Abstract
Tumor-cell apoptosis is the basis of many cancer therapies1,2,3, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies4,5,6,7. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-γ in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-γ in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.*
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Notes
NOTE: In the version of this article published online, Figure 2c was incorrectly referenced on page 2. The correct figure reference is to Figure 2d. Also, an abbreviation written incorrectly. On page 2, CTLS should have read CTLs. This has been corrected for all versions of the article.
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Acknowledgements
We thank A. Rolink for monoclonal antibody to mouse CD40 (FGK45). This work was supported by the Ministry of Education, Science, and Culture, Japan. M.J.S. was also supported by a National Health and Medical Research Council of Australia Program Grant and Research Fellowship and the Susan G. Komen Breast Cancer Foundation.
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Supplementary information
Supplementary Fig. 1
Initial tumor cell death induction followed by CD40- and CD137-specific monoclonal antibodies treatment is sufficient for rejection of established tumors. (PDF 1208 kb)
Supplementary Fig. 2
Induction of 4T1 tumor-specific CTL by trimAb therapy. (PDF 1527 kb)
Supplementary Fig. 3
Involvement of IFN-γ and perforin in trimAb-induced tumor rejection. (PDF 755 kb)
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Uno, T., Takeda, K., Kojima, Y. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 12, 693–698 (2006). https://doi.org/10.1038/nm1405
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DOI: https://doi.org/10.1038/nm1405
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