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

Brian Kavanagh, Andrew Ko, Alan Venook, Kim Margolin, Herbert Zeh, Michael Lotze, Brian Schillinger, Weihong Liu, Ying Lu, Peggie Mitsky, Marta Schilling, Nadege Bercovici, Maureen Loudovaris, Roy Guillermo, Sun Min Lee, James Bender, Bonnie Mills, Lawrence Fong

Research output: Contribution to journalArticle

76 Scopus citations

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-γ). 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 35×10 cells were administered intradermally every 3 weeks. Immune response was assessed by IFN-γ 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-γ can induce immune responses to multiple tumor-associated antigens in patients with advanced CRC.

Original languageEnglish (US)
Pages (from-to)762-772
Number of pages11
JournalJournal of Immunotherapy
Volume30
Issue number7
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

Keywords

  • Carcinoembryonic antigen
  • Colorectal cancer
  • Dendritic cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Kavanagh, B., Ko, A., Venook, A., Margolin, K., Zeh, H., Lotze, M., Schillinger, B., Liu, W., Lu, Y., Mitsky, P., Schilling, M., Bercovici, N., Loudovaris, M., Guillermo, R., Lee, S. M., Bender, J., Mills, B., & Fong, L. (2007). Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. Journal of Immunotherapy, 30(7), 762-772. https://doi.org/10.1097/CJI.0b013e318133451c