Abstract: 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 leukemia3–5 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 cells3–6,8. 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. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: signal transduction; adult; controlled study; human cell; nonhuman; comparative study; letter; cd3 antigen; antigen expression; animal cell; mouse; animal tissue; tumor volume; animal experiment; animal model; cell fate; drug potency; protein tyrosine kinase; b lymphocyte induced maturation protein 1; lymphocyte differentiation; t lymphocyte receptor; acute leukemia; chimeric antigen receptor; effector cell; upregulation; immunostimulation; protein bcl 6; th1 cell; memory cell; chemokine receptor ccr7; t lymphocyte activation; cd19 antigen; cd28 antigen; protein kinase zap 70; transcription factor 7; complementary dna; cd45ra antigen; nuclear reprogramming; differentiation; lymphoid enhancer factor 1; b cell leukemia; memory t lymphocyte; adult disease; l selectin; interleukin 7 receptor; human; priority journal; kruppel like factor 2; immunoreceptor tyrosine based activation motif; chimeric antigen receptor immunotherapy
Journal Title: Nature Medicine
Volume: 25
Issue: 1
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2019-01-01
Start Page: 82
End Page: 88
Language: English
DOI: 10.1038/s41591-018-0290-5
PUBMED: 30559421
PROVIDER: scopus
DOI/URL:
Notes: Letter -- Export Date: 1 February 2019 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Michel W J Sadelain
    449 Sadelain
  2. Zeguo Zhao
    10 Zhao
  3. Mohamad   Hamieh
    13 Hamieh
  4. Jie   Sun
    4 Sun
  5. Justin Gabriel Andre Francois Eyquem
    13 Eyquem
  6. Judith Carolin Feucht
    8 Feucht
  7. Anton Dobrin
    2 Dobrin
  8. Yu-jui Ho
    3 Ho