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.
Melanoma represents a significant malignancy in humans and dogs.,Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model.,Canine melanomas rarely arise in sun-exposed sites.,Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma.,The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis.,Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs.,Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation.,We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas.,This represents opportunity to explore canine oral cavity melanoma as a preclinical model.