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Apeldoorn, Netherlands

Gerritsen W.R.,mc Cancer Center Amsterdam
Annals of Oncology | Year: 2012

The prognosis for men with metastatic, castration-resistant prostate cancer (CRPC) is limited, and patients have very few treatment options, particularly if the treatment failed with docetaxel (Taxotere). As a result, there is a requirement for novel approaches to therapy. Using immunotherapy to induce immune responses to prostate cancer in preclinical and clinical studies appears to be a valid therapeutic approach. In a pivotal phase III trial, treatment with sipuleucel-T, an autologous cellular vaccine consisting of activated antigen-presenting cells loaded with prostatic acid phosphatase (PAP), gave a median overall survival of 25.8 months compared with 21.7 months for placebo-treated patients, resulting in a 22% relative reduction in the risk of death. Based on these results, sipuleucel-T became the first therapeutic vaccine approved for any type of cancer in the USA. PROSTVAC. ®-VF, a poxvirus-based vaccine engineered to present prostate-specific antigen (PSA) and three immune costimulatory molecules, and GVAX, a vaccine consisting of two prostate cancer cell lines (LnCAP and PC3) and genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), both showed promising results in phase II studies, although GVAX failed to meet its primary end point of overall survival when compared with docetaxel in a phase III study. T-cell modulation is another potential immunotherapeutic strategy for CRPC. Ipilimumab, an antibody against the cytotoxic T-lymphocyte-associated antigen-4, is being evaluated in phase I/II studies, both alone and in combination with chemotherapy, radiotherapy or GVAX, with activity in prostate cancer. CRPC is one of the few tumour types where immunotherapy is the current standard of care. Further research, however, will be necessary to improve antitumour responses and clinical benefits, including the use of novel combinatorial approaches. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Melero I.,University of Navarra | Gaudernack G.,University of Oslo | Gerritsen W.,mc Cancer Center Amsterdam | Huber C.,Johannes Gutenberg University Mainz | And 7 more authors.
Nature Reviews Clinical Oncology | Year: 2014

The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy. © 2014 Macmillan Publishers Limited.

Steenbergen R.D.M.,mc Cancer Center Amsterdam | Ongenaert M.,Ghent University | Snellenberg S.,mc Cancer Center Amsterdam | Trooskens G.,Ghent University | And 8 more authors.
Journal of Pathology | Year: 2013

Transformation of epithelial cells by high-risk human papillomavirus (hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations, often affecting tumour suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping (MSDK) to screen for genome-wide DNA-methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes (CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX- 1, PHACTR3, PRDM14, SOST and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation-specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3 and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed significantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16-transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3 and PRDM14 genes in cervical carcinogenesis. These genes may provide promising triage markers to assess the presence of (pre)cancerous cervical lesions in hrHPV-positive women. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Bierkens M.,mc Cancer Center Amsterdam | Hesselink A.T.,mc Cancer Center Amsterdam | Meijer C.J.L.M.,mc Cancer Center Amsterdam | Heideman D.A.M.,mc Cancer Center Amsterdam | And 4 more authors.
International Journal of Cancer | Year: 2013

Combined detection of cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation-associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high-risk human papillomavirus (hrHPV)-positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV-positive women with no underlying high-grade disease, high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN-grade of the corresponding biopsy and second to CIN-grade stratified by the presence of 'normal' or 'abnormal' cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with ≤CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV-positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and ≥5 years). Methylation levels were determined by quantitative methylation-specific PCR and normal cytology scrapes of hrHPV-positive women with histologically ≤CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3- and 6.2-fold in CIN2/3, respectively, and 143.5- and 454.9-fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5- and 13.6-fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer. What's new? The worse the cervical disease, the more heavily methylated the promoters of two genes, CADM1 and MAL, according to a new study. The authors compared the promoter methylation level of the two genes in hrHPV-positive cervical scrapes with the CIN-grade of the underlying disease to try to spot any correlation. Patients with CIN 2/3 had significantly increased promoter methylation of both genes, and those with carcinomas had tremendous increases. Methylation levels also seem to be higher with longer duration of HPV infection, and in hrHPV-positive cervical scrapes with abnormal cytology. Overall, testing for promoter methylation of CADM1 and MAL in cervical scrapes appears to be quite useful for detecting whether a patient requires treatment for cervical disease. Copyright © 2013 UICC.

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