Purpose Alternative strategies to EGFR blockage by mAbs is necessary in order to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status. Experimental Design NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN-γ release, and T cell chemotaxis towards human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer. Results NK cell lysis of cetuximab-coated wild-type and mutant KRAS pancreatic cancer cell lines was significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21 treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine. Conclusions These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy.

Purpose: mAbs including cetuximab can induce antibodydependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell-mediated ADCC and production of cytokines. Patients and Methods: This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m 2 i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcgRIIIa polymorphisms, and an analysis of myeloidderived suppressor cell (MDSC) frequency in peripheral blood. Results: The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNg, IP-10, and TNFa at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy. Conclusions: Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.

McMichael et al.: Interleukin-21 activates natural killer cell activity against cetuximab-coated pancreatic tumor cells.

To determine the efficacy of mandatory preoperative nicotine cessation on postoperative nicotine use, and to identify independent predictors of nicotine use relapse in subjects undergoing hip preservation surgery or total hip arthroplasty by a single fellowship-trained orthopedic surgeon. MethodsConsecutive subjects that underwent hip surgery from November 2014 to December 2017 were reviewed. Subjects who self-reported nicotine use, quit prior to surgery, and completed a minimum one-year follow-up were included. Multiple linear regression models were constructed to determine the effect of independent variables on nicotine use relapse following surgery. ResultsSixty subjects were included in the study (mean follow-up 35.1 months (17-57 months), mean age 44.9 years (20-82 years), and 23 (38.3%) males). Twenty-eight subjects (46.7%) remained nicotine-free at final followup. The mean number of cigarettes per day decreased from 13.4 preoperatively to 8.4 postoperatively in the subjects who relapsed (P=0.002). The mean time to return to nicotine postoperatively was 2.4 months. The number of preoperative cigarettes per day was the only independent predictor of tobacco use relapse (P=0.005). ConclusionMandatory preoperative nicotine cessation prior to elective hip surgery demonstrates a 46.7% nicotine-free survivorship at final follow-up with the number of preoperative cigarettes per day found to be the only independent predictor of nicotine use relapse. Level of evidenceThe level of evidence of this research study is Level III since it is a non-experimental study with a cohort of patients.

<div>Abstract<p><b>Purpose:</b> Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of <i>KRAS</i> mutation status.</p><p><b>Experimental Design:</b> NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN-γ release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The <i>in vivo</i> efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer.</p><p><b>Results:</b> NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21–treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine.</p><p><b>Conclusions:</b> These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of <i>KRAS</i> mutation status, and may be a potential therapeutic strategy. <i>Clin Cancer Res; 23(2); 489–502. ©2016 AACR</i>.</p></div>