Synchronous BRAF(V600E) and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity.

The BRAF inhibitor (BRAFi) treatment has led to impressive responses in BRAF(V600E) mutation-positive melanomas, but responses are not durable in many patients. As most of the BRAFi escape mechanisms involve ERK reactivation, combinations with MEK inhibitors (MEKi) are currently tested to improve BRAFi-mediated response durations. Additionally, such a combination is expected to reduce MEKi-induced skin toxicities, as these drugs are thought to have antagonistic effects on ERK activation in keratinocytes.

Expression of the embryological morphogen Nodal in stage III/IV melanoma.

The characterization of factors involved in the etiology of melanoma may lead to the identification of new targets for therapy and prognostic markers. Recent data indicate that Nodal can be expressed by malignant melanoma cells and this expression seems to contribute to melanoma development and progression. The aim of this study was to investigate the potential of Nodal as a prognostic marker for stage III/IV patients and as a treatment target for melanoma immunotherapy.

Combination of targeted therapy and immunotherapy in melanoma.

The treatment of human melanoma has progressed markedly in recent years. Building on the observation that immune recognition is a frequent event in melanoma, a series of immunotherapeutic approaches have been evaluated in clinical trials, culminating in the first phase III study improving overall survival of melanoma patients since 20 years. However, the response rates seen upon immunotherapeutic interventions such as anti-CTLA4 treatment are often low.

Overall survival and PD-L1 expression in metastasized malignant melanoma.

Background: Cancers are known to elude the immune system, for example, by MHC loss, FAS up-regulation, or increased secretion of TGF-beta. Recently, ligands of coinhibitory receptors like programmed cell death ligand-1 (PD-L1, B7-H1) have come to attention for their role in tumor immune escape. Various tumors have been tested for PD-L1 expression, and conflicting results were obtained regarding its correlative impact on patient survival.

Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.

The transfer of T cell receptor (TCR) genes can be used to induce immune reactivity toward defined antigens to which endogenous T cells are insufficiently reactive. This approach, which is called TCR gene therapy, is being developed to target tumors and pathogens, and its clinical testing has commenced in patients with cancer. In this study we show that lethal cytokine-driven autoimmune pathology can occur in mouse models of TCR gene therapy under conditions that closely mimic the clinical setting.