title: Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.
abstract: This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Mayanagi
authors.forename: Minoru
authors.initials: M
authors.lastname: Kitago
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsuda
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Fujita
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Taguchi
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Itano
authors.forename: Koichi
authors.initials: K
authors.lastname: Aiura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Takaishi
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D016209:Interleukin-8 / Q000097:blood; D008113:Liver Neoplasms / Q000556:secondary; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D010865:Pilot Projects; D016896:Treatment Outcome; D014611:Vaccination; D025721:WT1 Proteins / Q000276:immunology* / Q000494:pharmacology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C508606:CXCL8 protein, human; D019496:Cancer Vaccines; D016209:Interleukin-8; D025721:WT1 Proteins; C583751:WT1 protein, human; D003841:Deoxycytidine; D002097:C-Reactive Protein; D000093542:Gemcitabine
keywords: Delayed-type hypersensitivity; dendritic cell vaccination; first-line therapy; immunotherapy; neutrophil lymphocyte ratio