Open AccessHuman chimeric antigen receptor macrophages for cancer immunotherapy
Author(s) -
Michael Klichinsky,
Marco Ruella,
Olga Shestova,
Xueqing Maggie Lu,
Andrew Best,
Martha E. Zeeman,
Maggie Schmierer,
Konrad Gabrusiewicz,
Nicholas Anderson,
Nicholas E. Petty,
Katherine D. Cummins,
Feng Shen,
Xinhe Shan,
Kimberly Veliz,
Kristin Blouch,
Yumi Yashiro–Ohtani,
Saad S. Kenderian,
Miriam Kim,
Roddy S. O’Connor,
Stephen R. Wallace,
Miroslaw Kozlowski,
Dylan M. Marchione,
Maksim Shestov,
Benjamin A. García,
Carl H. June,
Saar Gill
Publication year - 2020
Publication title -
nature biotechnology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.358
H-Index - 445
eISSN - 1546-1696
pISSN - 1087-0156
DOI - 10.1038/s41587-020-0462-y
Subject(s) - chimeric antigen receptor , antigen , immunotherapy , cancer immunotherapy , tumor microenvironment , cancer research , immunology , chemokine , phagocytosis , antigen presentation , macrophage , tumor antigen , t cell , biology , immune system , in vitro , biochemistry
Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging 1-4 . Given the unique effector functions of macrophages and their capacity to penetrate tumors 5 , 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.