The Promises of Natural Killer Cell Therapy in Endometriosis

Endometriosis is a gynaecological disease defined by the growth of endometrium-like tissue outside the uterus. The disease is present in approximately 5-10% of women of reproductive age and causes pelvic pain and infertility. The pathophysiology is not completely understood, but retrograde menstruation and deficiency in natural killer (NK) cells that clear endometriotic cells in the peritoneal cavity play an important role. Nowadays, hormonal therapy and surgery to remove endometriosis lesions are used as treatment. However, these therapies do not work for all patients, and hormonal therapy prevents patients from getting pregnant. Therefore, new treatment strategies should be developed. Since the cytotoxicity of NK cells is decreased in endometriosis, we performed a literature search into the possibility of NK cell therapy. Available treatment options include the inhibition of receptor-ligand interaction for KIR2DL1, NKG2A, LILRB1/2, and PD-1/PD-L1; inhibition of TGF-β; stimulation of NK cells with IL-2; and mycobacterial treatment with BCG. In preclinical work, these therapies show promising results but unfortunately have side effects, which have not specifically been studied in endometriosis patients. Before NK cell treatment can be used in the clinic, more research is needed

The correlation between clinical and urodynamic diagnosis in classifying the type of urinary incontinence in women. A systematic review of the literature

Article first published online: 4 FEB 2011Abstract not availableSanne A.L. van Leijsen, Janneke S. Hoogstad-van Evert, Ben Willem J. Mol, Mark E. Vierhout, Alfred L. Milani, John P.F.A. Heesakkers and Kirsten B. Kluiver

The Correlation Between Clinical and Urodynamic Diagnosis in Classifying the Type of Urinary Incontinence in Women. A Systematic Review of the Literature

Aims: To determine the reclassification rate of clinically diagnosed stress, mixed, and urge urinary incontinence after urodynamic investigation. Methods: A systematic review of the published literature in MEDLINE and EMBASE of clinical trials among women with urinary incontinence. Studies were included in case the diagnosis based on symptoms and/or signs was compared with the diagnosis after urodynamic investigation. Results: Twenty-three articles involving 6,282 women with urinary incontinence met the inclusion criteria. A clinical diagnosis of stress urinary incontinence was reclassified into mixed urinary incontinence in 9% of women and into detrusor overactivity (DO) in 7% of cases. The pooled reclassification rate was highest among patients with symptoms of mixed urinary incontinence, where 46% of the patients had stress urinary incontinence and 21% had DO on urodynamic investigation. The available literature does not allow the identification of the additional value of non-invasive test, such as stress test and voiding diary, accessory to symptoms. None of the studies had therapeutic effects as an outcome measure. Conclusions: This review of clinical studies shows that the level of agreement between classification based on clinical evaluation and based on urodynamic investigation is poor. Urodynamic observations are regarded as gold standard, but based on the poor correlation, this assumption should be questioned. Neurourol. Urodynam. 30: 495-502, 2011. (C) 2011 Wiley-Liss, In

TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer

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CD34(+) progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rg(null) mice

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Decitabine enhances targeting of AML cells by CD34(+) progenitor-derived NK cells in NOD/SCID/IL2Rg(null) mice

Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34(+) hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rg(null) mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML