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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.
AuthorsRenee Vermeij, Ninke Leffers, Baukje-Nynke Hoogeboom, Ineke L E Hamming, Rinze Wolf, Anna K L Reyners, Barbara H W Molmans, Harry Hollema, Joost Bart, Jan W Drijfhout, Jaap Oostendorp, Ate G J van der Zee, Cornelis J Melief, Sjoerd H van der Burg, Toos Daemen, Hans W Nijman
JournalInternational journal of cancer (Int J Cancer) Vol. 131 Issue 5 Pg. E670-80 (Sep 01 2012) ISSN: 1097-0215 [Electronic] United States
PMID22139992 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 UICC.
Chemical References
  • CA-125 Antigen
  • Cancer Vaccines
  • Cytokines
  • Peptide Fragments
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Interferon-gamma
  • Cyclophosphamide
Topics
  • Amino Acid Sequence
  • CA-125 Antigen (metabolism)
  • CD4-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (therapeutic use)
  • Cell Proliferation
  • Cyclophosphamide (therapeutic use)
  • Cystadenocarcinoma, Serous (immunology, therapy)
  • Cytokines (metabolism)
  • Drug Synergism
  • Endometrial Neoplasms (immunology, therapy)
  • Enzyme-Linked Immunospot Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunization
  • Interferon-gamma (metabolism)
  • Lymphocyte Activation
  • Molecular Sequence Data
  • Ovarian Neoplasms (immunology, therapy)
  • Peptide Fragments (immunology)
  • T-Lymphocytes, Regulatory (immunology)
  • Tumor Suppressor Protein p53 (immunology)

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