Targeted in vivo delivery of genetic medicines utilizing an engineered lentiviral vector platform results in CAR T and NK cell generation

Abstract

The development of chimeric antigen receptor (CAR) T cell therapies has greatly impacted the treatment of B cell malignancies; however, manufacturing these patient-specific, autologous cell therapies is complex, costly, and requires preconditioning chemotherapy prior to infusion, limiting patient access. Here we describe the development of a lentiviral platform based on a novel, detargeted viral fusogen (Gen 2.1 Fusogen) and a membrane-bound targeting moiety to enable in vivo targeted delivery of stably integrating genetic medicines without the need for lymphodepletion. INT2104 employs a single chain variable fragment (scFv) targeting CD7 ("CD7 Binder") to deliver a CAR20 transgene to CD7⁺ T and natural killer (NK) cells. Preclinical data generated in mouse and cynomolgus macaque models indicate INT2104 results in both CAR T cells (CD4⁺ and CD8⁺) and CAR NK cells with subsequent depletion of CD20⁺ B cells following a single intravenous administration. Thus, INT2104 could potentially provide a more accessible, off-the-shelf treatment option for patients who may benefit from CAR therapies.

Keywords: CAR T and NK cells; engineered lentiviral vector; genetic medicine; in vivo delivery.