Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer

• Published in: Molecular therapy Vol. 20; no. 3; p. 679
• Main Authors: Senzer, Neil, Barve, Minal, Kuhn, Joseph, Melnyk, Anton, Beitsch, Peter, Lazar, Martin, Lifshitz, Samuel, Magee, Mitchell, Oh, Jonathan, Mill, Susan W, Bedell, Cynthia, Higgs, Candice, Kumar, Padmasini, Yu, Yang, Norvell, Fabienne, Phalon, Connor, Taquet, Nicolas, Rao, Donald D, Wang, Zhaohui, Jay, Chris M, Pappen, Beena O, Wallraven, Gladice, Brunicardi, F Charles, Shanahan, David M, Maples, Phillip B, Nemunaitis, John
• Format: Journal Article
• Language: English
• Published: United States 01-03-2012
• Subjects: Adult; Aged; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - therapeutic use; Female; Furin - genetics; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Humans; Interferon-gamma - biosynthesis; Leukocytes, Mononuclear - immunology; Male; Middle Aged; Neoplasm Staging; Neoplasms - immunology; Neoplasms - mortality; Neoplasms - pathology; Neoplasms - therapy; RNA, Small Interfering - therapeutic use; Survival Analysis; Transgenes; Treatment Outcome
• ISSN: 1525-0024
• DOI: 10.1038/mt.2011.269

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.