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T cells expressing chimeric antigen receptors (CAR) have transformed cell therapies against some hematological cancers. Genome engineering is a fast-moving field and recent advances in engineering of primary T cells have expanded the horizon of CAR-T cell therapies, and unlocked the potential to target a broader range of malignancies and to improve overall T cell fitness. However, the manufacturing process of CAR-T cell therapies is time-consuming, complex and costly. This limits the potential reach of CAR-T cell therapies around the world. The overall goal of our research is to develop strategies for precisely engineered CAR-T cell therapies in vivo, and to use the latest technologies in advanced gene engineering to improve their efficacy. To succeed with these goals, we will mainly use adeno-associated viruses (AAV) targeting T cells to generate gene targeted CAR-T cells in vivo. These AAVs are combined with a variety of in vivo delivery vehicles for Cas9 nucleases, such as viral-like particles (VLP) or lipid nanoparticles (LNP). These studies will be performed in translational humanized mouse models and in fully immunocompetent syngeneic mouse models. The second part of our mission is to improve CAR-T cell therapies by advances gene engineering, to succeed with this goal we are using pooled knock-in screens of large libraries of synthetic receptors that help CAR-T cells relay inhibitory signals commonly found in tumor microenvironments (TME) to co-stimulatory signals that may improve T cell fitness. These studies are performed in immunocompetent mouse models that represent a wide variety of different TME challenges. Our research promises to democratize access to advanced CAR-T cell therapies by avoiding ex vivo cell manufacturing, as well as improve the potential for CAR-T cell therapies in challenging solid tumors.