Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

Robert Weinkove, Philip George, Nathaniel Dasyam, Alexander D McLellan, Robert Weinkove, Philip George, Nathaniel Dasyam, Alexander D McLellan

Abstract

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4-1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti-CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct- and disease-specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

Keywords: T cells; immunology; immunotherapy; lymphocytes.

Figures

Figure 1
Figure 1
Costimulation in unmodified T cells and within chimeric antigen receptor (CAR) T cells. (a) T cells express a TCR specific for peptide in the context of major histocompatibility complex. Costimulation eliciting optimal T cell activity, proliferation and survival requires expression of costimulatory receptor ligands such as CD80 and CD86 on APCs. (b) T cells transduced to present a CAR incorporating an intracellular costimulatory domain, such as that of CD28, can undergo potent activation upon exposure to cells expressing the target antigen without target cell expression of costimulatory receptor ligands. Since CAR costimulatory domains lack the original costimulator extracellular structures, they are unable to transmit negative signals from inhibitory ligands.
Figure 2
Figure 2
Generalised mechanism of chimeric antigen receptor (CAR) signalling provided by CD3‐ζ ITAMs and a costimulator domain. Ligation of the CAR scFv to tumor antigen provokes aggregation of the CAR polypeptide. CD3‐mediated activation proceeds via classical Zap70‐mediated pathway resulting in Ca++ influx and release from intracellular stores and translocation of de‐phosphorylated NFAT to the nucleus. Costimulatory domains preferentially recruit PI3 kinase and TRAF to enhance cytokine and cell survival gene transcription, particularly through AP‐1 and NF‐κB translocation to the nucleus. Costimulator domain signalling activates cytoskeletal mobilisation, enabling colocalisation of CAR to membrane rafts.
Figure 3
Figure 3
Examples of costimulator domain organisation within chimeric antigen receptor (CAR) constructs: (a, b) Second‐generation CAR, (c–e) third‐generation CAR and (f) an example of trans‐costimulation provided by small molecule‐mediated aggregation of the MyD88‐CD40 domains using AP1903.17 The inclusion of relevant transmembrane domains, as well as the orientation of the cytoplasmic domains, imparts critical functionality to the various CAR constructs.
Figure 4
Figure 4
Survey of registered clinical trials utilising distinct costimulator domain structures. A search for anti‐CD19 chimeric antigen receptor (CAR) T cell trials registered at ClinicalTrials.gov obtained information on costimulatory domains in 55 trials. Information on costimulatory domains in a further 15 trials was obtained by emailing the trial contact on ClinicalTrials.gov, leading to a total of 69 anti‐CD19 CAR T cell trials available for data analysis. The second‐generation CAR T cell trials in ‘other’ include 2 trials where an admix of second‐generation CARs containing 41BB and CD28 was administered, and two trials where either 41BB or CD28 containing second‐generation CARs were administered. The third/fourth‐generation CAR T cell trials in ‘other’ includes one trial where an admix of a third‐generation CAR utilising CD28 and 41BB costimulation plus a CD28 containing second‐generation CAR was administered, one trial where costimulation of CD28 and TLR2 was utilised, one trial where costimulation of CD28 and CD27 was utilised and one trial where costimulation of 41BB and CD27 was utilised.

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