title: Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides.
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.
authors: Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA.
authors: Brian
authors: B
authors: Kavanagh
authors: Andrew
authors: A
authors: Ko
authors: Alan
authors: A
authors: Venook
authors: Kim
authors: K
authors: Margolin
authors: Herbert
authors: H
authors: Zeh
authors: Michael
authors: M
authors: Lotze
authors: Brian
authors: B
authors: Schillinger
authors: Weihong
authors: W
authors: Liu
authors: Ying
authors: Y
authors: Lu
authors: Peggie
authors: P
authors: Mitsky
authors: Marta
authors: M
authors: Schilling
authors: Nadege
authors: N
authors: Bercovici
authors: Maureen
authors: M
authors: Loudovaris
authors: Roy
authors: R
authors: Guillermo
authors: Sun Min
authors: SM
authors: Lee
authors: James
authors: J
authors: Bender
authors: Bonnie
authors: B
authors: Mills
authors: Lawrence
authors: L
authors: Fong
mesh_terms: D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006433:Hemocyanins / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D017780:Malaria Vaccines / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010455:Peptides / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D017780:Malaria Vaccines; C401223:PADRE 45; D010455:Peptides; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin