Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12.
Generation of antitumor immunity by adenoviral gene transfer of interleukin-12 (IL-12) is a very promising concept in cancer gene therapy. Systemically, IL-12 has provoked toxic side effects at therapeutically relevant doses. Native IL-12 lacks effectiveness in clinical trials even when expressed intratumorally from adenoviral vectors. Our strategy was to increase the therapeutic efficacy of IL-12 by expressing a fusion protein of its two subunits (scIL-12) in an adenoviral vector and to evaluate the effects after intratumoral administration. In a rat model of hepatocellular carcinoma, this vector revealed antitumor effects even at a low dosage of 4.6 x 10(5) i.u. in a dose-dependent manner. Long-term antitumor effects were determined at 2.3 x 10(6) and 2.3 x 10(7) i.u. per animal, resulting in 82% and 90% surviving animals, respectively. Magnetic resonance imaging (MRI) enabled individual tumor size follow-up and revealed the scIL-12 effects on large tumors. Treating one hepatic lesion also led to tumor elimination in a second non-treated hepatic lesion. Animals rechallenged with tumor cells remained tumor-free. Compared to studies applying native IL-12, our data show that the fusion of IL-12 subunits provides approximately 1000-fold higher biological activity. As a consequence of the observed gain in activity, scIL12 promises a substantially improved antitumor efficacy and safety profile of intratumoral adenoviral IL-12 immunotherapy, supporting its clinical use.
Waehler
Reinhard
R
Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246 Hamburg, Germany.
Ittrich
Harald
H
Mueller
Lars
L
Krupski
Gerrit
G
Ameis
Detlev
D
Schnieders
Frank
F
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D006652:Histological Techniques; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D051379:Mice; D051381:Rats
D018664:Interleukin-12