Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides.
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.
Kavanagh
Brian
B
Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA.
Ko
Andrew
A
Venook
Alan
A
Margolin
Kim
K
Zeh
Herbert
H
Lotze
Michael
M
Schillinger
Brian
B
Liu
Weihong
W
Lu
Ying
Y
Mitsky
Peggie
P
Schilling
Marta
M
Bercovici
Nadege
N
Loudovaris
Maureen
M
Guillermo
Roy
R
Lee
Sun Min
SM
Bender
James
J
Mills
Bonnie
B
Fong
Lawrence
L
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
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