Harnessing natural killer cells for the treatment of ovarian cancer

Contains fulltext : 220786.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Adoptive cellular immunotherapy could be an interesting new treatment option for ovarian carcinoma (OC), as research has demonstrated that OC is an immunogenic disease. In particular, natural killer (NK) cells have attracted attention due to their ability to kill tumor cells without prior sensitization. The therapeutic value of allogeneic NK cells has been first observed in hematological cancers and is increasingly being explored in solid tumors. METHODS: To substantiate the rationale for NK cell therapy in OC we performed a literature search in the Pubmed database and in the international trial register clinicaltrials.gov with attention for the effect of OC on NK cell function, the effect of current treatment on NK cell biology and the evidence on the therapeutic value of NK cell therapy against OC. RESULTS: In six clinical trials only 31 OC patients have been reported that received NK cell adoptive transfer. The majority of patients reached stable disease after NK cell therapy, with a mild pattern of side effects. In patients who received repeated infusions, more complete responses are described. All reported studies investigated the intravenous infusion of NK cells. Whereas the studies that are currently recruiting, investigate intraperitoneal infusion of allogeneic NK cells. CONCLUSION: In this review the pre-clinical evidence and current trials on NK cell immunotherapy in OC patients are summarized. Furthermore, challenges that have to be overcome for NK cell adoptive therapy to have a significant impact on disease outcome are discussed.01 juni 202

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

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