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Phase I Trial of “bi-shRNAifurin/GMCSF DNA/Autologous Tumor Cell” Vaccine (FANG) in Advanced Cancer

2011; Elsevier BV; Volume: 20; Issue: 3 Linguagem: Inglês

10.1038/mt.2011.269

1525-0024

Neil Senzer, Minal Barve, Joseph A. Kuhn, Anton Melnyk, Peter D. Beitsch, Martin L. Lazar, Samuel Lifshitz, Mitchell J. Magee, Jonathan Oh, Susan W Mill, Cynthia Bedell, Candice Higgs, Padmasini Kumar, Yang Yu, Fabienne Norvell, Connor Phalon, Nicolas Taquet, Donald D. Rao, Zhaohui Wang, Chris Jay, Beena O. Pappen, Gladice Wallraven, F. Charles Brunicardi, David Shanahan, Phillip B. Maples, John Nemunaitis,

Virus-based gene therapy research

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.