Suchergebnisse

Abstract Background: Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression and therapy resistance. Specific tools for image-guided analysis of spatio-temporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of [18F]DPA-714 (TSPO) PET-MRI in the assessment of the immunosuppressive TME in glioma patients and (ii) to cross-correlate imaging findings with in-depth immunophenotyping. Methods: To characterize the glioma TME, a mixed collective of nine glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]FET-PET-MRI. Image-guided biopsy samples were immuno-phenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity. Results: We found a strong relationship (r = 0.84, p = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to HLA-DR+ activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution. Conclusion: [18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME. ; This work has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 675417 AND from the Innovative Medicines Initiative 2 Joint Undertaking under grant ...

Introduction Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. Methods and analysis Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. Ethics and dissemination Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. ; A FACTT network (Cost Action) [BM1305]; EU Framework Program Horizon 2020; European Union's Horizon 2020 research and innovation program [779316]; applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders [IWT-TBM 140191]; Platform for Clinical Research and Clinical Trial Units, Spanish Clinical Research Network, SCReN [PI11/02416, PI14/01175, PI16/01737, PT13/0002/0038]; Health Institute Carlos III -Subdireccion General de Evaluacion y Fomento de la Investigacion of the Spanish Ministry of Economy and Competitiveness; Fondo Europeo de Desarrollo Regional (FEDER)European Union (EU); Fundacio La Marato de TV3 [07/2410]; Sanofi Genzyme, Belgium; Research Foundation Flanders (FWO)FWO; Hospital Germans Trias i Pujol ('Germans Trias Talents 2016-2018'); University of Antwerp; Research Foundation FlandersFWO [FWO 1701919N]; Spanish Patient association 'Treball de Vida' (Associacio d'Afectats d'Esclerosi Multiple del Barcelones Nord i Maresme)