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 over-expressed antigens. However, negative selection in the thymus against these normal non-mutated antigens severely limits the ability to generate high avidity anti-cancer T-cells. The importance of neoantigens to each patient’s unique cancer as targets for immunotherapy has been extensively studied, by our group and others. It is now clear that neoantigen-specific T-cells are present in most cancers and these neoantigens derived from somatic mutations offer a specific and highly immunogenic target for personalized vaccination. We developed a process to identify immunogenic T-cell epitopes derived from tumor-specific mutations using tumor-infiltrating lymphocytes. Methods: We combined, for the first time, validated defined neoantigens, predicted neoepitopes and mutations in driver genes into a single mRNA concatemer (mRNA-4650) to vaccinate patients with metastatic common epithelial cancers. We are conducting a phase I/II trial in patients with metastatic melanoma, gastrointestinal, or genitourinary cancers with at least one lesion that is resectable. Patients must have an ECOG status of ≤1 with adequate organ and bone marrow function. Patients are vaccinated intramuscularly at two-week intervals for four cycles, and dosing may be repeated for a second course of vaccination. Key primary endpoints are safety, tolerability and the development of T-cell reactivity as well as objective response rate. Results: mRNA-4650 is safe at all dose levels studied to date with no reported DLTs or drug related SAEs. Neoantigen specific CD8 and CD4 T cells responses against neoepitopes included in the vaccine have been observed and no tumor regressions were seen. Conclusions: Our data show that such a personalized mRNA vaccination is feasible and can elicit neoantigen specific T cell responses. Combination of vaccines with checkpoint inhibitors or adoptive T cell therapy can open the possibility to develop effective immunotherapies for patients with the common epithelial cancers. Clinical trial information: NCT03480152