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- W4313356078 abstract "Abstract Ex vivo expansion of human NK cells with CD137L and IL-15 is being explored both preclinically and clinically as a means of increasing the number and activation of NK cells for a variety of cancers, but results to date have not shown consistent efficacy. JAK1/2 inhibition impairs NK cell maturation, activation and cytotoxicity. However, the absence or mutation of STAT1/3 molecules which are typically phosphorylated by JAK1/2 enhance NK cytotoxicity. We hypothesize that inhibition of the JAK/STAT pathway in CD137L/IL-15 activated NK cells stimulate NK cell activation and increase more potent effectors if combined with a BCL2 inhibitor. NKs were ex vivo expanded with CD137L/IL-15 for 12 days, then exposed to increasing concentrations of Ruxolitinib (0.313 – 10μM) and/or Venetoclax (6.25 – 200nM) for 24 hours before analysis. Ruxolitinib and Venetoclax enriched a CD56dim cytotoxic subset and decreased a CD56 bright cytokine-producing subset in a dose-dependent manner. Ruxolitinib alone increased CD16 and CD69 expression which indicates NK cell activation. Importantly, both drugs did not induce markers associated with senescence (CD57) or exhaustion (PD-1/Tim-3) or decrease NK cell viability. Treatment of two human T cell acute lymphoblastic leukemia (T-ALL) cell lines with 1.25μM Ruxolitinib and 25nM Venetoclax decreased proliferation and increased apoptosis of T-ALL cells in a synergistic manner (CI<1; p<0.001). Usage of Ruxolitinib and Venetoclax has implications on both the biology of ex vivo activated NK cells and T-ALL, and may be a novel pharmacologic combination for improving adoptive cell therapy of leukemia." @default.
- W4313356078 created "2023-01-06" @default.
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- W4313356078 date "2017-05-01" @default.
- W4313356078 modified "2023-09-27" @default.
- W4313356078 title "Combined inhibition of JAK/STAT and BCL2 during <i>ex vivo</i> NK cell expansion enriches a highly cytotoxic NK cell subset" @default.
- W4313356078 doi "https://doi.org/10.4049/jimmunol.198.supp.121.16" @default.
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