Eradication of established tumors in mice by a combination antibody-based therapy

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.*

Cite this article

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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