In vivo CAR T-cell generation in nonhuman primates using lentiviral vectors displaying a multidomain fusion ligand
Christopher J. Nicolai, Maura H. Parker, Jim Qin, Weiliang Tang, Justin Theophilus Ulrich-Lewis, Rebecca Gottschalk, Sara Cooper, Susana López, Don Parrilla, Richard S. Mangio, Nolan G. Ericson, Alissa Brandes, Saluwa Umuhoza, Kathryn Michels, Mollie M. McDonnell, L. P. Park, Seungjin Shin, Wai‐Hang Leung, Andrew M. Scharenberg, Hans‐Peter Kiem, Ryan Larson, Laurie Beitz, Byoung Y. Ryu
Abstract
ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high costs and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVec platform, a lentiviral vector capable of generating CAR T cells in vivo. Here, we describe the incorporation of T-cell activation and costimulatory signals onto the surface of VivoVec particles (VVPs) in the form of a multidomain fusion protein and show enhanced in vivo transduction and improved CAR T-cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into nonhuman primates resulted in the robust generation of anti-CD20 CAR T cells and the complete depletion of B cells for >10 weeks. These data validate the VivoVec platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies.