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

Abstract

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 × 107 or 2.5 × 107 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/106 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.

DOI: 10.1038/mt.2011.269
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@article{Senzer2012PhaseIT, title={Phase I Trial of "bi-shRNAifurin/GMCSF DNA/Autologous Tumor Cell" Vaccine (FANG) in Advanced Cancer.}, author={Neil N. Senzer and Minal Barve and Joseph A. Kuhn and Anton M Melnyk and Peter D. Beitsch and Martin Lazar and Samuel Lifshitz and M. J. Magee and Jonathan Oh and Susan W Mill and Cynthia Bedell and Candice Higgs and Padmasini Kumar and Yang Yu and Fabienne Norvell and Connor Phalon and Nicolas Taquet and Donald D. Rao and Zhaohui Wang and Chris Jay and Beena O Pappen and Gladice Wallraven and Francis Charles Brunicardi and David M Shanahan and Phillip B. Maples and John Nemunaitis}, journal={Molecular therapy : the journal of the American Society of Gene Therapy}, year={2012}, volume={20 3}, pages={679-686} }