Journal
MOLECULAR THERAPY
Volume 20, Issue 3, Pages 679-686Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2011.269
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Funding
- Jasper L. and Jack Denton Wilson Foundation
- Summerfield G. Roberts Foundation
- Crowley-Carter Foundation
- Crowley Shanahan Foundation
- Linda Tallen and David Paul Kane Cancer Educational and Research Foundation
- Marilyn Augur Family Foundation
- Gradalis, Inc.
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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(7) or 2.5 x 10(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 >= 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 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. Received 15 September 2011; accepted 7 November 2011; published online 20 December 2011. doi:10.1038/mt.2011.269
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