Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release.

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS-CoV-2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS-CoV-2 and highlight the multiple distinct mechanisms by which SARS-CoV-2 subverts tetherin function.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410.

BACKGROUND: The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy. METHODS: A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar. CONCLUSION: Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.

PURPOSE: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P

A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy.

BACKGROUND: Irinotecan (1) and cisplatin (P) are active chemotherapy agents with clinical synergy in non-small-cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum-containing regimen(s). METHODS: Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0-2, and progressive disease after nonplatinum-based chemotherapy. Treatment consisted of I (65 mg/m2) and P (30 mg/m2) i.v. on Days 1 and 8 of a 21-day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients. RESULTS: Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42-74) were enrolled. Twenty-four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty-five patients had adenocarcinoma and 6 had squamous-cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow-up of 18.5 months, the median survival time was found to be 9.3 months, with a 1-year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity. CONCLUSIONS: The irinotecan and cisplatin combination is an active and well-tolerated regimen for the patients with advanced NSCLC that progressed after nonplatinum-containing regimen(s).

Phase I evaluation of docetaxel and topotecan for patients with advanced solid tumors.

BACKGROUND: The authors administered a combination of docetaxel and topotecan with granulocyte-colony-stimulating factor (G-CSF) support in a Phase I study to define the maximum tolerated dose (MTD) of this regimen. METHODS: Patients with advanced-stage solid tumors were eligible for this trial if they had a Zubrod performance status of /= 244 weeks, respectively. At the time of last follow-up, both patients with nasopharyngeal carcinoma were still alive at 241 weeks and 244 weeks, respectively. CONCLUSIONS: This trial demonstrated that a regimen of docetaxel and topotecan with G-CSF support was generally well tolerated and had promising activity in patients with nasopharyngeal and SCLC.

Initial clinical trial of oral TAC-101, a novel retinoic acid receptor-alpha selective retinoid, in patients with advanced cancer.

PURPOSE: The goals of this study were to determine the safety, toxicity, and pharmacokinetics of TAC-101, a novel synthetic retinoic acid receptor-alpha (RAR-alpha) selective retinoid, in patients with advanced cancer. PATIENTS AND METHODS: Twenty-nine patients at two centers received oral TAC-101 at doses ranging from 12 to 34 mg/m(2)/d. Pharmacokinetic sampling was performed on days 1 and 28. RESULTS: The most frequent toxicities were myalgia/arthralgia, fatigue, and triglyceridemia. No dose-limiting toxicities were observed within the first 28 days up to 28 mg/m(2). However, seven of 21 patients experienced venous thromboembolic events (VTEs) during TAC-101 treatment. Eight additional patients who received 34 mg/m(2) were treated after a hypercoagulable work-up to exclude potential risk factors for VTE, and two of eight patients subsequently experienced VTEs. The maximum tolerated dose was exceeded at 34 mg/m(2)/d within the first 28 days, with one grade 3 hypertriglyceridemia, two grade 3 myalgia/arthralgia, and one grade 3 fatigue. One patient with advanced non-small-cell lung cancer had a complete response. No other responses were observed. No autoinduction of metabolism was observed with dosing over 28 days. CONCLUSION: This is the first human clinical study with TAC-101, a RAR-alpha selective retinoid. Musculoskeletal toxicity and hypertriglyceridemia were observed characteristics of previously studied retinoids. The recommended phase II dose is 24 mg/m(2) with this treatment schedule. Alternative treatment schedules and prospective evaluation of thrombotic risk will be investigated in subsequent studies.

Twice daily irradiation increases locoregional control in patients with medically inoperable or surgically unresectable stage II-IIIB non-small-cell lung cancer.

PURPOSE: To evaluate the effect of q.d. or b.i.d. radiotherapy (RT) on the outcome of patients with locally advanced non-small-cell lung cancer. METHODS AND MATERIALS: We retrospectively reviewed the outcome of 261 patients with medically inoperable or surgically unresectable Stage II-IIIB non-small-cell lung cancer, who were treated with combined modality cisplatin-based chemotherapy and RT. Chemotherapy was administered either sequentially or concurrently with thoracic RT. The median follow-up was 18 months (range 2-92). Treatment groups included sequential chemotherapy and q.d. RT (n = 109), concurrent chemotherapy and q.d. RT (n = 48), and concurrent chemotherapy and b.i.d. RT (n = 104). Of the 261 patients, 97% had a Karnofsky performance score > or =80, and 86.2% had < or =5% weight loss in the 3 months before diagnosis; 66.7% had nonsquamous cell histologic features. All but 8 patients had Stage IIIA-B disease. RESULTS: The 2- and 5-year locoregional control rate was 42.4% and 25.7% for the q.d. group and 70.6% and 45.8% for the b.i.d. group, respectively (p = 0.0001). The 2- and 5-year disease-free survival rate was 26.7% and 6.5% for the q.d. group and 39.6% and 27.3% for the b.i.d. group, respectively (p = 0.0114). The corresponding overall survival rates were 35.9% and 9.4% for the q.d. group and 38.7% and 26.1% for the b.i.d. group. No difference was found in the rate of distant metastasis between the 2 groups. Multivariate analysis indicated that b.i.d. RT was a favorable prognostic factor for locoregional control and disease-free survival. CONCLUSION: RT b.i.d. significantly improved locoregional control and disease-free survival compared with RT q.d. in patients with Stage IIIA-B non-small-cell lung cancer.

Impact of institutional experience on survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small-cell lung cancer.

PURPOSE: Clinical experience of both physicians and institutions has been shown to significantly influence the outcome of patients. We conducted this retrospective cohort study to examine its impact on the outcome of patients undergoing combined chemoradiation therapy for the treatment of locally advanced inoperable non-small-cell lung cancer. METHODS AND MATERIALS: We compared the clinical data from 239 patients who were enrolled in two consecutive Radiation Therapy Oncology Group (RTOG) trials (RTOG 91-06, RTOG 92-04) according to the number of patients enrolled from each institution in either trial alone or the two trials combined. RESULTS: Overall, patients treated at the institutions that enrolled > or = 5 patients survived longer than those treated at the institutions that enrolled <5 patients (median survival 20.5 vs. 13.4 months, p = 0.0006) with a more than doubling of the 2- and 3-year survival rates (45% and 31% vs. 20% and 13%, respectively). Multivariate analyses confirmed that the number of patients enrolled from each institution was an important prognostic factor for the entire group (p = 0.001) and also for RTOG 91-06 (p = 0.05) and RTOG 92-04 (p = 0.004) when the data were analyzed separately. CONCLUSION: Institutional experience has a significant impact on the survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small cell lung cancer.

Expression of cyclooxygenase-1 and cyclooxygenase-2 in bronchial epithelium and nonsmall cell lung carcinoma.

BACKGROUND: Cyclooxygenase (Cox) is the main target enzyme for the nonsteroidal antiinflammatory drugs that have been shown to suppress carcinogenesis in both experimental models and epidemiologic studies. METHODS: To evaluate its utility as an intermediate biomarker in bronchial chemoprevention trials, the authors examined Cox 1 and Cox 2 expression in normal and premalignant bronchial epithelial cells and nonsmall cell lung carcinoma (NSCLC) samples using an immunohistochemical staining technique. Included in the current study were 101 NSCLC samples and 77 bronchial biopsy samples obtained from 15 healthy smokers. RESULTS: In the normal bronchial epithelium, Cox 2 expression was found to be completely negative whereas Cox 1 expression was noted in a few scattered cells. The areas of basal cell hyperplasia and squamous metaplasia demonstrated the same pattern. There were relatively more Cox 2-positive tumors, as defined by positive staining in > 10% of tumor cells, than Cox 1-positive tumors (30 of 101 tumors [30%] vs. 14 of 101 tumors [14%]; P = 0.01). When tumor types were considered, there were more Cox 2-positive adenocarcinomas compared with squamous cell carcinomas (21 of 51 adenocarcinomas [41%] vs. 9 of 46 squamous cell carcinomas [20%]; P = 0.03). In contrast, fewer adenocarcinomas tended to show Cox 1 expression compared with squamous cell carcinomas (4 of 51 adenocarcinomas [8%] vs. 9 of 46 squamous cell carcinomas [20%]; P = 0.14). Although smokers tended to have more Cox 2-positive tumors than nonsmokers (29 of 91 tumors in the smokers [32%] vs. 1 of 10 tumors in the nonsmokers [10%]; P = 0.15), there was no statistically significant relation found between Cox 1 or Cox 2 expression and smoking status or prognostically significant clinicopathologic features. CONCLUSIONS: The results of the current study suggest that Cox 1 and Cox 2 expression may not be a useful intermediate biomarker in bronchial chemoprevention trials. Nevertheless, considering the patterns of Cox 1 and Cox 2 expression in tumor cells, Cox expression status may be a useful parameter when designing treatment strategies for a subset of NSCLC patients.