Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors
Ryan A. Wilcox, … , Larry R. Pease, Lieping Chen
Ryan A. Wilcox, … , Larry R. Pease, Lieping Chen
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):651-659. https://doi.org/10.1172/JCI14184.
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Article Immunology

Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

Abstract

Treatment of advanced, poorly immunogenic tumors in animal models, considered the closest simulation available thus far for conditions observed in cancer patients, remains a major challenge for cancer immunotherapy. We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen–specific cytotoxic T lymphocyte responses. In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti–4-1BB mAb. We provide evidence that immunological ignorance, rather than anergy or deletion, of tumor antigen–specific CTLs during the progressive growth of tumors prevents costimulation by anti–4-1BB mAb. Breaking CTL ignorance by immunization with a tumor antigen–derived peptide, although insufficient to stimulate a curative CTL response, is necessary for anti–4-1BB mAb to induce a CTL response leading to the regression of established tumors. Our results suggest a new approach for immunotherapy of human cancers.

Authors

Ryan A. Wilcox, Dallas B. Flies, Gefeng Zhu, Aaron J. Johnson, Koji Tamada, Andrei I. Chapoval, Scott E. Strome, Larry R. Pease, Lieping Chen

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Regression of established C3 tumors after treatment with the E7 peptide ...
Regression of established C3 tumors after treatment with the E7 peptide and mAb 2A. Mice were injected subcutaneously with 1 × 106 C3 cells. Seven days later, mice were divided into two groups and were immunized intradermally with either Vp2 or E7 peptide (50 μg/mouse) emulsified in IFA. On days 7 and 10, mice received 100 μg of the control rat IgG or mAb 2A intraperitoneally. Tumor size was assessed weekly for each mouse, and the mice were sacrificed at the times indicated, when the average tumor diameter reached 15 mm (filled circles). Mice bearing tumors less than an average of 15 mm in diameter were sacrificed upon termination of the experiment, at 13 weeks (open circles). Data was combined from two similarly performed experiments. The improved survival observed in the treatment group receiving both the E7 peptide and mAb 2A was statistically significant, as determined by the χ2 test. (P ≤ 0.01).