Intratumoral delivery of adenovirus-mediated interleukin-12 gene in mice with metastatic cancer in the liver.
Clinical trials of recombinant human interleukin-12 (rhIL-12) delivered by intravenous administration have shown dose-limiting toxicities with limited tumor responses at the doses tested. We have previously reported that intratumoral injection of an adenovirus vector expressing murine interleukin-12 (Adv.RSV-mIL-12) was effective in inducing antitumor immune responses, tumor regression, and long-term survival in mice with established metastatic cancer in the liver. We now report additional studies in the same murine tumor model to assess the safety of intratumoral Adv.RSV-mIL-12 injection. At vector doses that were previously shown to be therapeutically effective, no inflammation in the liver or lungs, and no significant elevations in serum creatinine and aminotransferases were seen after vector injection. Serum elevations of IL-12 and interferon-gamma (IFN-gamma) were 17- and 19-fold lower than peak levels after intravenous recombinant IL-12 at the maximal tolerated dose in clinical trials. No elevations in serum proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) were noted up to 2 weeks after vector injection. No systemic dissemination of the vector was detected on polymerase chain reaction (PCR) assays at therapeutically effective vector doses. At higher supratherapeutic vector doses of Adv.RSV-mIL-12, however, inflammation in the liver and lungs with elevation in serum aminotransferases were seen, but not in controls injected with the equivalent particle number of an empty adenoviral vector. These results support the cautious testing in patients with hepatic metastases of adenovirus mediated IL-12 gene delivery by intratumoral injection.
Sung
Max W
MW
Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 13-20, New York, NY 10029, USA.
Chen
Shu-Hsia
SH
Thung
Swan N
SN
Zhang
David Y
DY
Huang
Tian-Gui
TG
Mandeli
John P
JP
Woo
Savio L C
SL
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D003404:Creatinine / Q000097:blood; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin