This article was originally published here
Mol Ther. 2022 May 20:S1525-0016(22)00316-1. doi: 10.1016/j.ymthe.2022.05.018. Online ahead of print.
Chimeric antigen receptor (CAR) T cells are a cancer immunotherapy of extremes: Unprecedentedly effective, but complex and costly to manufacture, they are not yet a therapeutic option for all who would benefit. This disparity has motivated worldwide efforts to simplify treatment. Among the proposed solutions, the generation of CAR T cells directly in the patient, i.e. in vivo, is arguably simultaneously the most technically challenging and clinically useful approach to convert CAR therapy from a cell-based autologous medicinal product into a universally applicable off-the-shelf treatment. Here we review the current state-of-the-art of in vivo CAR therapy, focusing especially on the vector technologies used. These cover lentiviral vectors, adenovirus-associated vectors as well as synthetic polymer nanocarriers and lipid nanoparticles. Proof-of-concept, i.e. the generation of CAR cells directly in mouse models, has been demonstrated for all vector platforms. Receptor-targeting of vector particles is crucial, as it can prevent CAR gene delivery into off-target cells, thus reducing toxicities. We discuss the properties of the vector platforms, such as their immunogenicity, potency, and modes of CAR delivery (permanent versus transient). Finally, we outline the work required to advance in vivo CAR therapy from proof-of-concept to a robust, scalable technology for clinical testing.