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.
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Authors | Renee 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 |
Journal | International journal of cancer
(Int J Cancer)
Vol. 131
Issue 5
Pg. E670-80
(Sep 01 2012)
ISSN: 1097-0215 [Electronic] United States |
PMID | 22139992
(Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 UICC. |
Chemical References |
- CA-125 Antigen
- Cancer Vaccines
- Cytokines
- Peptide Fragments
- TP53 protein, human
- Tumor Suppressor Protein p53
- Interferon-gamma
- Cyclophosphamide
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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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