Science translational medicine
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Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. ⋯ The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
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The therapeutic effects of centrally acting pharmaceuticals can manifest gradually and unreliably in patients, making the drug discovery process slow and expensive. Biological markers providing early evidence for clinical efficacy could help prioritize development of the more promising drug candidates. A potential source of such markers is functional magnetic resonance imaging (fMRI), a noninvasive imaging technique that can complement molecular imaging. fMRI has been used to characterize how drugs cause changes in brain activity. ⋯ A proof-of-concept version of this approach was developed and is shown here for analgesics (pain medication), and validated with eight separate studies of analgesic compounds. Our results show that the systematic integration of multistudy data permits the generalized inferences required for drug discovery. Multistudy integrative strategies of this type could help optimize the drug discovery and validation pipeline.
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Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the gene encoding type VII collagen, resulting in fragile skin and mucous membranes that blister easily in response to mechanical stress. Induced pluripotent stem cells (iPSCs) carry the potential to fundamentally change cell-based therapies for human diseases, in particular for RDEB, for which no effective treatments are available. To provide proof of principle on the applicability of iPSCs for the treatment of RDEB, we developed iPSCs from type VII collagen (Col7a1) mutant mice that exhibited skin fragility and blistering resembling human RDEB. ⋯ Corrected iPSC-derived fibroblasts did not form tumors in vivo and could be traced up to 16 weeks after intradermal injection. Moreover, iPSC-based cell therapy resulted in faithful and long-term restoration of type VII collagen deposition at the epidermal-dermal junction of Col7a1 mutant mice. Intradermal injection of genetically repaired iPSC-derived fibroblasts restored the mechanical resistance to skin blistering in mice with RDEB, suggesting that RDEB skin could be effectively and safely repaired using iPSC-based cell therapy.