GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin. METHODS: Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS). RESULTS: A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively. DISCUSSION: Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C.

OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients.

UNLABELLED: Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-γ) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factor-apoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log(10) first-phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log(10) first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-α responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second-phase virological response. CONCLUSION: These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy.

Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C.

BACKGROUND & AIMS: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. METHODS: Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response. RESULTS: Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16+NK cells (P<.05) and a trend toward increased production of tumor necrosis factor-related apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks. CONCLUSIONS: IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-α-based treatment and suggests the involvement of the innate immune cells in viral clearance.

Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection display great variability in disease activity and progression. Although virus-specific adaptive immune responses have been characterized extensively and found to be impaired in chronic hepatitis C, the role of innate immune responses in disease activity and progression of chronic hepatitis C is not well understood. METHODS: We studied 42 HCV-infected patients and 12 healthy uninfected controls. RESULTS: We found an increased frequency of natural killer (NK) cells expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), NKp44, NKG2C, and CD122 in chronic hepatitis C as compared with healthy controls (P < .05 for all markers) and stronger activation of NK cells in the liver than in the blood (P < .05). This NK cell phenotype was associated with polarization of NK cell function toward CD107a expression as a marker of degranulation, but with not increased interferon (IFN)-gamma production of CD56(dim) NK cells. The polarized NK cell phenotype correlated with alanine aminotransferase levels (r(2) = 0.312, P = .03). To investigate whether in vivo exposure of NK cells to HCV-induced type I IFN was causing this NK cell phenotype, peripheral blood mononuclear cells from 10 healthy controls and 8 HCV-infected patients were stimulated in the presence of IFN-alfa, which resulted in increased NK cell expression of TRAIL and CD107a (P < .001), but not IFN-gamma. CONCLUSIONS: Collectively, these results describe a polarized NK cell phenotype induced by chronic exposure to HCV-induced IFN-alfa. This phenotype may contribute to liver injury through TRAIL expression and cytotoxicity, whereas the lacking increase in IFN-gamma production may facilitate the inability to clear HCV.

Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine - a Phase I trial.

MICRO-ABSTRACT: In a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage. INTRODUCTION: We present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability. RESULTS: Twenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect. CONCLUSION: Daily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.

Vinflunine in the Treatment of Upper Tract Urothelial Carcinoma - Subgroup Analysis of an Observational Study.

BACKGROUND/AIM: Despite an expected prognostic disadvantage for upper tract versus lower tract metastatic urothelial carcinomas (UTUC/LTUC), only few studies have been conducted to elucidate potential differences in chemotherapy treatment. PATIENTS AND METHODS: A post-hoc subgroup analysis of a non-interventional study investigating vinflunine after failure of a platinum-based chemotherapy in metastatic/locally advanced UC patients was performed. RESULTS: A total of 18 and 59 out of 77 patients had UTUC and LTUC, respectively. The effectiveness of vinflunine treatment was comparable with an overall response rate of 22.2% and 23.7% respectively and a median progression-free survival of 2.76 months in both groups. Median overall survival was 5.0 months in UTUC compared to 8.2 months in the LTUC group (p=0.478). The safety profile was in accordance with previous vinflunine experiences, with a comparable frequency of adverse events in both groups. CONCLUSION: Vinflunine can be applied in the 2nd line for UC regardless of the primary tumor localization.

Dendritic cells transfected with Her2 antigen-encoding RNA replicons cross-prime CD8 T cells and protect mice against tumor challenge.

Antigen-specific T cells can be induced by direct priming and cross-priming. To investigate cross-priming as a vaccination approach dendritic cells were transfected with cytopathogenic viral RNA-replicons that expressed domains of the tumor-associated Her2-antigen and injected into MHC-discordant mice that did not allow direct priming. Upon tumor challenge 75% of the vaccinated, but none of the mock-vaccinated mice remained tumor-free. The anti-tumor effect required T cells and correlated with the vigor of the cross-primed CD8 T cell response. Her2-specific antibodies were not detected. This study highlights the potential of T cell cross-priming in cancer immunotherapy.