NovaRx (United States)

8056 Background: Belagenpumatucel-L (Lucanix) is a therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified, irradiated, allogeneic NSCLC cell lines. Methods: The trial enrolled patients (...

Abstract This study examines the correlative/predictive value of cellular- and humoral-mediated immune response on the clinical responsiveness of patients who received belagenpumatucel-L, a therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified allogeneic non-small cell lung cancer (NSCLC) cell lines in a phase II clinical trial in which subjects with stage III/IV NSCLC received intradermal injections of the vaccine every 4-8 weeks. We performed assays of cellular (ELISPOT) and humoral (antibody ELISA) immunity on 36 subjects in the trial and correlated these data with the long term assessment of overall survival. All but one subject in the study showed an increase in immune reactivity in at least one of the cellular or humoral assays. Eleven subjects who demonstrated an aggregate increase in both cellular and humoral immune reactivity (positive by three of four criteria tested) had a median survival of 32.5 months (95% CI, 25.2 to 39.8). This was significantly better than the median survival of only 11.6 months (95% CI, 5.6 to 17.6) for the 25 subjects who showed an increase in one or none of the measured immune parameters (p=0.015, log-rank test). The demonstration of a statistically significant correlation between cellular and humoral immune responses and overall survival in subjects treated with belagenpumatucel-L suggest that both compartments of the immune system likely impact the clinical response and are important for the induction of clinically significant antitumor immunity by the vaccine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5364. doi:1538-7445.AM2012-5364

Choline acetyltransferase (ChAT) synthesizes acetylcholine in neurons and other cell types. Decreases in ChAT activity are associated with a number of disease states, and mutations in ChAT cause congenital neuromuscular disorders. The crystal structure of ChAT reported here shows the enzyme divided into two domains with the active site in a solvent accessible tunnel at the domain interface. A low-resolution view of the complex with one substrate, coenzyme A, defines its binding site and suggests an additional interaction not found in the related carnitine acetyltransferase. Also, the preference for choline over carnitine as an acetyl acceptor is seen to result from both electrostatic and steric blocks to carnitine binding at the active site. While half of the mutations that cause motor disorders are positioned to affect enzyme activity directly, the remaining changes are surprisingly distant from the active site and must exert indirect effects. The structure indicates how ChAT is regulated by phosphorylation and reveals an unusual pattern of basic surface patches that may mediate membrane association or macromolecular interactions.