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-Inducible Protein-10 and Another Encoding IL-12, Results in Marked Antitumoral Synergy1
Departments of
*
Medicine and
Genetics, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain
We have constructed a recombinant defective adenovirus that
expresses functional murine IFN-
-inducible protein-10 (IP-10)
chemokine (AdCMVIP-10). Injection of AdCMVIP-10 into s.c. tumor nodules
derived from the CT26 murine colorectal adenocarcinoma cell line
displayed some antitumor activity but it was not curative in most
cases. Previous studies have shown that injection of similar s.c. CT26
tumor nodules with adenovirus-encoding IL-12 (AdCMVIL-12) induces tumor
regression in nearly 70% of cases in association with generation of
antitumor CTL activity. AdCMVIP-10 synergizes with the antitumor effect
of suboptimal doses of AdCMVIL-12, reaching 100% of tumor eradication
not only against injected, but also against distant noninjected tumor
nodules. Colocalization of both adenoviruses at the same tumor nodule
was required for the local and distant therapeutic effects.
Importantly, intratumoral gene transfer with IL-12 and IP-10 generated
a powerful tumor-specific CTL response in a synergistic fashion, while
both CD4 and CD8 T cells appeared in the infiltrate of regressing
tumors. Moreover, the antitumor activity of IP-10 plus IL-12 combined
gene therapy was greatly diminished by simultaneous in vivo depletion
of CD4+ and CD8+ T cells but was largely
unaffected by single depletion of each T cell subset. An important role
for NK cells was also suggested by asialo GM1 depletion experiments.
From a clinical point of view, the effects of IP-10 permit one to lower
the required gene transfer level of IL-12, thus preventing
dose-dependent IL-12-mediated toxicity while improving the therapeutic
efficacy of the elicited antitumor response.
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