In vivo CAR T-cell generation in nonhuman primates using lentiviral vectors displaying a multidomain fusion ligand

• Published in: Blood Vol. 144; no. 9; pp. 977 - 987
• Main Authors: Nicolai, Christopher J., Parker, Maura H., Qin, Jim, Tang, Weiliang, Ulrich-Lewis, Justin T., Gottschalk, Rebecca J., Cooper, Sara E., Hernandez Lopez, Susana A., Parrilla, Don, Mangio, Richard S., Ericson, Nolan G., Brandes, Alissa H., Umuhoza, Saluwa, Michels, Kathryn R., McDonnell, Mollie M., Park, Lisa Y., Shin, Seungjin, Leung, Wai-Hang, Scharenberg, Andrew M., Kiem, Hans-Peter, Larson, Ryan P., Beitz, Laurie O., Ryu, Byoung Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2024; The American Society of Hematology
• Subjects: Animals; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Genetic Vectors; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive - methods; Lentivirus - genetics; Ligands; Lymphocyte Activation; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transduction, Genetic
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024024523

•Lentiviral vectors displaying T-cell activation and costimulatory molecules (VivoVec) generate CAR T cells in vivo without lymphodepletion.•VivoVec administration in nonhuman primates generates anti-CD20 CAR T cells in vivo, leading to prolonged complete B-cell depletion. [Display omitted] 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. Chimeric antigen receptor (CAR) T-cell administration has become an important modality for therapy for B-cell lymphoma, but it is hampered by the inherent delay of individual product manufacture. Nicolai et al report the development of a viral vector expressing surface T-cell activation and costimulatory signals for in vivo transduction of CAR T cells. Administration of the vector to nonhuman primates led to anti-CD20 CAR T cells and B-cell depletion, suggesting this may offer a new paradigm for CAR T-cell therapy.