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

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy faces challenges in solid tumors, including immunosuppressive tumor microenvironments and variable antigen expression.
• Bacterial outer membrane vesicles (OMVs) are immunomodulatory and suitable for engineered drug delivery.

Purpose of the Study:

• To develop a bacterial OMV-based platform, BROAD-CAR, for reversing immunosuppression and optimizing antigen presentation in CAR-T cell therapy for solid tumors.
• To enhance the anti-tumor activity and expansion of CAR-T cells by targeting the PD-1/PD-L1 pathway and modifying tumor antigens.

Main Methods:

• Engineered bacterial outer membrane vesicles (OMVs) to express anti-PD-L1 antibodies and deliver target antigen plasmids for CARs.
• Utilized the BROAD-CAR platform to block PD-1/PD-L1 signaling and modify tumor antigens in situ.
• Evaluated the efficacy of BROAD-CAR in combination with CAR-T cells in vitro and in vivo breast cancer mouse models.

Main Results:

• The BROAD-CAR platform effectively blocked the PD-1/PD-L1 signaling pathway, enhancing CAR-T cell anti-tumor activity and proliferation.
• BROAD-CAR ameliorated the immunosuppressive tumor microenvironment, leading to improved CAR-T cell expansion.
• The platform facilitated in situ tumor antigen modification, enabling CAR-T cell-mediated lysis of antigen-heterogeneous and antigen-negative tumors, and inhibited recurrence and metastasis.

Conclusions:

• The bacterial OMV-based BROAD-CAR platform offers a safe and efficient strategy to overcome key limitations of CAR-T cell therapy in solid tumors.
• This approach enhances CAR-T cell efficacy and broadens applicability, particularly for antigen-heterogeneous and antigen-negative solid tumors.
• BROAD-CAR represents a promising advancement for improving CAR-T cell therapy outcomes in challenging solid tumor settings.