Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma

Cancer Immunol Immunother. 2015 Apr;64(4):507-18. doi: 10.1007/s00262-015-1656-x. Epub 2015 Feb 7.


Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / immunology*
  • Antineoplastic Agents, Alkylating / administration & dosage*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Cholesterol / immunology*
  • Cohort Studies
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Female
  • Follow-Up Studies
  • Humans
  • Lymphatic Metastasis
  • Male
  • Melanoma / immunology
  • Melanoma / secondary
  • Melanoma / therapy*
  • Membrane Proteins / immunology*
  • Middle Aged
  • Neoplasm Staging
  • Phospholipids / immunology*
  • Prognosis
  • Saponins / immunology*
  • T-Lymphocytes, Regulatory / immunology


  • Antigens, Neoplasm
  • Antineoplastic Agents, Alkylating
  • CTAG1B protein, human
  • Cancer Vaccines
  • Drug Combinations
  • Membrane Proteins
  • Phospholipids
  • Saponins
  • Cyclophosphamide
  • Cholesterol