Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells

Cancer Cell. 2015 Oct 12;28(4):415-428. doi: 10.1016/j.ccell.2015.09.004.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19 / immunology
  • Antigens, CD19 / metabolism
  • CD28 Antigens / biosynthesis
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology*
  • Hematologic Neoplasms / immunology*
  • Hematologic Neoplasms / pathology
  • Hematologic Neoplasms / therapy
  • Humans
  • Immunotherapy, Adoptive
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-gamma / metabolism
  • Kinetics
  • Lymphocyte Activation / immunology
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / biosynthesis
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*


  • Antigens, CD19
  • CD28 Antigens
  • Interferon Regulatory Factor-7
  • Receptors, Antigen
  • Recombinant Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interferon-gamma