Human chimeric antigen receptor macrophages for cancer immunotherapy.
Michael KlichinskyMarco RuellaOlga ShestovaXueqing Maggie LuAndrew BestMartha ZeemanMaggie SchmiererKonrad GabrusiewiczNicholas R AndersonNicholas E PettyKatherine D CumminsFeng ShenXinhe ShanKimberly VelizKristin BlouchYumi Yashiro-OhtaniSaad S KenderianMiriam Y KimRoderick O'ConnorStephen R WallaceMiroslaw S KozlowskiDylan M MarchioneMaksim ShestovBenjamin A GarciaCarl H JuneSaar I GillPublished in: Nature biotechnology (2020)
Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging1-4. Given the unique effector functions of macrophages and their capacity to penetrate tumors5, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.