title: Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma.
abstract: OBJECTIVE
  Eradication of post-treatment residual myeloma cells is needed to prevent relapses, and immunostimulatory monoclonal antibodies (mAb) such as anti-CD137, CTLA-4, CD40, etc., which enhance the immune response against malignancies, represent a means of achieving this purpose. This study explores anti-CD137 mAbs for multiple myeloma treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers.
  
  
  METHODS
  The antitumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40, and anti-ICAM-2 mAbs. The antitumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human multiple myeloma. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection.
  
  
  RESULTS
  Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against i.p. HOPC tumors, resulting in extended survival of mice that also became immune to rechallenge. Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma production. Antitumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice despite the fact that CD28 signaling increases the expression of CD137 on CD8(+) T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model.
  
  
  CONCLUSIONS
  The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans.
authors.affiliation: Gene Therapy Unit, Centro de Investigación Médica Aplicada, Pamplona, Spain.
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: Anjana
authors.initials: A
authors.lastname: Gupta
authors.forename: Brandon
authors.initials: B
authors.lastname: McCluskey
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.forename: Asís
authors.initials: A
authors.lastname: Palazón
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ochoa
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Sarai
authors.initials: S
authors.lastname: Solano
authors.forename: José L
authors.initials: JL
authors.lastname: Pérez-Gracia
authors.forename: Babatunde O
authors.initials: BO
authors.lastname: Oyajobi
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy*; D010954:Plasmacytoma / Q000188:drug therapy* / Q000276:immunology; D016019:Survival Analysis; D047368:Tumor Burden; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9