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Table 3 Next-generation CAR-NK cells

From: Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

Enhancement strategy

Target

Aim

References

Cytokine co-expression

IL-12

Improve persistence

Koneru [203]

Improve anti-tumor activity

Pegram [204]

IL-15

Liu [30]

Krenciute [205]

IL-18

Avanzi [206]

Hu [207]

Cytokine/JAK/STAT co-expression

IL-2Rβ + STAT3/5

Improve persistence

Kagoya [208]

Improve anti-tumor activity

Cytokine receptor co-expression

IL-7Rα

Improve persistence

Shum [209]

Improve anti-tumor activity

Chemokine co-expression

CCR2, CCR2b, CCR4, CCR7, CXCR2, CXCR4

Promote trafficking into tumor microenvironment

Brown [210]

Craddock [211]

Moon [212]

Rapp [213]

Di Stasi [214]

Carlsten [215]

Kershaw [216]

Hillerdal [217]

Dual CAR (two antigens required for activation)

BCMA + CS1

Enhanced safety and efficacy

Chen [218]

Split CAR (separation of co-stimulatory domains)

PSMA + PSCA

Achieve tumor-specificity in the absence of a truly tumor-restricted antigen

Kloss [219]

Multi-antigen targeting (bi-specific CAR)

HER2 + IL13Rα2

Improve anti-tumor activity

Hegde [220]

HER2 + IL13Rα2 + EphA2

Prevent antigen escape

Bielamowicz [221]

Universal CAR

CD16 (Fc receptor)

Precise control of CAR reactivity based on Ab half-life

Caratelli [222]

Antibody tag

Re-use of approved antibodies, requiring only one CAR construct

Tamada [223]

Feldmann [224]

FITC

Tamada [223]

Inhibitory CAR

Controllable CAR expression systems

Healthy tissue antigen, e.g., CD19 (with inhibitory domain, e.g., PD-1, CTLA-4)

Improve specificity, better discrimination healthy and tumor tissue

Fedorov [225]

Syn/Notch

Controlled CAR expression

Morsut [226]

 

Inducible co-stimulation

Inducible CAR activation

Mata [227]

Knockout of checkpoint inhibitor

PD-1

Improve persistence

Rupp [228]

Improve anti-tumor activity

Ren [229]

Cherkassy [194]

Daher [70]

  1. Examples of enhancements to CAR constructs, mostly derived from the CAR-T field