Potentiation of a P53-SLP vaccine by cyclophosphamide in ovarian cancer, A single ARM phase II study

R. Vermeij, N. Leffers, B.-N. Hoogeboom, I.E. Hamming, R. Wolf, A.K.L. Reyners, B.H.W. Molmans, H. Hollema, J. Bart, J.W. Drijfhout, J. Oostendorp, A.G.J. Van Der Zee, C.J. Melief, S.H. Van Der Burg, T. Daemen, H.W. Nijman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Introduction: In view of the poor prognosis of ovarian cancer, new treatment modalities such as immunotherapy are under investigation. We have shown that a p53-SLP vaccine induces p53-specific T-cell responses. Yet, no clinical responses were observed possibly due to immune suppressive activity of regulatory T-cells (Tregs). Objective: Purpose of this phase II single-arm clinical trial was to evaluate whether administration of low dose cyclophosphamide before vaccination improves immunogenicity of the p53-SLP vaccine in recurrent ovarian cancer patients. Methods: Eleven ovarian cancer patients with recurrent elevation of CA-125 were immunized with the p53-SLP vaccine preceded by low-dose cyclophosphamide. Vaccine-induced p53-specific T-cell responses were evaluated by IFN-γ ELISPOT, proliferation assay, flow cytometry and cytokine bead array. Treg activity was measured by Treg suppression assay. Tumor responses were evaluated with CA-125 levels and CT-scans. Results: Vaccine-induced p53-specific T-cells were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Cyclophosphamide induced neither quantitative nor qualitative reduction of Tregs after administration of cyclophosphamide. Nonetheless, the number of vaccine-induced p53-specific T-cells was higher in the current study, compared to our previous study (p ≤ 0.012). Stable disease was observed in 2/10 (20.0%) patients and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. Conclusion: Combination of cyclophosphamide with p53-SLP induced no reduction of circulating Tregs. However cyclophosphamide enhanced the induction of a strong p53-specific T-cell response. Our results warrant new studies on the use of low-dose cyclophosphamide to potentiate the immunogenicity of anti-tumor vaccines.
Original languageEnglish
Pages (from-to)67
Number of pages1
JournalInternational Journal of Gynecological Cancer
Volume21
Issue number12
DOIs
Publication statusPublished - 1-Oct-2011

Keywords

  • protein p53
  • cyclophosphamide
  • vaccine
  • CA 125 antigen
  • cytokine
  • tumor vaccine
  • human
  • ovary cancer
  • society
  • phase 2 clinical trial
  • oncology
  • regulatory T lymphocyte
  • T lymphocyte
  • patient
  • low drug dose
  • assay
  • cancer patient
  • immunogenicity
  • clinical trial
  • arm
  • prognosis
  • immunotherapy
  • vaccination
  • flow cytometry
  • neoplasm
  • computer assisted tomography
  • immunization
  • enzyme linked immunospot assay

Cite this