Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms

• Published in: Molecular therapy Vol. 30; no. 7; pp. 2401 - 2415
• Main Authors: Michels, Alexander, Ho, Naphang, Buchholz, Christian J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2022; American Society of Gene & Cell Therapy
• Subjects: AAV; Animals; Immunotherapy, Adoptive; lentiviral vector; Liposomes; LNP; Mice; nanoparticle; Nanoparticles; off the shelf; Precision Medicine; Receptors, Antigen, T-Cell - genetics; Receptors, Chimeric Antigen - genetics; Review; T lymphocyte; T-Lymphocytes; nanoparticle; T lymphocyte; off the shelf; AAV; lentiviral vector; LNP
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.05.018

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 and 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. [Display omitted] Buchholz and colleagues review recent publications providing preclinical proof of concept for the generation of CAR T cells directly in vivo. They find that in this advance toward a new generation of immunotherapies, receptor-targeted viral and synthetic vector systems mediating selective gene transfer into T lymphocytes have played a critical role.