Human acute myeloid leukemia CD34+CD38- stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells

Langenkamp, Ulrich; Siegler, Uwe; Jörger, Simon; Diermayr, Stefan; Gratwohl, Aloïs; Kalberer, Christian P.; Wodnar-Filipowicz, Aleksandra

doi:10.3324/haematol.2009.005967

Cited by 26 publications

(18 citation statements)

References 25 publications

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“…ULBP-1 and ULBP-3 expression was slightly increased on A2780 and PEO-1 cells, and ULBP-4 expression was slightly elevated on OVCAR5 and A2780 cells. Consistent with other reports (Armeanu et al, 2005;Langenkamp et al, 2009), the surface expression of NKG2DLs on normal primary ovarian epithelial cells, which occurred at low levels, remained stable after VPA treatment (Fig. 4C).…”

Section: Vpa Treatment Increases Surface Expression Of Nkg2d Ligands supporting

confidence: 93%

Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Song

Santoro

et al. 2013

Human Gene Therapy

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NKG2D ligands (NKG2DLs) are widely expressed on ovarian cancers to various degrees, making them attractive targets for immunotherapy. Here, we applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human ovarian cancer cells and evaluated the impact of pharmacological upregulation of NKG2DLs on immune recognition. Various NKG2DLs, including MICA/B and ULBP-1, -2, -3, and -4, were expressed at various levels on the surface of all established ovarian cancer cell lines and primary ovarian cancer samples tested. To redirect human T cells against NKG2DLs, an NKG2DL-specific CAR was generated by fusing the extracellular domain of the NKG2D receptor to the 4-1BB costimulatory and CD3-ζ chain signaling domains. In vitro expansion of chimeric NKG2D CAR T cells was delayed compared with untransduced T cells and control CAR T cells; the likely result of fratricide among activated T cells expressing NKG2DLs. However, NKG2D CAR T cells did expand and were selectively enriched during prolonged culture. In coculture, CD4(+) and CD8(+) NKG2D CAR T cells specifically recognized and killed NKG2DL-expressing ovarian cancer cell lines but not NKG2DL-negative cells. Notably, pretreatment of ovarian cancer cells expressing moderate to low levels of NKG2DLs with the histone deacetylase inhibitor sodium valproate (VPA) upregulated NKG2DL cell surface expression and consequently enhanced their immune recognition by chimeric NKG2D CAR T cells. Our results demonstrate that VPA-induced upregulation of NKG2DL expression enhances the immune recognition of ovarian cancer cells by engineered NKG2D CAR T cells, and rationalizes the use of VPA in combination with NKG2DL-targeted immunotherapy in ovarian cancer.

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Section: Vpa Treatment Increases Surface Expression Of Nkg2d Ligands supporting

confidence: 93%

Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Song

Santoro

et al. 2013

Human Gene Therapy

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“…97 In analogy with the lowered activating receptor expression, surface expression of NKG2D ligands (MIC and ULBP molecules) is low or absent on AML blasts and is related to impaired NK cell-mediated cytotoxicity (Table 1). 28,[42][43][44]98 In addition, secretion of soluble NKG2D ligands in AML contributes to evasion of NK cell surveillance (Table 1). 43,44 In this regard, an attractive immunotherapy would be to upregulate these ligands on AML cells to enhance their susceptibility to NK cell recognition and restore their sensitivity to NK cell killing.…”

Section: Nk Cell Immune Escape In Aml E Lion Et Almentioning

confidence: 99%

Natural killer cell immune escape in acute myeloid leukemia

et al. 2012

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“…Secondary replating has been used to characterize clonogenic MM cells, but this method could also be useful for evaluating novel cancer stem cell targeting therapeutics in NK cell line cytotoxicity in MM haematologica | 2012; 97 (7) 1025 38 That study was the first to evaluate the self-renewal of clonogenic cells after immune effector cell treatment, but cumulative clonogenic inhibition to account for self-renewal of residual colonies after NK cell treatment was not calculated. We determined the clonogenic inhibition of NCI-H929 by NK-92 to be 93% at 20:1 (E:T) ratio, and when the self renewal of residual NCI-H929 colonies was included, the cumulative clonogenic inhibition was 99%.…”

confidence: 99%

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model

Swift

Williams²,

Kosaka³

et al. 2012

Haematologica

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The online version of this artivle has a Supplementary Appendix. BackgroundNovel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. Design and MethodsThe cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. ResultsThree multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2-to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. ConclusionsThis study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted. Haematologica 2012;97(7):1020-1028. doi:10.3324/haematol.2011 ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Human acute myeloid leukemia CD34+CD38- stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells

Cited by 26 publications

References 25 publications

Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Natural killer cell immune escape in acute myeloid leukemia

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model

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