No abstract

On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n ¼ 495) or lapatinib in combination with capecitabine (n ¼ 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55-0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55-0.85), P ¼ 0.0006]. The most common adverse reactions in patients receiving adotrastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit-risk profile was considered favorable. Clin Cancer Res; 20(17); 4436-41. Ó2014 AACR.

Wild-type human respiratory syncytial virus (HRSV) is a poor inducer of alpha/beta interferons (IFN-␣/␤).However, recombinant HRSV lacking the NS1 and NS2 genes (⌬NS1/2) induced high levels of IFN-␣ and -␤ in human pulmonary epithelial cells (A549) as well as in macrophages derived from primary human peripheral blood monocytes. Results with NS1 and NS2 single-and double-gene-deletion viruses indicated that the two proteins function independently as well as coordinately to achieve the full inhibitory effect, with NS1 having a greater independent role. The relative contributions of the individual NS proteins were the converse of that recently described for bovine RSV (J. F. Valarcher, J. Furze, S. Wyld, R. Cook, K. K. Conzelmann, and G. Taylor, J. Virol. 77:8426-8439, 2003). This pattern of inhibition by HRSV NS1 and NS2 also extended to the newly described antiviral cytokines IFN-1, -2 and -3.Human respiratory syncytial virus (HRSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide, and a vaccine is needed (9, 10). HRSV belongs to the genus Pneumovirus of the family Paramyxoviridae and has single-stranded, negative-sense RNA as its genome (10). One of the differences between the members of the genus Pneumovirus and other members of Paramyxoviridae is that Pneumovirus species express two putative nonstructural proteins, NS1 and NS2, from separate mRNAs encoded by the first two genes in the viral gene order. Recombinant HRSVs in which the NS1 and/or NS2 genes have been deleted singly or in combination (⌬NS1, ⌬NS2, and ⌬NS1/2 viruses) exhibit reduced replication in cultured cells that are competent to produce alpha interferon (IFN-␣) and IFN-␤, as well as in mice, monkeys, and chimpanzees, but replicate more like wild-type (wt) HRSV in Vero cells that lack the IFN-␣/␤ genes (15, 16, 21-23, 25, 28). Clinical trials of recombinant HRSV (rHRSV) vaccine candidates lacking NS1 or NS2 are under way or in preparation. Bovine RSV (BRSV) is an animal counterpart of HRSV that exhibits a strong host range specificity in vivo and differs from HRSV by up to 71% with regard to the amino acid sequences of the various individual proteins (5). Studies with BRSV provided evidence that its NS1 and NS2 proteins can function independently as well as cooperatively to reduce the effectiveness of the IFN ␣/␤-mediated antiviral state (3,19). How this occurs is unclear, although it does not appear to involve an inhibition of either intracellular signaling or the expression of IFN-stimulated genes (4, 27).In the present study, we describe inhibition of the induction of IFN-␣ and -␤ by the NS1 and NS2 proteins of HRSV. In addition, we investigated the effect of HRSV infection and of deleting NS1 and/or NS2 on the expression of the newly described antiviral cytokines IFN-1, -2 and -3 (alternatively designated interleukin 29 (IL-29), -28A, and -28B, respectively) (17, 20). These cytokines differ genetically and structurally from INF-␣/␤ but share the following characteristics. They appear to be broa...