title: Phase I trial of "bi-shRNAi(furin)/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 × 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.
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas 75201, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: Minal
authors.initials: M
authors.lastname: Barve
authors.forename: Joseph
authors.initials: J
authors.lastname: Kuhn
authors.forename: Anton
authors.initials: A
authors.lastname: Melnyk
authors.forename: Peter
authors.initials: P
authors.lastname: Beitsch
authors.forename: Martin
authors.initials: M
authors.lastname: Lazar
authors.forename: Samuel
authors.initials: S
authors.lastname: Lifshitz
authors.forename: Mitchell
authors.initials: M
authors.lastname: Magee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Oh
authors.forename: Susan W
authors.initials: SW
authors.lastname: Mill
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bedell
authors.forename: Candice
authors.initials: C
authors.lastname: Higgs
authors.forename: Padmasini
authors.initials: P
authors.lastname: Kumar
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Fabienne
authors.initials: F
authors.lastname: Norvell
authors.forename: Connor
authors.initials: C
authors.lastname: Phalon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Taquet
authors.forename: Donald D
authors.initials: DD
authors.lastname: Rao
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.forename: Chris M
authors.initials: CM
authors.lastname: Jay
authors.forename: Beena O
authors.initials: BO
authors.lastname: Pappen
authors.forename: Gladice
authors.initials: G
authors.lastname: Wallraven
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.forename: David M
authors.initials: DM
authors.lastname: Shanahan
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Maples
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D045683:Furin / Q000235:genetics*; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D016019:Survival Analysis; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; C573235:FANG vaccine; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D045683:Furin