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NK cells engineered with a IL-15/IL-15Rα complex and CD19-targeted CAR show in vitro expansion and tumor regression in a murine xenograft model of B-cell leukemia in vivo

ABSTRACT: Natural killer (NK) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers and unlike T cells, offer their use in allogeneic settings. The translation of NK cells into the clinic is still hampered by the inability of CAR-NK cells to expand in vitro and in vivo. Adoptive transfer of CAR-NK cells holds the promise of therapeutic benefit with a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, adoptive transfer of CAR-NK cells has not yet achieved breakthrough clinical results, and further improvement of CAR-NK cells is necessary. Here, we demonstrated that a fourth-generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) 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. Surprisingly, CAR construct comprising the IL-15/IL-15Rα was superior to CAR co-expressing the soluble form of IL-15 in terms of sustained proliferation, viability, but importantly also in their ability to control CD19+ B-cell lymphoma in a murine xenograft model. 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-15Rα comprising fourth-generation CARs may overcome the limitations of NK cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals

ORGANISM(S): Homo sapiens

PROVIDER: GSE234733 | GEO | 2023/08/29

REPOSITORIES: GEO

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NK cells engineered with a IL-15/IL-15Rα complex and CD19-targeted CAR show in vitro expansion and tumor regression in a murine xenograft model of B-cell leukemia in vivo

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