Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells Journal Article


Authors: Zhao, Z.; Condomines, M.; Van Der Stegen, S. J. C.; Perna, F.; Kloss, C. C.; Gunset, G.; Plotkin, J.; Sadelain, M.
Article Title: Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells
Abstract: T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities. © 2015 Elsevier Inc.
Journal Title: Cancer Cell
Volume: 28
Issue: 4
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2015-10-12
Start Page: 415
End Page: 428
Language: English
DOI: 10.1016/j.ccell.2015.09.004
PROVIDER: scopus
PUBMED: 26461090
PMCID: PMC5003056
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Michel W J Sadelain
    452 Sadelain
  2. Zeguo Zhao
    11 Zhao
  3. Fabiana Perna
    45 Perna
  4. Gertrude Mary Gunset
    13 Gunset
  5. Jason Plotkin
    11 Plotkin
  6. Christopher Carl Kloss
    11 Kloss