Phase I Trial of "bi-shRNAi super(furin)/GMCSF DNA/ Autologous Tumor Cell" Vaccine (FANG) in Advanced Cancer

• Published in: Molecular therapy Vol. 20; no. 3; pp. 679 - 686
• Main Authors: Senzer, Neil, Barve, Minal, Kuhn, Joseph, Melnyk, Anton, Beitsch, Peter, Lazar, Martin, Lifshitz, Samuel, Magee, Mitchell, Oh, Jonathan, Mill, Susan W
• Format: Journal Article
• Language: English
• Published: 01-03-2012
• ISSN: 1525-0016; 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) beta 1 and beta 2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 x 10 super(7) or 2.5 x 10 super(7) cells/ml injection). GMCSF, TGF beta 1, TGF beta 2, 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 > or =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 super(6) cells/ml. Mean TGF beta 1 and beta 2 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.