Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy. [Display omitted] •Uni-Vect combines constitutive and inducible expression in a single lentivirus•IL-12 delivered by Uni-Vect safely enhances the efficacy of CAR-T cells in vivo•Autonomous release of an IL-6R-blocking antibody in CAR-T cells ameliorates CRS•Transient transcription factor expression improves CAR-T cell expansion in vivo Smole et al. develop a single-vector lentiviral system that combines constitutive and antigen-inducible transgene expression, called Uni-Vect. The therapeutic impact of Uni-Vect is demonstrated in CAR-T cells using an immunostimulatory cytokine that safely enhances efficacy, an antibody that ameliorates cytokine-release syndrome (CRS), and a transcription factor that enhances expansion.