RESUMEN

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.

Asunto(s)

Vectores Genéticos , Inmunoterapia Adoptiva , Lentivirus , Receptores Quiméricos de Antígenos , Linfocitos T , Animales , Lentivirus/genética , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Humanos , Inmunoterapia Adoptiva/métodos , Ligandos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Transducción Genética , Antígenos CD20/inmunología , Antígenos CD20/genética , Activación de Linfocitos