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.

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:. 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.