Human chimeric antigen receptor macrophages for cancer immunotherapy

Nat Biotechnol. 2020 Aug;38(8):947-953. doi: 10.1038/s41587-020-0462-y.

Michael Klichinsky ¹ ² ³, Marco Ruella ¹ ⁴, Olga Shestova ¹, Xueqing Maggie Lu ¹ ⁵, Andrew Best ¹ ³, Martha Zeeman ³, Maggie Schmierer ³, Konrad Gabrusiewicz ³, Nicholas R Anderson ³, Nicholas E Petty ¹, Katherine D Cummins ¹, Feng Shen ¹, Xinhe Shan ¹, Kimberly Veliz ¹, Kristin Blouch ¹, Yumi Yashiro-Ohtani ³, Saad S Kenderian ¹ ⁶, Miriam Y Kim ¹ ⁷, Roddy S O'Connor ¹, Stephen R Wallace ¹, Miroslaw S Kozlowski ¹, Dylan M Marchione ² ⁸, Maksim Shestov ¹, Benjamin A Garcia ⁸, Carl H June ¹ ² ⁹, Saar Gill ¹⁰ ¹¹ ¹²

Affiliations

1 Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
2 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
3 Carisma Therapeutics, Philadelphia, PA, USA.
4 Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
5 Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.
6 Division of Hematology, Mayo Clinic, Rochester, MN, USA.
7 Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, MO, USA.
8 Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
9 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
10 Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. [email protected].
11 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. [email protected].
12 Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. [email protected].

PMID: 32361713 DOI: 10.1038/s41587-020-0462-y

Abstract

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 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.

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