七种 CD19 CAR 设计用于工程化 NK 细胞以增强抗肿瘤活性的比较

Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is emerging as a promising cancer treatment, with notable safety and source diversity benefits over CAR-T cells.

This study focused on optimizing CAR constructs for NK cells to maximize their therapeutic potential.

We designed seven CD19 CAR constructs and expressed them in NK cells using a retroviral system, assessing their tumour-killing efficacy and persistence. Results showed all constructs enhanced tumour-killing and prolonged survival in tumour-bearing mice. In particular, CAR1 (CD8 TMD-CD3 SD)-NK cells showed superior efficacy in treating tumour-bearing animals and exhibited enhanced persistence when combined with OX40 co-stimulatory domain. Of note, CAR1-NK cells were most effective at lower effector-to-target ratios, while CAR4 (CD8 TMD-OX40 CD- Fc RI SD) compromised NK cell expansion ability.

Superior survival rates were noted in mice treated with CAR1-, CAR2 (CD8 TMD- Fc RI SD)-, CAR3 (CD8 TMD-OX40 CD- CD3 SD)- and CAR4-NK cells over those treated with CAR5 (CD28 TMD- Fc RI SD)-, CAR6 (CD8 TMD-4-1BB CD-CD3 1-ITAM SD)- and CAR7 (CD8 TMD-OX40 CD-CD3 1-ITAM SD)-NK cells, with CAR5-NK cells showing the weakest anti-tumour activity. Increased expression of exhaustion markers, especially in CAR7-NK cells, suggests that combining CAR-NK cells with immune checkpoint inhibitors might improve anti-tumour outcomes.

These findings provide crucial insights for developing CAR-NK cell products for clinical applications.