title: CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice.
abstract: Previous studies by others using transplantable murine tumor models have demonstrated that the administration of antibodies that block CTLA-4 interaction with B7 can provoke the elimination of established tumors, and that the tumor suppression is mediated by T-cells and/or cells expressing NK1.1. Studies from our lab have established in a human/severe combined immunodeficient (SCID) mouse chimeric model that autologous peripheral blood leukocytes (PBL) can suppress the growth of tumor xenografts in a PBL dose-dependent fashion, and that this suppression is dependent upon the patient's T and NK cells. Using this human/mouse chimeric model, we sought to determine whether an antibody blockade of CTLA-4 would enhance the anti-tumor response of a patient's PBL. It was first important to determine whether the tumor suppression observed in the SCID model was dependent upon CD28/B7 co-stimulation. Blockade of B7 with a human CTLA-4-Ig fusion protein completely abrogated the lymphocyte-mediated tumor suppression, confirming in this model that tumor suppression is dependent upon a CD28/B7 co-stimulation. Using two different CTLA-4 specific monoclonal antibodies, we observed that CTLA-4 blockade significantly enhanced the human lymphocyte-mediated tumor suppression in mice co-engrafted with PBL and tumor cells. This enhancement was observed in both an allogeneic setting (in which the PBL were allogeneic with respect to the tumor) and an autologous setting (in which the PBL and tumor were from the same patient). These results sustain the notion that human anti-tumor immune response can be augmented (in vivo) by blocking the interaction between CTLA-4 and B7.
authors.affiliation: Department of Surgery, 3304 Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. msabel@umich.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hess
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Conway
authors.forename: Fang-An
authors.initials: FA
authors.lastname: Chen
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology*; D000950:Antigens, Ly; D000954:Antigens, Surface; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D000954:Antigens, Surface; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; C527203:KLRB1 protein, human; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D000069594:Abatacept