title: Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.
abstract: The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ninke
authors.initials: N
authors.lastname: Leffers
authors.forename: Annechien J A
authors.initials: AJ
authors.lastname: Lambeck
authors.forename: Marloes J M
authors.initials: MJ
authors.lastname: Gooden
authors.forename: Baukje-Nynke
authors.initials: BN
authors.lastname: Hoogeboom
authors.forename: Rinze
authors.initials: R
authors.lastname: Wolf
authors.forename: Ineke E
authors.initials: IE
authors.lastname: Hamming
authors.forename: Bouke G
authors.initials: BG
authors.lastname: Hepkema
authors.forename: Pax H B
authors.initials: PH
authors.lastname: Willemse
authors.forename: Barbara H W
authors.initials: BH
authors.lastname: Molmans
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Sluiter
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.forename: Loraine M
authors.initials: LM
authors.lastname: Fathers
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Melief
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Toos
authors.initials: T
authors.lastname: Daemen
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D002465:Cell Movement; D005260:Female; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008875:Middle Aged; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma