Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor--secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors

Clin Cancer Res. 2009 Mar 1;15(5):1623-34. doi: 10.1158/1078-0432.CCR-08-1825. Epub 2009 Feb 10.


Purpose: The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy, which is known to stimulate potent and long-lasting antigen-specific immune responses, in combination with PD-1 blockade, which has been shown to augment cellular immune responses.

Experimental design: Survival studies were done in the B16 melanoma and CT26 colon carcinoma tumor models. Immune monitoring studies were done in the B16 model. GM-CSF-secreting tumor cell immunotherapy was administered s.c. and the anti-PD-1 antibody was administered i.p.

Results: The studies reported here show that combining PD-1 blockade with GM-CSF-secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with strong antigen-specific T-cell responses detected by tetramer staining and an in vivo CTL assay, higher secretion levels of proinflammatory cytokines by splenocytes, and the persistence of functional CD8+ T cells in the tumor microenvironment. Furthermore, in the biweekly multiple treatment setting, repeated antigen-specific T-cell expansion was only observed following administration of the cellular immunotherapy with the PD-1 blockade and not when the cellular immunotherapy or PD-1 blockade was used as monotherapy.

Conclusion: The combination of PD-1 blockade with GM-CSF-secreting tumor cell immunotherapy leads to significantly improved antitumor responses by augmenting the tumor-reactive T-cell responses induced by the cellular immunotherapy. Readministration of the cellular immunotherapy with the anti-PD-1 antibody in subsequent immunotherapy cycles was required to reactivate these T-cell responses.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Proliferation
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / therapy*
  • Cytokines / metabolism
  • Drug Synergism
  • Enzyme-Linked Immunosorbent Assay
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology*
  • Immunotherapy*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism
  • Programmed Cell Death 1 Receptor
  • Rats
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology


  • Antibodies, Monoclonal
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Cytokines
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Recombinant Fusion Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor