Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides

J Immunother. 2007 Oct;30(7):762-72. doi: 10.1097/CJI.0b013e318133451c.

Abstract

Developing a process to generate dendritic cells (DCs) applicable for multicenter trials would facilitate cancer vaccine development. Moreover, targeting multiple antigens with such a vaccine strategy could enhance the efficacy of such a treatment approach. We performed a phase 1/2 clinical trial administering a DC-based vaccine targeting multiple tumor-associated antigens to patients with advanced colorectal cancer (CRC). A qualified manufacturing process was used to generate DC from blood monocytes using granulocyte macrophage colony-stimulating factor and IL-13, and matured for 6 hours with Klebsiella-derived cell wall fraction and interferon-gamma (IFN-gamma). DCs were also loaded with 6 HLA-A*0201 binding peptides derived from carcinoembryonic antigen (CEA), MAGE, and HER2/neu, as well as keyhole limpet hemocyanin protein and pan-DR epitope peptide. Four planned doses of 35x10(6) cells were administered intradermally every 3 weeks. Immune response was assessed by IFN-gamma enzyme-linked immunosorbent spot (ELISPOT). Matured DC possessed an activated phenotype and could prime T cells in vitro. In the trial, 21 HLA-A2+ patients were apheresed, 13 were treated with the vaccine, and 11 patients were evaluable. No significant treatment-related toxicity was reported. T-cell responses to a CEA-derived peptide were detected by ELISPOT in 3 patients. T cells induced to CEA possessed high avidity T-cell receptors. ELISPOT after in vitro restimulation detected responses to multiple peptides in 2 patients. All patients showed progressive disease. This pilot study in advanced CRC patients demonstrates DC-generated granulocyte macrophage colony-stimulating factor and IL-13 matured with Klebsiella-derived cell wall fraction and IFN-gamma can induce immune responses to multiple tumor-associated antigens in patients with advanced CRC.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic
  • Adolescent
  • Adult
  • Aged
  • Antigen Presentation
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / immunology*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / therapy*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / transplantation
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Hemocyanins / immunology
  • Hemocyanins / metabolism
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunotherapy, Adoptive*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Malaria Vaccines / immunology
  • Malaria Vaccines / metabolism
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Peptides / immunology
  • Peptides / metabolism

Substances

  • Adjuvants, Immunologic
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Histocompatibility Antigens Class I
  • Malaria Vaccines
  • PADRE 45
  • Peptides
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Hemocyanins
  • keyhole-limpet hemocyanin