The pharmacology of second-generation chimeric antigen receptors

Nat Rev Drug Discov. 2015 Jul;14(7):499-509. doi: 10.1038/nrd4597.


Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

Publication types

  • Review

MeSH terms

  • Animals
  • CD28 Antigens / immunology
  • CD28 Antigens / therapeutic use
  • Chimera
  • Humans
  • Immunotherapy / methods*
  • Immunotherapy / trends
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Receptors, Antigen / immunology*
  • Receptors, Antigen / therapeutic use*
  • T-Lymphocytes / immunology*


  • CD28 Antigens
  • Receptors, Antigen