BackgroundTumor-associated immune cells are prognostic in non-small cell lung cancer (NSCLC) but findings have been conflicting.ObjectivesTo determine the prognostic role of immune cells according to localization in NSCLC patients.MethodsA systematic literature review and meta-analysis was performed on dendritic cell (DC), tumor associated macrophages (TAM), mast cells (MC), natural killer (NK) cells, T and B cells and tumor CTLA-4 and PD-L1 studies.ResultsWe analysed 96 articles (n= 21,752 patients). Improved outcomes were seen with increased tumor DCs (overall survival (OS) hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.44–0.68), NK cells (OS HR 0.45; 0.31–0.65), TAMs (OS HR 0.33; 0.17–0.62), M1 TAMs (OS HR 0.10; 0.05–0.21), CD3+ T cells (disease specific survival (DSS) HR 0.64; 0.48–0.86), CD8+ T cells (OS HR 0.78; 0.66–0.93), B cells (OS HR 0.65; 0.42–0.99) and with increased stroma DC (DSS HR 0.62; 0.47–0.83), NK cells (DSS HR 0.51; 0.32–0.82), M1 TAMs (OS HR 0.63; 0.42–0.94), CD4+ T cells (OS HR 0.45; 0.21–0.94), CD8+ T cells (OS HR 0.77; 0.69–0.86) and B cells (OS HR 0.74;0.56–0.99). Poor outcomes were seen with stromal M2 TAMs (OS HR 1.44; 1.06–1.96) and Tregs (relapse free survival (RFS) HR 1.80; 1.34–2.43). Tumor PD-L1 was associated with worse OS (1.40; 1.20–1.69), RFS (1.67) and DFS (1.24).ConclusionTumor and stroma DC, NK cells, M1 TAMs, CD8+ T cells and B cells were associated with improved prognosis and tumor PD-L1, stromal M2 TAMs and Treg cells had poorer prognosis. Higher quality studies are required for confirmation.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.Patients and Methods: In a phase I trial, patients with treatmentrefractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.Results: In 60 cultures with cells from 31 subjects, median NKcell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n ¼ 9) included multiple cycles of NK cells (1 Â 10 7 /kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 Â 10 7 /kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.