RESUMEN
Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high cost and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVecTM 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 VivoVecTM particles (VVPs) in the form of a multi-domain 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 non-human primates resulted in the robust generation of anti-CD20 CAR T-cells and the complete depletion of B cells for more than 10 weeks. These data validate the VivoVecTM 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.
RESUMEN
eIF4E plays a conserved role in initiating protein synthesis, but with multiple eIF4E isoforms present in many organisms, these proteins also adopt specialized functions. Previous RNAi studies showed that ife-3, encoding the sole canonical eIF4E isoform of Caenorhabditis elegans, is essential for viability. Using ife-3 gene mutations, we show here that it is maternal ife-3 function that is essential for embryogenesis, but ife-3 null progeny of heterozygous animals are viable. We find that zygotic ife-3 function promotes body growth and regulates germline development in hermaphrodite worms. Specifically, the normal transition from spermatogenesis to oogenesis in the hermaphrodite germline fails in ife-3 mutants. This failure to switch is reversed by inhibiting expression of the key masculinizing gene, fem-3, suggesting ife-3 resembles a growing number of genes that promote the sperm/oocyte switch by acting genetically as upstream inhibitors of fem-3.