Nimotuzumab Induces NK Cell Activation, Cytotoxicity, Dendritic Cell Maturation and Expansion of EGFR-Specific T Cells in Head and Neck Cancer Patients.

Survival benefit and long-term duration of clinical response have been seen using the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody (mAb) nimotuzumab. Blocking EGFR signaling may not be the only mechanism of action underlying its efficacy. As an IgG1 isotype mAb, nimotuzumab's capacity of killing tumor cells by antibody dependent cellular cytotoxicity (ADCC) and to induce an immune response in cancer patients have not been studied. ADCC-induced by nimotuzumab was determined using a 51Cr release assay. The in vitro effect of nimotuzumab on natural killer (NK) cell activation and dendritic cell (DC) maturation and the in vivo frequency of circulating regulatory T cells (Tregs) and NK cells were assessed by flow cytometry. Cytokine levels in supernatants were determined by ELISA. ELISpot was carried out to quantify EGFR-specific T cells in nimotuzumab-treated head and neck cancer (HNSCC) patients. Nimotuzumab was able to kill EGFR+ tumor cells by NK cell-mediated ADCC. Nimotuzumab-activated NK cells promoted DC maturation and EGFR-specific CD8+ T cell priming. Interestingly, nimotuzumab led to upregulation of some immune checkpoint molecules on NK cells (TIM-3) and DC (PD-L1), to a lower extent than another EGFR mAb, cetuximab. Furthermore, circulating EGFR-specific T cells were identified in nimotuzumab-treated HNSCC patients. Notably, nimotuzumab combined with cisplatin-based chemotherapy and radiation increased the frequency of peripheral CD4+CD39+FOXP3+Tregs which otherwise were decreased to baseline values when nimotuzumab was used as monotherapy. The frequency of circulating NK cells remained constant during treatment. Nimotuzumab-induced, NK cell-mediated DC priming led to induction of anti-EGFR specific T cells in HNSCC patients. The association between EGFR-specific T cells and patient clinical benefit with nimotuzumab treatment should be investigated.

The ability of orthodontists and laypeople to discriminate mandibular stepwise advancements in a Class II retrognathic mandible.

OBJECTIVES: This study analysed the ability of orthodontists and laypeople to discriminate mandibular stepwise advancements. MATERIALS AND METHODS: Four pictures (in duplicate) were taken of a male patient with Class II malocclusion and mandibular deficiency with the mandible positioned in habitual maximum intercuspation (HMI) and with stepwise advancements of 2mm, 4mm and 6mm. These images were examined by orthodontists (n=30) and laypeople (n=30). The Wilcoxon signed-rank test was used to evaluate intra-examiner agreement. Intra-examiner ability to discriminate stepwise mandibular advancements was examined by Friedman's test. A Mann-Whitney's test was carried out to analyse score difference between orthodontists and laypeople. Type I error (alpha) was set as 5% for all statistical tests. RESULTS: We observed a satisfactory to excellent level of methodological reliability. While laypeople were able to notice mandibular advancements ≥4 mm (p<0.05), orthodontists were able to observe mandibular advancements ≥2 mm (p<0.05). The orthodontists were more critical than laypeople with regard to the facial profile evaluation when facial convexity increased (p<0.001), but no significant difference was observed when the sagittal maxillo-mandibular relationship approached normality (p<0.05). CONCLUSIONS: Considering that the mean sagittal mandibular growth due to the use of functional orthopaedic appliances is reported in the literature as 2mm, it seems that laypeople may not able to discriminate this amount of change in facial-profile attractiveness.