The overall goal of this project is to establish humanized genetically engineered mice exhibiting a fully human adaptive immune system. These mice will then be used for immunological profiling and drug discovery for personalized cancer immunotherapy. To accomplish this, we will use highly advanced methods in systems and synthetic immunology and genome editing, and patient-derived tumor models. We will establish a set of generalized principles for rapidly and efficiently generating engineered mice. Concurrently, we will leverage our expertise in systems immunology to rationally design synthetic human immunogenomic loci. We will then generate humanized genetically engineered mice with a complete human immune repertoire. All of this will be performed using the general principles genome editing established combined with optimized synthetic designs. These mice will be then fully characterized for their capacity to generate humanized immune receptors, which can then be served as the basis for future drug candidates in personalized cancer immunotherapy.