Baukje-Nynke Hoogeboom

Publications (9)45.88 Total impact

• Article: Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.

  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
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  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.
  International Journal of Cancer 12/2011; 131(5):E670-80. · 5.44 Impact Factor
• Article: Heterologous prime-boost immunizations with a virosomal and an alphavirus replicon vaccine.

  Mateusz Walczak, Arjan de Mare, Annelies Riezebos-Brilman, Joke Regts, Baukje-Nynke Hoogeboom, Jeroen T Visser, Marc Fiedler, Pidder Jansen-Dürr, Ate G J van der Zee, Hans W Nijman, Jan Wilschut, Toos Daemen
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  ABSTRACT: Heterologous prime-boost immunization strategies in general establish higher frequencies of antigen-specific T lymphocytes than homologous prime-boost protocols or single immunizations. We developed virosomes and recombinant Semliki Forest virus (rSFV) as antigen delivery systems, each capable of inducing strong CTL responses in homologous prime-boost protocols. Here, we demonstrate that a heterologous prime-boost with recombinant Semliki Forest virus (rSFV) encoding a fusion protein of E6 and E7 of human papillomavirus (HPV) type 16 and virosomes containing the HPV16 E7 protein resulted in higher numbers of antigen-specific CTL in mice than homologous protocols. Evasion of vector-specific immunity appeared to play a role in establishing these high frequencies, as coinduction of vector-specific responses during the prime immunization reduced the frequency of antigen-specific CTL after a heterologous booster. However, the high numbers of CTL initially primed by the heterologous protocols did not correlate with enhanced responsiveness to in vitro antigenic stimulation, nor in improved cytolytic activity or antitumor responses in vivo compared to a homologous protocol with rSFV. This lack of correlation could not be explained by changes in numbers of regulatory T cells. However, we observed differences in the frequencies of T cell subsets within the E7-specific CD8(+) T cell population, e.g. higher frequencies of central memory T cells upon homologous immunizations compared to heterologous immunizations. The induction of central memory T cells is crucial for a cancer vaccine as these cells are known to rapidly expand upon recall stimulation. This study demonstrates that the strongly increased number of antigen-specific CTL as induced by heterologous prime-boost immunizations, often used as a proof for the enhanced efficacy of such regimes, does not necessarily equal superior functional antitumor responses.
  Molecular Pharmaceutics 02/2011; 8(1):65-77. · 4.78 Impact Factor
• Article: Long-term clinical and immunological effects of p53-SLP® vaccine in patients with ovarian cancer.

  Ninke Leffers, Renee Vermeij, Baukje-Nynke Hoogeboom, Ute R Schulze, Rinze Wolf, Ineke E Hamming, Ate G van der Zee, Kees J Melief, Sjoerd H van der Burg, Toos Daemen, Hans W Nijman
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  ABSTRACT: Vaccine-induced p53-specific immune responses were previously reported to be associated with improved response to secondary chemotherapy in patients with small cell lung cancer. We investigated long-term clinical and immunological effects of the p53-synthetic long peptide (p53-SLP®) vaccine in patients with recurrent ovarian cancer. Twenty patients were immunized with the p53-SLP® vaccine between July 2006 and August 2007. Follow-up information on patients was obtained. Clinical responses to secondary chemotherapy after p53-SLP® immunizations were determined by computerized tomography and/or tumor marker levels (CA125). Disease-specific survival was compared to a matched historical control group. Immune responses were analyzed by flow cytometry, proliferation assay, interferon gamma (IFN-γ) ELISPOT and/or cytokine bead array. Lymphocytes cultured from skin biopsy were analyzed by flow cytometry and proliferation assay. Of 20 patients treated with the p53-SLP® vaccine, 17 were subsequently treated with chemotherapy. Eight of these patients volunteered another blood sample. No differences in clinical response rates to secondary chemotherapy or disease-specific survival were observed between immunized patients and historical controls (p = 0.925, resp. p = 0.601). p53-specific proliferative responses were observed in 5/8 patients and IFN-γ production in 2/7 patients. Lymphocytes cultured from a prior injection site showing inflammation during chemotherapy did not recognize p53-SLP®. Thus, treatment with the p53-SLP® vaccine does not affect responses to secondary chemotherapy or survival, although p53-specific T-cells do survive chemotherapy.
  International Journal of Cancer 02/2011; 130(1):105-12. · 5.44 Impact Factor
• Article: Role of T cell competition in the induction of cytotoxic T lymphocyte activity during viral vector-based immunization regimens.

  Annechien J A Lambeck, Hans W Nijman, Baukje Nynke Hoogeboom, Joke Regts, Arjan de Mare, Jan Wilschut, Toos Daemen
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  ABSTRACT: T cell competition between antigen- and vector-specific T cells may determine the outcome of viral vector-based immunization regimens, as we previously proposed. Here, we unravelled the interplay between antigen- and vector-specific immunity, using recombinant Semliki Forest virus (rSFV). Priming of mice with rSFV, encoding LacZ (SFVLacZ), or with empty rSFV strongly suppressed subsequent induction of ovalbumin or Human Papilloma virus (HPV) E6/E7-specific CTL activity by a booster with SFVeOVA or SFVeE6,7, respectively. Yet, priming with irradiated, i.e. replication-defective, SFVLacZ did not affect subsequent CTL induction, indicating that the interfering vector-specific immunity was directed against the viral replicase. However, immune responses against the strongly immunogenic nucleoprotein of influenza virus encoded by SFV were less severely affected by priming with SFVLacZ. Thus the outcome of heterologous prime-boost immunizations appears to depend on the immunogenicity of the respective antigens.
  Vaccine 06/2010; 28(26):4275-82. · 3.77 Impact Factor
• Article: Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.

  Ninke Leffers, Annechien J A Lambeck, Marloes J M Gooden, Baukje-Nynke Hoogeboom, Rinze Wolf, Ineke E Hamming, Bouke G Hepkema, Pax H B Willemse, Barbara H W Molmans, Harry Hollema, Jan W Drijfhout, Willem J Sluiter, A Rob P M Valentijn, Loraine M Fathers, Jaap Oostendorp, Ate G J van der Zee, Cornelis J Melief, Sjoerd H van der Burg, Toos Daemen, Hans W Nijman
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  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.
  International Journal of Cancer 06/2009; 125(9):2104-13. · 5.44 Impact Factor
• Article: Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer.

  Ninke Leffers, Marloes J M Gooden, Renske A de Jong, Baukje-Nynke Hoogeboom, Klaske A ten Hoor, Harry Hollema, H Marieke Boezen, Ate G J van der Zee, Toos Daemen, Hans W Nijman
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  ABSTRACT: Ovarian cancer patients with intra-tumoral CD3(+) T-lymphocytes in primary tumor tissue have a better prognosis. This study aims to analyze the presence and relative influence of three important T-lymphocyte subsets, tumor-infiltrating CD8(+) cytotoxic T-lymphocytes (CTL), CD45R0(+) memory T-lymphocytes, and FoxP3(+) regulatory T-lymphocytes (Treg), in primary tumor tissue and omental metastases of patients with ovarian cancer. The number of CD8(+), CD45R0(+), and FoxP3(+) T-lymphocytes was determined by immunohistochemistry on a tissue micro array containing ovarian tumor tissue and/or omental metastases obtained at primary debulking surgery from 306 FIGO stage I-IV ovarian cancer patients. Immunohistochemistry data were correlated to clinicopathological parameters and survival data. High number of CD8(+) CTL and a high CD8(+)/FoxP3(+) ratio in ovarian-derived tumor tissue were associated with increased disease-specific survival and proved to be independent prognostic factors in multivariate analyses. In advanced stage patients, the presence of CD8(+) CTL, CD45R0(+) memory T-lymphocytes, FoxP3(+) Treg or a high CD8(+)/FoxP3(+) ratio in ovarian-derived tumor tissue was associated with an increased disease specific survival in univariate analysis, as was the presence of CD45R0(+) memory T-lymphocytes and FoxP3(+) Treg in omental metastases. Furthermore, in advanced stage patients CD8(+) cytotoxic and FoxP3(+) regulatory T-lymphocytes infiltrating ovarian-derived tumor tissue were independent predictors of increased prognosis. T-lymphocytes infiltrating primary and metastatic ovarian cancer sites are associated with improved prognosis. These associations are especially distinct in advanced stage patients, underlining the potential for immunotherapy as a broadly applicable therapeutic strategy.
  Cancer Immunology and Immunotherapy 10/2008; 58(3):449-59. · 3.70 Impact Factor
• Article: P53-specific T cell responses in patients with malignant and benign ovarian tumors: implications for p53 based immunotherapy.

  Annechien Lambeck, Ninke Leffers, Baukje-Nynke Hoogeboom, Wim Sluiter, Ineke Hamming, Harry Klip, Klaske ten Hoor, Martha Esajas, Magda van Oven, Jan-Wouter Drijfhout, Inge Platteel, Rienk Offringa, Harry Hollema, Kees Melief, Sjoerd van der Burg, Ate van der Zee, Toos Daemen, Hans Nijman
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  ABSTRACT: Despite intensive treatment, 70% of the ovarian cancer patients will develop recurrent disease, emphasizing the need for new approaches such as immunotherapy. A promising antigenic target for immunotherapy in ovarian cancer is the frequently overexpressed p53 protein. The aim of the study was to evaluate the nature and magnitude of the baseline anti-p53 immune response in ovarian cancer patients. P53-specific T cell responses were detected in both half of the ovarian cancer patients as in the group of control subjects, consisting of women with benign ovarian tumors and healthy controls. Importantly, while in the control group p53-specific immunity was detected among the CD45RA(+) naïve subset of T cells only, the p53-specific T-cell responses in ovarian cancer patients were also present in the CD45RO(+) memory T-cell subset, suggesting that in the cancer patients sufficient amounts of cancer-derived p53 was presented to induce the formation of a p53-specific memory T-cell response. Further characterization of the p53-specific memory T-cell responses revealed that in addition to the type 1 cytokine IFN-gamma also the type 2 cytokines IL-4 and IL-5, as well as the immunosuppressive cytokine IL-10 were produced. Notably, p53-specific T cells were not only detected in the peripheral blood, but also among tumor infiltrating lymphocytes and in tumor-draining lymph nodes. In conclusion, the existence of a weak mixed T-helper type 1 and 2 p53-specific T-cell repertoire supports the rationale of using p53 long peptides in vaccination strategies aiming at the induction of p53-specific Th1/CTL immunity.
  International Journal of Cancer 09/2007; 121(3):606-14. · 5.44 Impact Factor
• Article: Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia.

  Jeroen Visser, Debbie van Baarle, Baukje Nynke Hoogeboom, Nathalie Reesink, Harry Klip, Ed Schuuring, Esther Nijhuis, Michael Pawlita, Laura Bungener, Jacqueline de Vries-Idema, Hans Nijman, Frank Miedema, Toos Daemen, Ate van der Zee
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  ABSTRACT: It has been suggested that local invasive procedures may alter the natural course of (pre)malignant cervical disease. This could be due to partial excision of the lesions, or via induction of cellular immunity against human papillomavirus (HPV) by the local invasive procedures. We studied the influence of local invasive procedures on HPV-16 E7 specific immune responses in patients with different grades of cervical intra-epithelial neoplasia (CIN) and different stages of cervical cancer. Blood was obtained at intake and after invasive procedures from patients with CIN or cervical cancer. Antigen specific T-cell responses were measured by IFN-gamma ELISPOT analysis, after stimulation with recombinant HPV-16 E7 protein. As expected, HPV-16 E7 specific IFN-gamma T cell responses were more frequent in HPV-16 DNA positive patients compared with that in HPV-16 DNA negative patients (39/50 vs. 16/36, (p=0.006, chi2 test). After invasive procedures, a small number of HPV-16 DNA positive CIN patients, but a considerable proportion of HPV-16 DNA positive cervical cancer patients, showed an enhancement of T cell responses against HPV-16 E7. Induction of T cell reactivity was most pronounced in cervical cancer patients who had undergone previous invasive procedures. Both CD4+ and CD8+ T cells showed E7 specific IFN-gamma production upon in-vitro stimulation. Our study shows that invasive procedures may enhance HPV-specific cell-mediated immunity in a considerable number of patients with cervical cancer, but in only a minority of CIN patients. Our data indicate that invasive procedures should be considered as possible confounding factors when analyzing the effectiveness of therapeutic immunization studies, especially, when induction of HPV-specific immune responses is used as intermediate end-point.
  International Journal of Cancer 06/2006; 118(10):2529-37. · 5.44 Impact Factor
• Source

  Available from: Toos Daemen

  Article: HLA class I alleles and cervical neoplasia.

  Jeroen T J Visser, Baukje Nynke Hoogeboom, Nathalie Reesink-Peters, Harry Klip, Bouke Hepkema, Hans van Velde, Ate G J van der Zee, Toos Daemen
  The Journal of Infectious Diseases 06/2003; 187(10):1675-6. · 6.41 Impact Factor