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.
Successful platforms to generate immune receptors for use as drugs have relied on genetically engineered mice with humanized immune systems. Immunization of these mice with antigens results in an immune response that harbors fully human immune receptors. These immune receptors can then be screened directly for potential therapeutic candidates; this approach has successfully resulted in the clinical approval of several drugs. However, current engineered mice are only partially humanized and thus are not able to be used for all applications. Furthermore, these mice have mostly been developed by private industry, thus they are heavily protected either by intellectual property rights, trade secrets, and/or exclusivity clauses, making them nearly inaccessible for the academic research community. Therefore, developing next-generation mouse platforms that are accessible to the research community would greatly enable drug discovery in personalized medicine.
