Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50-60% of the patients have no clinical benefit.,Here, we searched for predictive biomarkers to ACT in melanoma.,Whole exome- and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma.,All patients had previously progressed on other immunotherapies.,We report that clinical benefit is associated with significantly higher predicted neoantigen load.,High mutation and predicted neoantigen load are significantly associated with improved progression-free and overall survival.,Further, clinical benefit is associated with the expression of immune activation signatures including a high MHC-I antigen processing and presentation score.,These results improve our understanding of mechanisms behind clinical benefit of ACT in melanoma.,Adoptive T cell therapy (ACT) has yielded high response rates in melanoma, however 50-60% of patients experience no clinical benefit.,Here, the authors identify predictive biomarkers, high non-synonymous mutation and high expressed neoantigen load, that associate with clinical benefit in ACT melanoma patients.
BRAFV600E/K is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032.,Our studies with melanoma tumor cells that are BRAFV600E/K and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAFV600E/K, it activated the pathway in the resistant BRAFWT cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN.,The persistently active ERK1/2 triggered downstream effectors in BRAFWT melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control.,Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions.,The results suggest that the drug can confer an advantage to BRAFWT primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.