Nanocomplex-Mediated In Vivo Programming to Chimeric Antigen Receptor-M1 Macrophages for Cancer Therapy

Chimeric antigen receptor-T (CAR-T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo cell-manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR-T cell infiltration to solid tumors and inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR-M1 macrophages displaying enhanced cancer-directed phagocytosis and anti-tumor activity. In vivo injected nanocomplexes of macrophage-targeting nanocarriers and CAR-interferon-gamma-encoding plasmid DNA induce CAR-M1 macrophages that are capable of CAR-mediated cancer phagocytosis, anti-tumor immunomodulation, and inhibition of solid tumor growth. Together, this study describes an off-the-shelf CAR-macrophage therapy that is effective for solid tumors and avoids the complex and costly processes of ex vivo CAR-cell manufacturing.

Automated summary

The study proposes a simple method to transform macrophages that can naturally infiltrate solid tumors into CAR-M1 macrophages with enhanced cancer-directed phagocytosis and anti-tumor activity. Injected nanocomplexes of macrophage-targeting nanocarriers and CAR-interferon-gamma-encoding plasmid DNA induce CAR-M1 macrophages capable of CAR-mediated cancer phagocytosis, tumor immunomodulation, and inhibiting solid tumor growth, providing an effective off-the-shelf CAR-macrophage therapy for solid tumors without the need for complex and costly ex vivo CAR-cell manufacturing processes.