Co-expression of PD-L1 Antibodies Enhances the Anti-Tumor Efficacy of Chimeric Antigen Receptor T Cells

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy against solid tumors has shown limited success in clinical trials. Solid tumors with highly immunosuppressive tumor microenvironment limit the anti-tumor efficacy of CAR-T cell therapy. Herein we generated a novel vector that co-express human mesothelin (MSLN)-targeted CAR and secretory human anti-programmed death ligand 1 (PD-L1) antibodies. The anti-PD-L1 antibodies secreted from the transduced T cells were able to block the interaction of PD-1/PD-L1 to overcome PD-L1-mediated immune suppression. The CAR-T cells targeting mesothelin and secreting PD-L1 antibodies enhanced cytolytic activity against MSLN+PD-L1+ tumor cells and increased the production of cytokines IL-2, TNFα, and IFNγ. The CAR-T cells targeting MSLN and secreting PD-L1 antibodies had enhanced anti-tumor efficacy when compared with the MSLN-targeted CAR-T cells in xenograft mouse models of mesothelioma, pancreatic and ovarian cancers. The results of this study demonstrated that the co-expression of PD-L1 antibody enhances the anti-tumor efficacy of CAR-T cell therapy against solid tumors.