Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12.
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Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12. / Waehler, Reinhard; Ittrich, Harald; Mueller, Lars; Krupski, Gerrit; Ameis, Detlev; Schnieders, Frank.
In: HUM GENE THER, Vol. 16, No. 3, 3, 2005, p. 307-317.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12.
AU - Waehler, Reinhard
AU - Ittrich, Harald
AU - Mueller, Lars
AU - Krupski, Gerrit
AU - Ameis, Detlev
AU - Schnieders, Frank
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 16
SP - 307
EP - 317
JO - HUM GENE THER
JF - HUM GENE THER
SN - 1043-0342
IS - 3
M1 - 3
ER -
