title: Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers.
abstract: p53 Mutations are found in up to 30% of breast cancers and peptides derived from over-expressed p53 protein are presented by class I HLA molecules and may act as tumor-associated epitopes in cancer vaccines. A dendritic cell (DC) based p53 targeting vaccine was analyzed in HLA-A2+ patients with progressive advanced breast cancer. DCs were loaded with 3 wild-type and 3 P2 anchor modified HLA-A2 binding p53 peptides. Patients received up to 10 sc vaccinations with 5 x 10(6) p53-peptide loaded DC with 1-2 weeks interval. Concomitantly, 6 MIU/m(2) interleukine-2 was administered sc. Results from a phase II trial including 26 patients with verified progressive breast cancer are presented. Seven patients discontinued treatment after only 2-3 vaccination weeks due to rapid disease progression or death. Nineteen patients were available for first evaluation after 6 vaccinations; 8/19 evaluable patients attained stable disease (SD) or minor regression while 11/19 patients had progressive disease (PD), indicating an effect of p53-specific immune therapy. This was supported by: (1) a positive correlation between p53 expression of tumor and observed SD, (2) therapy induced p53 specific T cells in 4/7 patients with SD but only in 2/9 patients with PD, and (3) significant response associated changes in serum YKL-40 and IL-6 levels identifying these biomarkers as possible candidates for monitoring of response in connection with DC based cancer immunotherapy. In conclusion, a significant fraction of breast cancer patients obtained SD during p53-targeting DC therapy. Data encourage initiation of a randomized trial in p53 positive patients evaluating the impact on progression free survival.
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. inge.m.svane@dadlnet.dk
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.forename: Anders E
authors.initials: AE
authors.lastname: Pedersen
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
authors.forename: Dorte
authors.initials: D
authors.lastname: Nielsen
authors.forename: Claus
authors.initials: C
authors.lastname: Kamby
authors.forename: Svend
authors.initials: S
authors.lastname: Ottesen
authors.forename: Eva
authors.initials: E
authors.lastname: Balslev
authors.forename: Eva
authors.initials: E
authors.lastname: Gaarsdal
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nikolajsen
authors.forename: Mogens H
authors.initials: MH
authors.lastname: Claesson
mesh_terms: D054392:Adipokines; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D000071451:Chitinase-3-Like Protein 1; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D037102:Lectins; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D014611:Vaccination
chemical_list: D054392:Adipokines; D014408:Biomarkers, Tumor; C084533:CHI3L1 protein, human; D019496:Cancer Vaccines; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D015850:Interleukin-6; D037102:Lectins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53