title: A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome.
abstract: BACKGROUND
  To evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor-II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.
  
  
  METHODS
  Eighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund's adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of "the cocktail of 5 peptides" on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks.
  
  
  RESULTS
  The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of "peptides cocktail" did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032).
  
  
  CONCLUSIONS
  Our cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.
  
  
  BACKGROUND
  UMIN-CTR number UMIN000004948.
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan. hazama@yamaguchi-u.ac.jp.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takenouchi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Tsunedomi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tokuhisa
authors.forename: Norio
authors.initials: N
authors.lastname: Iizuka
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shinozaki
authors.forename: Akira
authors.initials: A
authors.lastname: Kamiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D019496:Cancer Vaccines / Q000009:adverse effects* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D014611:Vaccination; D017778:Vaccines, Combined / Q000009:adverse effects* / Q000627:therapeutic use; D022223:Vaccines, Subunit / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D000939:Epitopes; D017778:Vaccines, Combined; D022223:Vaccines, Subunit; D007371:Interferon-gamma