(1) Wang Y (2) Li J (3) Wang Z (4) Liu Y (5) Wang T (6) Zhang M (7) Xia C (8) Zhang F (9) Huang D (10) Zhang L (11) Zhao Y (12) Liu L (13) Zhu Y (14) Qi H (15) Zhu X (16) Qian W (17) Hu F (18) Wang J

Cell proliferation

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.

Author Info: (1) Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Ce

Author Info: (1) Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (2) Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (3) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (4) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (5) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (6) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (7) Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. (8) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (9) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (10) Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. (11) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China. (12) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (13) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (14) Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. (15) State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. Center for Stem Cell Medicine & Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. (16) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, Hangzhou, China. (17) Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. (18) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.

Citation: Cell Prolif 2024 Jun 3 e13683 Epub06/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38830795

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