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Editorial
. 2019 Mar 19;3(2):e188.
doi: 10.1097/HS9.0000000000000188. eCollection 2019 Apr.

CAR-T Cells: Future Perspectives

Sarah Charrot  1   2 , Simon Hallam  1   2
Affiliations
Editorial

CAR-T Cells: Future Perspectives

Sarah Charrot et al. Hemasphere. .
No abstract available

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Figures

Figure 1
Figure 1
An analysis of CAR-T trials registered at clinicaltrials.gov. (A) Distribution of trials by condition targeted. (Note that the majority of trials target more than 1 condition; therefore, the sum does not add up to total number of trials.) (B) Distribution of trials by target antigen. Note that 12 of the trials registered do not target a specific antigen, but manufacture a personalized CAR depending on the disease phenotype. (C) The number of trials by phase and year first posted. ∗2018 to 7th December. CAR = chimeric antigen receptor.
Figure 2
Figure 2
The geographical distribution of chimeric antigen receptor-T trials registered at clinicaltrials.gov. Map created with mapchart.net ©.
Figure 3
Figure 3
Chimeric antigen receptor (CAR) design: novel developments in CAR technology. (A) The CAR is made up of an antigen-binding domain, hinge or spacer region, transmembrane region, and intracellular signaling domain, ±1 or more costimulatory domains. The hinge/spacer regions and antigen-binding domains can be made from a variety of different constructs as indicated, each with their own advantages and disadvantages. Intracellular costimulatory domains, for which there are also several options, have undergone 3 generations of development, leading to improvements in CAR-T efficacy, persistence, and survival. Further structural developments seek to either improve efficacy further or to reduce toxicity. (B) Measures to improve efficacy include recognition of multiple antigens, for example tandem CARs which work through OR logic gating, allowing recognition of more than 1 antigen leading to CAR activation, and adaptor CARs which allow recognition of a common attachment, such as FITC, to which selected antigen-binding domains can be attached. Other measures are targeted at overcoming the immunosuppressive tumor microenvironment, such as switch receptors and cytokine-secreting TRUCKs. Trafficking CARs have the ability to guide themselves to the tumor site, through recognition of either chemokines or localized hypoxia, and may be further programmed to activate only in these environments to minimize on-target off-tumor toxic effects. (C) Other methods to reduce toxicity include further developments in logic gating utilizing AND (dual or SynNotch CARs) and NOT (iCARs) Boolean logic to reduce on-target off-tumor effects. CARs with integral on-off switches or suicide switches allow for rapid elimination of the CAR should toxicity prove life threatening despite maximal medical therapy. FITC = fluorescein isothiocyanate.
Figure 4
Figure 4
CAR design: an idealized CAR. With so many parallel developments advancing CAR-T technology, it will take some time to unpick the ideal methods to optimize both efficacy and safety. The “ideal CAR” will, of course, continue to change as our progress in this area continues, and we learn more about the subtleties of the technologies we have already developed. CAR = chimeric antigen receptor.
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References

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