Immunotherapy of solid cancer using dendritic cells pulsed with the HLA-A24-restricted peptide of carcinoembryonic antigen.
Carcinoembryonic antigen (CEA), an oncofetal glycoprotein overexpressed in most gastrointestinal and lung cancers, is a candidate molecule for cancer immunotherapy. Recently, a CEA-derived 9-mer peptide, CEA652 (TYACFVSNL), has been identified as the epitope of cytotoxic T lymphocytes restricted with human leukocyte antigen (HLA)-A24, which is present in 60% of the Japanese population and in some Caucasians. The authors performed a clinical study of a vaccine using autologous dendritic cells (DCs) pulsed with CEA652 and adjuvant cytokines, natural human interferon alpha (nhuIFN-alpha), and natural human tumor necrosis factor alpha (nhuTNF-alpha), for the treatment of patients with CEA-expressing advanced metastatic malignancies. Ten HLA-A24 patients with advanced digestive tract or lung cancer were enrolled in the study to assess toxicity, tolerability and immune responses to the vaccine. DCs were generated from plastic adherent monocytes of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). Generated DCs showing an immature phenotype were loaded with CEA652 and injected into patients intradermally and subcutaneously with 50% of the dose administered by each route every 2 weeks for a total of ten vaccinations. The total dose of administered DCs ranged from 2.7x10(7)cells to 1.6x10(8)cells. Adjuvant cytokines, i.e., 1x10(6) U/body of nhuIFN-alpha and nhuTNF-alpha, were administered to patients twice a week during the vaccination period. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. In the delayed-type hypersensitivity (DTH) skin test, two patients showed a positive skin response to peptide-pulsed DCs after vaccination, although none of the patients tested positive prior to vaccination. In the two patients who showed a positive skin response disease remained stable for 6 and 9 months respectively. These results suggest that active immunization using DCs pulsed with CEA652 peptide in combination with the administration of adjuvant cytokines is a safe and feasible treatment procedure.
Itoh
Tsuyoshi
T
Department of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-0841, Japan. tito@koto.kpu-m.ac.jp
Ueda
Yuji
Y
Kawashima
Ichiro
I
Nukaya
Ikuei
I
Fujiwara
Hitoshi
H
Fuji
Nobuaki
N
Yamashita
Tetsuro
T
Yoshimura
Tetsunori
T
Okugawa
Kaori
K
Iwasaki
Tomoko
T
Ideno
Mitsuko
M
Takesako
Kazutoh
K
Mitsuhashi
Masakazu
M
Orita
Kunzo
K
Yamagishi
Hisakazu
H
D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000276:immunology / Q000628:therapy*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D015234:HLA-A Antigens / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007167:Immunotherapy / Q000379:methods*; D016898:Interferon-alpha / Q000008:administration & dosage; D007371:Interferon-gamma / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma