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Tumor Cells Expressing Anti-CD137 scFv Induce a Tumor-Destructive Environment

Department of Pathology, University of Washington, Seattle, Washington

Requests for reprints: Karl Erik Hellström, Department of Pathology, University of Washington, Box 35 99 39, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98109-2499. Phone: 206-341-4714; E-mail: hells{at}u.washington.edu.

For immunotherapy to become more effective, there is a need to maximize the antitumor response at the tumor site as well as to eliminate tumor cell variants that lack a given tumor antigen or the ability to present it. We have previously shown that wild-type (WT) cells from the K1735 melanoma (K1735-WT) are rejected following vaccination with cells (K1735-1D8) transfected to express scFv from the anti-CD137 monoclonal antibody 1D8, and that CD4⁺ T cells and natural killer (NK) cells are needed for this rejection. We now show that tumors harvested 4 to 10 days after mice had been transplanted with K1735-1D8 cells or a mixture of K1735-1D8 and K1735-WT cells contained more NK cells and that they had an increased percentage of CD4⁺ T lymphocytes producing IFN or tumor necrosis factor-. We further show that the percentage of NK cells was higher in B16-1D8 melanomas expressing anti-CD137 scFv than in the WT tumors and that the percentage of FoxP3⁺ cells was lower. Admixture of 10% K1735-1D8 cells prevented the progressive growth of transplanted K1735-WT cells in syngeneic mice and also of cells from the antigenically different sarcoma Ag104. Inhibition of WT tumor cells by tumor cells transfected to express anti-CD137 scFv was shown also with the TC1 carcinoma and B16 melanoma. Furthermore, injection of an adenovirus vector, Ad-1D8, which encodes anti-CD137 scFv into established B16 melanomas, significantly prolonged the survival of tumor-bearing mice and could induce regression. Our data suggest that targeting of anti-CD137 scFv to tumors should be explored for therapy for some human cancers. [Cancer Res 2007;67(5):2339–44]

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