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Maastricht, Netherlands

Erben R.G.,University of Veterinary Medicine Vienna | Silva-Lima B.,University of Lisbon | Reischl I.,Austrian Medicines and Medical Devices Agency | Steinhoff G.,University of Rostock | And 7 more authors.
Tissue Engineering - Part A | Year: 2014

The current White paper summarizes the discussions and exchange of experiences during the first European Interdisciplinary Summit on Cell-Based ATMPs held in Vienna, Austria, May 02-03, 2013. The meeting was supported by the Research Networking Programme REMEDIC (regenerative medicine) funded by the European Science Foundation and by the British Medical Research Council. To improve the competitiveness of Europe in the field of cell-based Advanced Medicinal Therapy Products (ATMPs), the following key issues were identified during the meeting: removal of national hurdles in the European Union, harmonization of national and subnational differences in Hospital Exemption rules, improved treatment algorithms for reimbursement, better knowledge on the mode of action, predictive preclinical efficacy and safety testing, need for innovative systems for preclinical testing, appropriate product characterization, manufacturing with cost of goods in mind, and appropriate design of clinical trials. © Copyright 2014, Mary Ann Liebert, Inc. Source


Van Elssen C.H.M.J.,Maastricht University | Van Elssen C.H.M.J.,PharmaCell | Vanderlocht J.,Maastricht University | Oth T.,Maastricht University | And 3 more authors.
Blood | Year: 2011

Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer-dendritic cell (NK-DC) cross-talk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-γ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Opposed to their inhibitory effects on peripheral blood-derived NK cells, PGE2 matured DCs induce IL-22 secretion of inflammation constraining NKp44+ NK cells present in mucosa-associated lymphoid tissue. The inhibition of NK-DC interaction is a novel regulatory property of PGE2 that is of possible relevance in dampening immune responses in vivo. © 2011 by The American Society of Hematology. Source


Frings P.W.H.,Maastricht University | Van Elssen C.H.M.J.,PharmaCell | Wieten L.,Maastricht University | Matos C.,Maastricht University | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2011

Metastatic breast cancer is currently incurable despite initial responsiveness, assumingly due to the presence of chemoresistant subpopulations that can be characterized as label retaining cells (LRC). In the 4T1 mouse breast cancer model, we previously achieved cure after Cyclophosphamide and Total Body Irradiation (CY + TBI) followed by haploidentical bone marrow and spleen transplantation (BMSPLT). CY + TBI without transplantation induced only transient impaired tumor growth indicating a critical role of donor immune cells. As it remained unknown if the 4T1 model resembles human disease with respect to the presence of subpopulations of chemoresistant LRC, we now demonstrate this is indeed the case. Chemoresistance of 4T1 LRC was demonstrated by in vitro co-incubation of fluorescently labeled 4T1 cells in limiting dilution with cyclophosphamide, doxorubicin or cisplatinum, after which only LRC containing colonies remained. LRC also remain in vivo after treatment with CY + TBI. Succeeding experiments set up to identify the haploidentical effector cell responsible for cure and, therefore, for the elimination of chemoresistant LRC designate donor NK cells crucial for the anti-tumor effect. NK cell depletion of the haploidentical graft fully abrogated the anti-tumor effect. Increased disease-free survival retained after transplantation of haploidentical bone marrow and NK cell-enriched spleen cell grafts, even in the absence of donor T-cells or of donor bone marrow. Tumor growth analysis indicates the anti-tumor effect being immediate (days). Based on these data, it is worthwhile to explore alloreactive adoptive NK cell therapy as consolidation for patients with metastasized breast cancer. © 2011 Springer Science+Business Media, LLC. Source


Van Elssen C.H.M.J.,Maastricht University | Van Elssen C.H.M.J.,PharmaCell | Vanderlocht J.,Maastricht University | Frings P.W.H.,Maastricht University | And 8 more authors.
European Journal of Immunology | Year: 2010

Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56 dimCD16 + NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-γ production, the latter of which contributes to Th1 polarization. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Van Elssen C.H.M.J.,Maastricht University | Van Elssen C.H.M.J.,PharmaCell | Frings P.W.H.,Maastricht University | Bot F.J.,Maastricht University | And 6 more authors.
Histopathology | Year: 2010

Aims: Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions.Methods and results: Paraffin-embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear-cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non-neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation-dependent glycoform and 84% the cancer-associated glycoform (Tn/Sialyl-Tn-epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer-associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes.Conclusions: The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1-associated Tn/STn-epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients. © 2010 Blackwell Publishing Limited. Source

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