To address key limitations of current CAR T cell therapies, Smole and Benton et al. developed a modular platform called Uni-Vect, combining constitutive and antigen-inducible transgene expression in a single lentiviral vector. Transient expression of IL-12 avoided systemic toxicity and boosted antitumor efficacy, constitutive anti-IL-6Rα expression decreased cytokine release syndrome, and inducible expression of transcription factors FOXO1-3A and TCF7 enhanced CAR T cell expansion in vivo. With improved manufacturing of a homogenous cell product compared to two vector systems, Uni-Vect is a foundation for next-generation CAR T cell therapies.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman S
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: anze.smole@nib.si. (2) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (3) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (4) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (5) Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy. (6) Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy. (7) Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy. (8) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (10) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (14) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (15) Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (16) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (17) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (20) Experimental Hematology Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute and University Vita-Salute San Raffaele, 20132 Milan, Italy. (21) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (22) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. (23) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (25) Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy. (26) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: poda@pennmedicine.upenn.edu.
