Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin

PLoS One. 2013 Dec 19;8(12):e84927. doi: 10.1371/journal.pone.0084927. eCollection 2013.


There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 × 10(6) ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8(+) T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-γ production. While administration of anti-CD137 mAb as a single agent similarly increases CD8(+) T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical 'translation'.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies, Monoclonal, Murine-Derived / administration & dosage
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / immunology*
  • Cisplatin / pharmacology*
  • Drug Synergism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Injections, Intraperitoneal
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Ovarian Neoplasms / drug therapy*
  • Programmed Cell Death 1 Receptor / administration & dosage
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / administration & dosage
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / antagonists & inhibitors*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology


  • Antibodies, Monoclonal, Murine-Derived
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Cisplatin