PhD Student The University of Hong Kong, Hong Kong
Abstract: Chimeric antigen receptor (CAR) immunotherapy in solid tumors remains limited due to the immunosuppressive microenvironment and poor infiltration of immune cells. Overcoming both is essential for CAR immunotherapy in solid tumors. Here, we designed AntiBody-CAR-Macrophage (AB-CAR-M) to remodel the immunosuppressive microenvironment and improve infiltration for the treatment of Hepatocellular Carcinoma (HCC). We engineering CAR-M to secrete single chain variable fragments (scFv) to block immunosuppressive signals. AB-CAR-M reinvigorated cytotoxic T-cells, macrophages and downregulates bystander CD4+ T-cells Treg programs by counteracting immunosuppressive signals, indicating that immunosuppressive signal blocking converted the immunosuppressive microenvironment into immunogenic. AB-CAR-M promoted in vitro phagocytosis and killing of liver cancer cells. We administered AB-CAR-M to the tumor-bearing immunodeficient NSG mice to examine infiltration. AB-CAR-M formed perivascular immunological hubs with host macrophages in the tumor. Co-administration of AB-CAR-M and T-cells reduced tumor volume on the ipsilateral site, while the contralateral site was unaffected, suggesting the spatial confinement of macrophage immunotherapy which is promising for local delivery of blocking scFv. Moreover, murine AB-CAR-M shrinks orthotopic liver cancer in immunocompetent mice models. Patients’ tumor slice cultures are underway to determine the nature of the immunological hubs formed by AB-CAR-M. Overall, these data reinforce AB-CAR-M as a solution for solid tumors. Our ultimate goal is to apply the AB-CAR-M in universal donor human pluripotent stem cells for off-the-shelf generation of cell therapy products.
