However negative selection in the thymus against these normal nonmutated a ntigens severely limits the abi lity to generate high avidity anti-cancer T cells. Suc h depletion can impair their anti tumor activity and limit tumor elimination. xThe National Cancer Institute Surg ery Branch (NCI SB) has develope d a pipeline for the identification of immunogenic T cell epitopes derived from neoa ntigens. xIn recent studies, we identified the neoantigens recognized by TIL that mediated regression in patients with metas tatic cancer. Using whole exome sequencing of a resected metastatic nodule followed by high throughput immunolog ic screening, we were able to demonstrate that tumor re gressions were associated with t he recognition by the administered TIL of unique somatic m utations that occurred in the cancer. xWe, therefore, aim to use this pipe line to identify immunogenic neoantigens from epithelial cancer patients and to us e these defined epitopes for a personalized therapeutic dendritic cell (DC) vaccine. Objectives: xPrimary objective: oTo determine the clinical respons e rate in patients with metast atic melanoma or epithelial cancer who receive this DC vaccine Eligibility: x$JH\HDUVDQG\HDUV xECOG 0 – 2 xEvaluable metastatic me lanoma or epithelial cancer refractory to standard treatment xMetastatic melanoma or epithelial cancer lesion(s) that is resect able for TIL or in selected cases, available PBMC Design: xPatients with metasta tic melanoma or epith elial cancer will und ergo surgical resection of tumor followed by exome and RNA sequencing to identify expresse d mutations (conducted under the NCI SB c ompanion protocol 03-C-0277). xPatients will undergo apheresis a nd DC will be cryopreserved for vaccine preparation. xImmunogenic neoantigens will be identified from TIL and PBMC by high throughput immunologic screening using long peptides and tandem minigenes c overing all mutated epitopes. xPatient will be vaccinated with aut ologous mature dendritic cells loaded with long peptides and minimal epitopes fro m defined neoantigens or highl y expressed mutations in tumor suppressor or driver genes. Abbreviated Title: Personalized DC Vaccine Version Date: March 26, 2018 3xDC will be administered intravenously and subcutaneously for four c ycles at biweekly intervals. xBlood samples will be taken every two weeks, and patients will b e monitored for the quantity and quality of circulating neoantigen-specific T cells. Abbreviated Title: Personalized DC Vaccine Version Date: March 26, 2018 4TABLE OF CONTENTS PRÉCIS.......................................................................................................................................... 2 TABLE OF CONTENTS ..............................................