title: Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer.
abstract: OBJECTIVE
  We performed a phase I trial to investigate the safety, clinical responses, and Wilms' tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II-restricted epitopes, in combination with chemotherapy.
  
  
  METHODS
  Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II-restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine.
  
  
  RESULTS
  The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4(+) T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days.
  
  
  CONCLUSIONS
  The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer.
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Clinical Medicine and Research, Departments of Oncology, shigeo_koido@jikei.ac.jp.
authors: Shigeo
authors: S
authors: Koido
authors: Oncology.
authors: Sadamu
authors: S
authors: Homma
authors: Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy;
authors: Masato
authors: M
authors: Okamoto
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Kazuki
authors: K
authors: Takakura
authors: Research and Development Division, Tella Inc., Tokyo;
authors: Masako
authors: M
authors: Mori
authors: Research and Development Division, Tella Inc., Tokyo;
authors: Shinji
authors: S
authors: Yoshizaki
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Shintaro
authors: S
authors: Tsukinaga
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Shunichi
authors: S
authors: Odahara
authors: Endoscopy.
authors: Seita
authors: S
authors: Koyama
authors: Endoscopy.
authors: Hiroo
authors: H
authors: Imazu
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Kan
authors: K
authors: Uchiyama
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Mikio
authors: M
authors: Kajihara
authors: Endoscopy.
authors: Hiroshi
authors: H
authors: Arakawa
authors: Surgery, and.
authors: Takeyuki
authors: T
authors: Misawa
authors: Surgery, and.
authors: Yoichi
authors: Y
authors: Toyama
authors: Surgery, and.
authors: Satoru
authors: S
authors: Yanagisawa
authors: Pathology, The Jikei University School of Medicine;
authors: Masahiro
authors: M
authors: Ikegami
authors: Oncology.
authors: Shin
authors: S
authors: Kan
authors: Oncology.
authors: Kazumi
authors: K
authors: Hayashi
authors: Oncology.
authors: Hideo
authors: H
authors: Komita
authors: Oncology.
authors: Yuko
authors: Y
authors: Kamata
authors: Oncology.
authors: Masaki
authors: M
authors: Ito
authors: Research and Development Division, Tella Inc., Tokyo;
authors: Takefumi
authors: T
authors: Ishidao
authors: Research and Development Division, Tella Inc., Tokyo;
authors: Sei-Ichi
authors: S
authors: Yusa
authors: Cell Processing Center, Shinshu University Hospital, Nagano;
authors: Shigetaka
authors: S
authors: Shimodaira
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Jianlin
authors: J
authors: Gong
authors: Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Osaka, Japan; and.
authors: Haruo
authors: H
authors: Sugiyama
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Toshifumi
authors: T
authors: Ohkusa
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors: Hisao
authors: H
authors: Tajiri
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001650:Bile Duct Neoplasms / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy; D001653:Bile Ducts, Intrahepatic / Q000276:immunology; D014408:Biomarkers, Tumor / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy; D018281:Cholangiocarcinoma / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology; D011379:Prognosis; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D025721:WT1 Proteins / Q000276:immunology*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D025721:WT1 Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine