Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: Outcome of a phase I study

Ki Kang Won Ki Kang, C. Park, Lee Yoon Hyunah Lee Yoon, Seog Kim Won Seog Kim, S. S. Yoon, M. H. Lee, K. Park, K. Kim, Sik Jeong Hyun Sik Jeong, J. A. Kim, S. J. Nam, J. H. Yang, Y. I. Son, C. H. Baek, J. Han, H. J. Ree, Soo Lee Eil Soo Lee, Hee Kim Sun Hee Kim, D. W. Kim, Chan Ahn Yong Chan AhnJae Huh Seung Jae Huh, Hyeon Choe Yeon Hyeon Choe, J. H. Lee, M. H. Park, G. S. Kong, E. Y. Park, Y. K. Kang, Y. J. Bang, N. S. Paik, Nam Lee Soon Nam Lee, S. H. Kim, S. Kim, P. D. Robbins, H. Tahara, M. T. Lotze, C. H. Park

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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 α (TNF-α) 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.

Original languageEnglish (US)
Pages (from-to)671-684
Number of pages14
JournalHuman gene therapy
Volume12
Issue number6
DOIs
StatePublished - Apr 9 2001
Externally publishedYes

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