Journal
FRONTIERS IN IMMUNOLOGY
Volume 14, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2023.1226518
Keywords
CAR-NK cells; NK-92; adoptive cell therapy; IL-15; IL-15 receptor; B-cell malignances; allogeneic therapy
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This study compared the effects of CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) and IL-15/IL-15R alpha (CAR.19-IL15/IL15R alpha) on NK cell proliferation, activation, and cytotoxicity against B-cell leukemia. The results showed that the fourth-generation CD19-targeted CAR (CAR.19) co-expressing IL-15 and its receptor IL-15/IL-15R alpha (CAR.19-IL-15/IL-15R alpha) significantly enhanced NK-92 cell proliferation, cytokine secretion, and cytotoxicity against B-cell cancer cells both in vitro and in a mouse model. This suggests that IL-15/IL-15R alpha might overcome the limitations of NK-92 cell-based targeted tumor therapies by providing the necessary signals for growth and activation.
Introduction: Natural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into clinical applications. Adoptive transfer of CAR-NK-92 cells holds out the promise of therapeutic benefit at a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, it has not achieved breakthrough clinical results yet, and further improvement of CAR-NK-92 cells is necessary.Methods: In this study, we conducted a comparative analysis between CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) with IL-15/IL-15R alpha (CAR.19-IL15/IL15R alpha) to promote NK cell proliferation, activation, and cytotoxic activity against B-cell leukemia. CAR constructs were cloned into lentiviral vector and transduced into NK-92 cell line. Potency of CAR-NK cells were assessed against CD19-expressing cell lines NALM-6 or Raji in vitro and in vivo in a murine model. Tumor burden was measured by bioluminescence.Results: We demonstrated that a fourth- generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15R alpha (CAR.19-IL-15/IL-15R alpha) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model.Conclusion: Together with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15R alpha comprising fourth-generation CARs may overcome the limitations of NK-92 cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals.
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