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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COPP treatment of established TC-1 and B16-F10 lung metastases. Mice wer...
COPP treatment of established TC-1 and B16-F10 lung metastases. Mice were given 1 × 104 TC-1 cells (a) or 1 × 105 B16-F10 cells (b) intravenously and were immunized intradermally 3 days later with the OVA peptide (circles), the E7 peptide (triangles in a), or the trp-2 peptide (triangles in b). The peptides were emulsified in IFA and the mice were given 50 μg of peptide at each of two immunization sites. On the day of immunization, and again 3 days later, the mice received 100 μg of either rat IgG or mAb 2A intraperitoneally. The mice were monitored daily for the duration of the experiment. Survival data from two identically performed experiments (n = 10) were combined. Mice treated with the E7 peptide (in a) or trp-2 peptide (in b) plus mAb 2A had a significant survival advantage in all experiments performed, as determined by the log rank test (P ≤ 0.001).