title: Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.
abstract: A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.
authors: Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: W K
authors: WK
authors: Kang
authors: C
authors: C
authors: Park
authors: H L
authors: HL
authors: Yoon
authors: W S
authors: WS
authors: Kim
authors: S S
authors: SS
authors: Yoon
authors: M H
authors: MH
authors: Lee
authors: K
authors: K
authors: Park
authors: K
authors: K
authors: Kim
authors: H S
authors: HS
authors: Jeong
authors: J A
authors: JA
authors: Kim
authors: S J
authors: SJ
authors: Nam
authors: J H
authors: JH
authors: Yang
authors: Y I
authors: YI
authors: Son
authors: C H
authors: CH
authors: Baek
authors: J
authors: J
authors: Han
authors: H J
authors: HJ
authors: Ree
authors: E S
authors: ES
authors: Lee
authors: S H
authors: SH
authors: Kim
authors: D W
authors: DW
authors: Kim
authors: Y C
authors: YC
authors: Ahn
authors: S J
authors: SJ
authors: Huh
authors: Y H
authors: YH
authors: Choe
authors: J H
authors: JH
authors: Lee
authors: M H
authors: MH
authors: Park
authors: G S
authors: GS
authors: Kong
authors: E Y
authors: EY
authors: Park
authors: Y K
authors: YK
authors: Kang
authors: Y J
authors: YJ
authors: Bang
authors: N S
authors: NS
authors: Paik
authors: S N
authors: SN
authors: Lee
authors: S H
authors: SH
authors: Kim
authors: S
authors: S
authors: Kim
authors: P D
authors: PD
authors: Robbins
authors: H
authors: H
authors: Tahara
authors: M T
authors: MT
authors: Lotze
authors: C H
authors: CH
authors: Park
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D012190:Retroviridae / Q000235:genetics*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12