Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jul;14(7):499-509.
doi: 10.1038/nrd4597.

The pharmacology of second-generation chimeric antigen receptors

Sjoukje J C van der Stegen  1 , Mohamad Hamieh  1 , Michel Sadelain  1
Affiliations
Review

The pharmacology of second-generation chimeric antigen receptors

Sjoukje J C van der Stegen et al. Nat Rev Drug Discov. 2015 Jul.

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.

PubMed Disclaimer

Figures

Figure 1:
Figure 1:. Chimeric Antigen Receptor evolution.
A: First fusion receptors as developed by the Weiss, Seed and Klausner teams, coupling CD3ζ to the CD4, CD8 or CD25 extracellular domains. B: First generation CAR (or T body), allowing for antigen recognition through addition of an scFv. C: Chimeric cytokine receptor, coupling an scFv to the intracellular domain of CD28 to induce antigen-specific costimulation. D: Second generation CARs, facilitating T cell reprogramming by incorporating a costimulatory-signalling domain in tandem with the CD3ζ chain.
Figure 2:
Figure 2:. Second generation anti-CD19-CARs used in clinical trials to treat Acute Lymphoblastic Leukaemia (ALL).
A. CAR tested in MKSCC-trials,, , consisting of SJ25C1 scFv, CD28 spacer, trans-membrane and signalling domain and CD3ζ chain B. CAR used in clinical trials at NCI. This CAR contains the FMC63 scFv but is otherwise the same as the MSKCC CAR shown in A. C. CAR used and developed by the Baylor College of Medicine team. This CAR utilizes the FMC63 scFv, IgG1 hinge, CD4 transmembrane domain, CD28 signalling domain and CD3ζ chain. D. Construct developed at St Jude Children’s Research Hospital and used by the CHOP and UPenn teams., This CAR contains the FMC63 scFv, CD8α hinge, and 4–1BB signalling domain in tandem with the CD3ζ chain.
See this image and copyright information in PMC

References

    1. Sadelain M, Riviere I & Brentjens R Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 3, 35–45 (2003). - PubMed
    1. Ho WY, Blattman JN, Dossett ML, Yee C & Greenberg PD Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3, 431–7 (2003). - PubMed
    1. Morgan RA et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–9 (2006). - PMC - PubMed
    1. Dossett ML et al. Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR. Mol Ther 17, 742–9 (2009). - PMC - PubMed
    1. Sadelain M, Brentjens R & Riviere I The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 21, 215–23 (2009). - PMC - PubMed