title: Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.
abstract: The purpose of the current phase II single-arm clinical trial was to evaluate whether pretreatment with low-dose cyclophosphamide improves immunogenicity of a p53-synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels of CA-125 after primary treatment were immunized four times with the p53-SLP vaccine. Each immunization was preceded by administration of 300 mg/m2 intravenous cyclophosphamide as a means to affect regulatory T cells (Tregs). Vaccine-induced p53-specific interferon-gamma (IFN-γ)-producing T cells evaluated by IFN-γ ELISPOT were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Proliferative p53-specific T cells, observed in 80.0% (8/10) and 62.5% (5/8) of patients, produced both T-helper 1 and T-helper-2 cytokines. Cyclophosphamide induced neither a quantitative reduction of Tregs determined by CD4+ FoxP3+ T cell levels nor a demonstrable qualitative difference in Treg function tested in vitro. Nonetheless, the number of vaccine-induced p53-specific IFN-γ-producing T cells was higher in our study compared to a study in which a similar patient group was treated with p53-SLP monotherapy (p≤0.012). Furthermore, the strong reduction in the number of circulating p53-specific T cells observed previously after four immunizations was currently absent. Stable disease was observed in 20.0% (2/10) of patients, and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. The outcome of this phase II trial warrants new studies on the use of low-dose cyclophosphamide to potentiate the immunogenicity of the p53-SLP vaccine or other antitumor vaccines.
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Renee
authors.initials: R
authors.lastname: Vermeij
authors.forename: Ninke
authors.initials: N
authors.lastname: Leffers
authors.forename: Baukje-Nynke
authors.initials: BN
authors.lastname: Hoogeboom
authors.forename: Ineke L E
authors.initials: IL
authors.lastname: Hamming
authors.forename: Rinze
authors.initials: R
authors.lastname: Wolf
authors.forename: Anna K L
authors.initials: AK
authors.lastname: Reyners
authors.forename: Barbara H W
authors.initials: BH
authors.lastname: Molmans
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Joost
authors.initials: J
authors.lastname: Bart
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
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: D000595:Amino Acid Sequence; D018394:CA-125 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000627:therapeutic use*; D018284:Cystadenocarcinoma, Serous / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000276:immunology / Q000628:therapy*; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D018394:CA-125 Antigen; D019496:Cancer Vaccines; D016207:Cytokines; D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; D003520:Cyclophosphamide