2 TABLE OF CO NTENTS ............................................................................................................. 4 1 INTRODUCTION............................................................................................................. 8 Study Objectives ............................................................................................................. 8 1.1.1 Primary Objectives...................................................................................................... 8 1.1.2 Secondary Objective ................................................................................................... 8 Background and Rationale .............................................................................................. 8 1.2.1 Cancer Vaccines.......................................................................................................... 8 1.2.2 Identification of Cancer-Specific Imm unogenic Epitopes Derived from Somatic Mutations ..................................................................................................................... ........... 9 1.2.3 Overview of mRNA-4650, a mRNA-Based, Personalized Cancer Vaccine ............ 11 1.2.4 Preclinical Experiments Evaluating th e Safety of mRNA-Based, Personalized Cancer Vaccines ............................................................................................................... ..... 11 1.2.5 Preclinical Experiments Evaluating the Immunogenicity of a mRNA-Based, Personalized Cancer Vaccine in Mice .................................................................................. 12 1.2.6 Preclinical Experiments Evaluating the Pr esentation of CD4 and CD8 Epitopes by Human Dendritic Cells ......................................................................................................... 16 1.2.7 Rationale for Selecting Defined Epit opes, Predicted Epitopes, and Tumor Suppressor and Driver Neoantigen s to Use in this Trial ....................................................... 17 1.2.8 Structure of NCI-4650 .............................................................................................. 17 1.2.9 Risk for NCI-4650 Monotherapy .............................................................................. 18 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ..............................................