In this dissertation, new immune and targeted therapies for advanced melanoma were investigated in daily practice in the Netherlands.From 2013 to 2017, new treatments were implemented fast and save... Show moreIn this dissertation, new immune and targeted therapies for advanced melanoma were investigated in daily practice in the Netherlands.From 2013 to 2017, new treatments were implemented fast and save with an increase of median survival. Increased LDH, distance metastases in ≥3 organsites, brain and liver metastases and ECOG performance score were associated with death. Survival of advanced mucosal melanoma lagged behind. Forty percent of patients receiving systemic treatment did not meet ≥1 selection criteria of clinical trials. In these patients, LDH was the most important prognostic factor, followed by the ECOG performance score and brain metastases. For anti-PD-1 antibody monotherapy, a median survival of 24 months was observed. A complete response or a shorter time to the first response were associated with disease controle when anti-PD-1 montherapy was discontinued in the absence of progression. Half of the patients treated with anti-CTLA-4 plus anti-PD-1 antibodies had a grade 3-4 adverse event, requiering hospital admission in 50%. On the other hand, 37% of patients reached disease control after 2 years, with a median survival of 28.7 months. This dissertation emphasizes that with new treatments there is an "knowledge-gap" between the clinical trials and real-world that should be bridged with real-world data. Show less
Induction of antigen-specific regulatory T cells (Tregs) in vivo is the holy grail of current immune-regulating therapies in autoimmune diseases, such as type 1 diabetes. Tolerogenic dendritic... Show moreInduction of antigen-specific regulatory T cells (Tregs) in vivo is the holy grail of current immune-regulating therapies in autoimmune diseases, such as type 1 diabetes. Tolerogenic dendritic cells (tolDCs) generated from monocytes by a combined treatment with vitamin D and dexamethasone (marked by CD52(hi) and CD86(lo) expression) induce antigen-specific Tregs. We evaluated the phenotypes of these Tregs using high-dimensional mass cytometry to identify a surface-based T cell signature of tolerogenic modulation. Naive CD4(+) T cells were stimulated with tolDCs or mature inflammatory DCs pulsed with proinsulin peptide, after which the suppressive capacity, cytokine production and phenotype of stimulated T cells were analysed. TolDCs induced suppressive T cell lines that were dominated by a naive phenotype (CD45RA(+)CCR7(+)). These naive T cells, however, did not show suppressive capacity, but were arrested in their naive status. T cell cultures stimulated by tolDC further contained memory-like (CD45RA(-)CCR7(-)) T cells expressing regulatory markers Lag-3, CD161 and ICOS. T cells expressing CD25(lo) or CD25(hi) were most prominent and suppressed CD4(+) proliferation, while CD25(hi) Tregs also effectively supressed effector CD8(+) T cells.We conclude that tolDCs induce antigen-specific Tregs with various phenotypes. This extends our earlier findings pointing to a functionally diverse pool of antigen-induced and specific Tregs and provides the basis for immune-monitoring in clinical trials with tolDC. Show less
Loosdrecht, A.A. van de; Wetering, S. van; Santegoets, S.J.A.M.; Singh, S.K.; Eeltink, C.M.; Hartog, Y. den; ... ; Gruijl, T.D. de 2018
