title: Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules.
abstract: The blockade of immune suppression against antitumor responses is a particularly attractive strategy when combined with agents that promote tumor-specific CTLs. In this study, we have attempted to further improve the CTL induction and potent antitumor efficacy of a combination mAb-based therapy (termed "trimAb therapy") that comprises tumor cell death-inducing anti-death receptor 5 mAb and immune activating anti-CD40 and anti-CD137 mAbs. Among trimAb-treated tumors, the infiltration of CD4(+) Foxp3(+) cells was greater in progressing tumors compared with stable tumors. Blockade of CTLA-4 (CD152)-mediated signals by an antagonistic mAb substantially increased the tumor rejection rate of trimAb therapy, although the immune responses of draining lymph node cells were not augmented. Interestingly, by comparison, additional treatment with agonistic anti-glucocorticoid-induced TNF receptor mAb, antagonistic anti-programmed death-1 (CD279) mAb, or agonistic anti-OX40 (CD134) mAb significantly augmented immune responses of draining lymph node cells, but did not augment the therapeutic effect of trimAb. CD4 T cell depletion reduced the antitumor effect of anti-CTLA-4 mAb treatment alone, but did not reduce the tumor rejection rate of trimAb in conjunction with anti-CTLA-4 mAb. Thus, the blockade of the CTLA-4-mediated inhibitory signal in tumor infiltrating CTL may be the most effective strategy to augment the effect of immune therapies that generate tumor-specific CTL.
authors.affiliation: Department of Immunology, Biomedical Research Center, Juntendo University School of Medicine, Tokyo, Japan. ktakeda@juntendo.ac.jp
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Uno
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000502:physiology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D003602:Cytotoxicity, Immunologic; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor; D021381:Protein Transport / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C505717:Tnfrsf4 protein, mouse