Association of TNFRSF10D DNA-Methylation with the Survival of Melanoma Patients

In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated in a test set using FFPE tissue samples from 32 melanoma patients. First, we identified the TNFRSF10D DNA-methylation status (TNFRSF10D methylated vs. unmethylated) as a prognostic marker for overall (p = 0.001) and for relapse-free survival (p = 0.008) in the training set. This finding was confirmed in the independent test set (n = 32; overall survival p = 0.041; relapse-free survival p = 0.012). In a multivariate Cox-regression analysis including all patients, the TNFRSF10D DNA-methylation status remained as the most significant prognostic parameter for overall and relapse-free survival (relative-risk (RR) of death, 4.6 (95% CI: 2.0–11.0; p < 0.001), RR of relapse, 7.2 (95% CI: 2.8–18.3; p < 0.001)). In this study, we demonstrate that TNFRSF10D DNA-methylation analysis of a small tissue-punch from archival FFPE melanoma tissue is a promising approach to provide prognostic information in patients with melanoma

Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo.

PURPOSE: We compared the efficacy of human Langerhans cells (LCs) as tumor immunogens in vivo with monocyte-derived DCs (moDCs) and investigated how IL15 supports optimal DC-stimulated antitumor immunity. EXPERIMENTAL DESIGN: AJCC stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167,www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. RESULTS: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than did moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro demonstrating LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-gamma profile even without exogenous IL15. When supplemented by low dose IL15, instead of IL2, moDCs stimulate 5-6 logs more tumor antigen-specific effector memory T-cells (T(EMRA)) over 3-4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T-cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. CONCLUSIONS: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs

Successful intra-class switching among IL-17 antagonists: a multicentre, multinational, retrospective study

IL-17 blockers are among the newer anti-psoriatic treatment options and little is known about the interclass switching. We have thus initiated a multi-center, multi-national, retrospective study to assess the treatment response of patients who were switched from one IL-17 blocker to another. Analysis consisted of data from patients with moderate-to-severe psoriasis who did not respond satisfactorily to one of the available IL-17 blockers (secukinumab, ixekizumab, brodalumab) and were subsequently switched to another drug of this class. After 12 weeks of treatment, patients’ PASIs were evaluated. Treatment success was defined as reaching PASI 75 after 12 weeks. Topical treatment was allowed and used in all patients. 26 patients were included (13 male, 13 female) and 29 switches were evaluated. Overall, 29 switches in 21 patients were evaluated. 18 patients changed their therapy from secukinumab to ixekizumab, or in 7 cases to brodalumab. Brodalumab was used in 3 cases after failure of treatment with ixekizumab. Only in one case, non-response of brodalumab resulted in a therapy switch to secukinumab. In 15 (52%) cases, PASI 75 was reached. In 6 (20%) patients, the switch led to a PASI 50 response. No success of treatment was seen among 8 (28%) participants. When patients fail to respond or do not tolerate an IL-17 blocker, switching to another anti-IL-17A/RA is a promising viable option. Larger studies are needed to confirm our results