Engineered outer membrane vesicles enhance solid tumour CAR-T cell therapy.

Abstract

Major challenges facing chimeric antigen receptor (CAR)-T cell therapy for solid tumours include the immunosuppressive tumour microenvironment and the heterogeneity of antigen expression. Bacterial outer membrane vesicles (OMVs) naturally activate the immune system and can be engineered for drug delivery. Here we develop a bacterial OMV-based immunosuppression reversal and optimized antigen decoration platform for CAR-T therapy (BROAD-CAR), in which OMVs are modified to express a high-affinity anti-PD-L1 antibody and load plasmids encoding the target antigen for CARs. By blocking the PD-1/PD-L1 signalling pathway, our tumour-targeting platform enhances the antitumour activity of CAR-T cells both in vitro and in vivo and boosts CAR-T cell expansion by ameliorating the tumour microenvironment. BROAD-CAR also facilitates the in situ antigenic modification of solid tumours and achieves CAR-mediated lysis of antigen-heterogeneous and antigen-negative tumours, inhibiting tumour recurrence and metastasis in the breast cancer mouse models. Our findings highlight a safe and efficient approach to enhance the efficacy and applicability of CAR-T therapy in solid tumours.