Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer

Background: * Therapeutic vaccination against cancer has proven very challenging with little clinical benefit. * Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and overexpressed antigens. However negative selection in the thymus against these normal nonmutated antigens severely limits the ability to generate high avidity anti-cancer T cells. Such depletion can impair their antitumor activity and limit tumor elimination. * The National Cancer Institute Surgery Branch (NCI SB) has developed a pipeline for the identification of immunogenic T cell epitopes derived from neoantigens. * In recent studies, we identified the neoantigens recognized by tumor infiltrating lymphocytes (TIL) that mediated regression in patients with metastatic cancer. Using whole exome sequencing of a resected metastatic nodule followed by high throughput immunologic screening, we were able to demonstrate that tumor regressions were associated with the recognition by the administered TIL of unique somatic mutations that occurred in the cancer. * We, therefore, aim to use this pipeline to identify immunogenic neoantigens from epithelial cancer patients and to use these defined epitopes for a personalized therapeutic dendritic cell (DC) vaccine. Objectives: -Primary objectives: --To determine the clinical response rate in patients with metastatic melanoma or epithelial cancer who receive this DC vaccine Eligibility: * Age greater than or equal to 18 and less than or equal to 70 years * Eastern Cooperative Oncology Group (ECOG) 0 - 2 * Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment * Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in selected cases, available peripheral blood mononuclear cells (PBMC). Design: * Patients with metastatic melanoma or epithelial cancer will undergo surgical resection of tumor followed by exome and ribonucleic acid (RNA) sequencing to identify expressed mutations (CONDUCTED UNDER THE National Cancer Institute Surgery Branch (NCI SB) COMPANION PROTOCOL 03-c-0277). * Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation. * Immunogenic neoantigens will be identified from TIL and PBMC by high throughput immunologic screening using long peptides and tandem minigenes covering all mutated epitopes. * Patient will be vaccinated with autologous mature dendritic cells loaded with long peptides and minimal epitopes from defined neoantigens or highly expressed mutations in tumor suppressor or driver genes. * DC will be administered intravenously and subcutaneously for four cycles at biweekly intervals. * Blood samples will be taken every two weeks, and patients will be monitored for the quantity and quality of circulating neoantigen-specific T cells.