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• W2559873596 abstract "Abstract Abstract 2463 Poster Board II-440 Acute myeloid leukemia (AML) is an aggressive malignancy for which current therapy fails to provide durable remission in approximately half of cases. Natural killer (NK) cells, as a key component of innate immunty, have recently shown clinical potential for adoptive immunotherapy against AML, particular when the donor and recipient are KIR mismatched. In addition to patients who do not have a suitable related donor, approximately 30% of patients bear all three families of KIR ligands and therefor can not benefit from KIR mismatch. Thus, the major obstacles for adoptive NK cell immunotherapy are 1) obtaining sufficient numbers of NK cells for effective thereapy and 2) finding a related donor with predicted KIR mismatch. Clinical trials with humanized or engineered mAbs against CD33 have validated this antigen as a target for immunotherapy of AML, but are complicated by side effects such as a hepatotoxicity due to CD33 expression on normal hepatocytes. To address the first hurdle, we developed a method to expand CD3-CD56+ primary NK cells in vitro using artificial APCs expressing membrane-bound IL21, and have validated electroporation as an efficient method for gene modification of these NK cells. To address the second hurdle and expand the therapeutic potential of KIR-matched expanded NK cells, we hypothesized that gene transfer of CD33 Chimeric Antigen Receptor (CAR) could provide additional activation signal to increase the lysis of AML blasts by expanded NK cells, and sought to compare signaling endodomains for this purpose. CD3z is a signal adapter molecule for NKp30, NKp46, and CD16 in NK cells. We developed a CD33CAR composed of a CD33 single-chain variable fragment fused with the CD3z transmembrane domain expressed in Sleeping Beauty transposon vector system, and compared a first generation (CD3z only) endodomain with second generation endodomains (CD3z plus either CD28 or CD137). Transient gene transfer of the CD33CAR DNA into NK cells was accomplished using the Amaxa Nucleofector device. Functional expression of the CAR was determined by binding of a Siglec3-IgG fusion protein to the cell surface followed by secondary staining with anti-IgG-FITC. Cytotoxicity of the NK cells against CD33+ AML cells and CD33-transduced HEK293T cells was determined in a 4h lysis assay using Calcein-AM. While the maximum electroporation efficiency was only 15% at 24h, expression levels as low as 4% significantly increased the cytotoxic activity of NK cells compared to unelectroporated NK cells. Each of the CD33CAR constructs harboring different endodomains yielded an equivalent increase in target cell lysis (Figure). This data supports recent observations that signal transduction through CD3z is sufficient to activate cytotoxic activity in NK cells. However, to increase the percentage of CAR-expressing NK cells we are further evaluating the role of endodomain signaling in CAR-dependent proliferation of NK cells electroporated with both transposon and transposase. Disclosures: No relevant conflicts of interest to declare." @default.
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• W2559873596 date "2009-11-20" @default.
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• W2559873596 title "The Contribution of Signaling Endodomains to CD33-Mediated Killing of Acute Myeloid Leukemia by Natural Killer Cells Transiently Modified with Chimeric Antigen Receptor." @default.
• W2559873596 doi "https://doi.org/10.1182/blood.v114.22.2463.2463" @default.
• W2559873596 hasPublicationYear "2009" @default.
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