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*
Pediatric Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892;
Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702;
Laboratory of Chemoprevention, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892;
Intramural Research Support Program, Science Applications International Corp.-Frederick, Frederick, MD 21702;
¶ Department of Oncology, Hoffmann-La Roche, Inc., Nutley, NJ 07110;
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Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and
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National Cancer Institute Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702
Using a novel transgenic mouse model of spontaneous mammary
carcinoma, we show here that the IL-12/pulse IL-2 combination can
induce rapid and complete regression of well-established autochthonous
tumor in a setting where the host immune system has been conditioned by
the full dynamic process of neoplastic progression and tumorigenesis.
Further, this regimen inhibits neovascularization of established
mammary tumors, and does so in conjunction with potent local induction
of genes encoding the IFN-
- and TNF-
-inducible antiangiogenic
chemokines IFN-inducible protein 10 and monokine induced by IFN-. In
contrast to untreated juvenile C3(1)TAg mice in which histologically
normal mammary epithelium predictably undergoes progressive
hyperplasia, atypical changes, and ultimately transition to overt
carcinoma, the current studies also demonstrate a unique preventative
therapeutic role for IL-12/pulse IL-2. In juvenile mice, early
administration of IL-12/pulse IL-2 markedly limits the expected
genetically programmed neoplastic transition within the mammary
epithelium and does so in conjunction with enhancement of constitutive
Fas and pronounced induction of local Fas ligand gene expression, T
cell infiltration, and induction of apoptosis within the mammary
epithelium. These events occur in the absence of a durable Ag-specific
memory response. Thus, this novel model system demonstrates that the
potent therapeutic activity of the IL-12/pulse IL-2 combination rapidly
engages potent apoptotic and antiangiogenic mechanisms that remain
active during the delivery of IL-12/pulse IL-2. The results also
demonstrate that these mechanisms are active against established tumor
as well as developing preneoplastic lesions.
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