Generating CAR-T cells in vivo by gene targeting

T cells expressing chimeric antigen receptors (CAR) have transformed cell therapies against some cancers.

As a postdoctoral fellow, I evolved a synthetic adeno-associated virus (AAV) with tropism against murine T cells, providing a unique tool to study gene targeted T cells in immunocompetent cancer models.

In this proposal, capitalizing on my break-through, I will develop novel strategies to generate functional gene targeted CAR-T cells in vivo, optimizing AAV delivery in immunocompetent mouse models and combining these methods with cutting-edge technologies for Cas9-delivery for T cell-specific gene editing.

Building a collaborative team in a strong translational research environment, we will evaluate the therapeutic potential of in vivo generated CAR-T cells against syngeneic tumors in immunocompetent mice, and include T cell adjuvant therapies to improve the efficacy. The ultimate goal of my proposal is to develop methods that can be translated to clinical trials in humans.

Therefore, we will establish a humanized mouse model that allows for targeting of human T cells in vivo, in which key findings from this research project will be translated for proof-of-concept experiments.

As the first ever study of gene targeted T cells in vivo, my research will provide in-depth profiling of in vivo engineered CAR-T cells and their therapeutic potential.

This study is a necessary first step forwards toward accessible and affordable in vivo generated CAR-T cell therapies in humans.