title: Eradication of established tumors in mice by a combination antibody-based therapy.
abstract: Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. 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)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma 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.
authors: Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Tomoyasu
authors: T
authors: Uno
authors: Kazuyoshi
authors: K
authors: Takeda
authors: Yuko
authors: Y
authors: Kojima
authors: Hirohisa
authors: H
authors: Yoshizawa
authors: Hisaya
authors: H
authors: Akiba
authors: Robert S
authors: RS
authors: Mittler
authors: Fumitake
authors: F
authors: Gejyo
authors: Ko
authors: K
authors: Okumura
authors: Hideo
authors: H
authors: Yagita
authors: Mark J
authors: MJ
authors: Smyth