Purpose: Clinical responses with programmed death (PD-1) receptor directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18 are attractive targets for therapeutic immunization, and offer an immune activation strategy that may be complementary to PD-1 inhibition. Experimental Design: We report Phase Ib/II safety, tolerability and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL-12 encoding plasmids) delivered by electroporation with CELLECTRA® constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions but no treatment related grade 3–5 adverse events (AEs). Eighteen of 21 evaluable patients showed elevated antigen specific T cell activity by IFNγ ELISpot and persistent cellular responses surpassing 100 SFU/106 PBMC were noted out to one year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4/5 post-immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all five patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow cytometric analyses revealed induction of HPV16 specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non^small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m 2 every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre-and post-celecoxib levels of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E 2 (PGE 2 ). We enrolled 56 patients (35 men, 21women; median age, 61years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001).When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE 2 synthesis in NSCLC seems warranted.Cyclooxygenase-2 (COX-2), a cyclic endoperoxidase that catalyzes the rate-limiting step in prostaglandin (PG) synthesis, is frequently overexpressed in human premalignant pulmonary lesions such as atypical adenomatous hyperplasia and carcinoma in situ, as well as in invasive carcinomas (1 -4). Preclinical and clinical data indicate that tumors with up-regulation of COX-2 synthesize high levels of prostaglandin E 2 (PGE 2 ; refs. 5 -11). In turn, high PGE 2 levels are associated with increased production of proangiogenic factors, altered immune responses, and enhanced metastatic potential (12 -16). These findings suggest that increased COX-2 expression may play a significant role in the development and growth of malignancies, such as nonsmall cell lung cancers (NSCLC), and possibly in the acquisition of an invasive and metastatic phenotype (17, 18). Thus, selective inhibition of COX-2 could prove useful both in understanding the role of eicosanoids in lung cancer pathogenesis as well as in the management of established malignancies (19,20).Docetaxel is modestly beneficial in the treatment of recurrent NSCLC (21). Notably, recent preclinical data indicate that the cytotoxic effect of docetaxel is enhanced in the presence of a selective COX-2 inhibitor (22). Based on these find...
A number of cell death pathways have been recognized.
Purpose: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials. Experimental Design: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition. Results: Seventeen patients with stage IIIA or IIIB non^small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E 2 , after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival. Conclusion: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.Lung cancer is the most prevalent cancer in the United States and the leading cause of cancer-related mortality, killing more patients than the next three deadliest malignancies (colorectal, breast, and prostate) combined (1). Approximately one third of non -small cell lung cancer (NSCLC) cases will present with locally advanced disease with mediastinum involvement either by metastatic lymph nodes or by primary (2). Because these patients are not good candidates for surgical resection, definitive treatment combining platinum-based chemotherapy and radiotherapy is considered the standard of care (3).Cyclooxygenase (COX) is a key enzyme in arachidonic acid conversion to prostaglandins and other eicosanoids. There are two isoforms of COX known as COX-1 and COX-2. Unlike constitutively expressed COX-1, COX-2 is inducible and upregulated by a variety of factors, which include cytokines, growth factors, and tumor promoters (4). COX-2 is overexpressed by various human cancers, including lung. Furthermore, a growing body of evidence suggests that up-regulation of COX-2 and its product, prostaglandin E 2 (PGE 2 ), is important in the growth of lung cancer (5, 6). COX-2 and its derived prostaglandins play a role in stimulating angiogenesis and apoptosis inhibition and in suppressing the immune response (7). COX-2 overexpression may also enhance the metastatic...
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