The pharmacology of second-generation chimeric antigen receptors Journal Article


Authors: Van Der Stegen, S. J. C.; Hamieh, M.; Sadelain, M.
Article Title: The pharmacology of second-generation chimeric antigen receptors
Abstract: 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. © 2015 Macmillan Publishers Limited.
Keywords: signal transduction; cancer survival; unclassified drug; fatigue; review; nonhuman; solid tumor; drug targeting; drug megadose; neurotoxicity; antineoplastic agent; binding affinity; cd3 antigen; antigen expression; lymphocyte proliferation; t lymphocyte; cell cycle progression; interleukin 2; ipilimumab; unindexed drug; cancer immunotherapy; low drug dose; melanoma; liver toxicity; cyclophosphamide; antineoplastic activity; cytotoxicity; drug potency; drug structure; protein bcl xl; drug design; kidney carcinoma; acute lymphoblastic leukemia; pneumonia; rash; acute kidney failure; b cell lymphoma; lymphocyte differentiation; t lymphocyte receptor; nonhodgkin lymphoma; pancreatitis; chimeric antigen receptor; cell therapy; cytokine production; dimerization; colon perforation; immunostimulation; dermatitis; antigen binding; cytokine release; structure analysis; chronic lymphatic leukemia; cell metabolism; cell expansion; cd134 antigen; drug binding; t lymphocyte activation; cd19 antigen; lung infiltrate; cd28 antigen; heart arrest; lymphocyte function; cis trans isomerism; cd33 antigen; cd27 antigen; tgn 1412; leukemia remission; natural killer cell receptor nkg2d; enterocolitis; uveitis; programmed death 1 receptor; immunopharmacology; metastatic melanoma; inducible costimulator; acute lung injury; cd137 antigen; cytokine release syndrome; nephritis; aplasia; cell engineering; cytokine storm; disseminated intravascular clotting; membrane potential; b cell aplasia; urelumab; human; priority journal; pembrolizumab; 4 1bb receptor zeta chain based chimeric antigen receptor; cd19 based chimeric antigen receptor; cd27 based chimeric antigen receptor; cd28 zeta chain based chimeric antigen receptor; cd3 zeta chain based chimeric antigen receptor; immune checkpoint antagonist; inducible costimulator zeta chain based chimeric antigen receptor; natural killer cell receptor nkg2d based chimeric antigen receptor; ox40 based chimeric antigen receptor
Journal Title: Nature Reviews Drug Discovery
Volume: 14
Issue: 7
ISSN: 1474-1776
Publisher: Nature Publishing Group  
Date Published: 2015-07-01
Start Page: 499
End Page: 509
Language: English
DOI: 10.1038/nrd4597
PROVIDER: scopus
PUBMED: 26129802
PMCID: PMC6410718
DOI/URL:
Notes: Export Date: 3 August 2015 -- Source: Scopus
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MSK Authors
  1. Michel W J Sadelain
    517 Sadelain
  2. Mohamad   Hamieh
    19 Hamieh