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Human chimeric antigen receptor macrophages for cancer immunotherapy.

Nat Biotechnol 2020 08 23;38(8):947-953. Epub 2020 Mar 23.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging. Given the unique effector functions of macrophages and their capacity to penetrate tumors, 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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August 2020
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Am J Respir Cell Mol Biol 2021 Feb 24. Epub 2021 Feb 24.

Weill Cornell Medical College, Medicine/ Pulmonary and Critical Care, New York, New York, United States;

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Inflamm Bowel Dis 2021 Feb 24. Epub 2021 Feb 24.

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Background: Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD.

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Wellcome Open Res 2020 9;5:286. Epub 2020 Dec 9.

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Efficient Immune Cell Genome Engineering with Enhanced CRISPR Editing Tools.

Immunohorizons 2021 Feb 23;5(2):117-132. Epub 2021 Feb 23.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

Clustered regularly interspaced short palindromic repeats (CRISPR)-based methods have revolutionized genome engineering and the study of gene-phenotype relationships. However, modifying cells of the innate immune system, especially macrophages, has been challenging because of cell pathology and low targeting efficiency resulting from nucleic acid activation of intracellular sensors. Likewise, lymphocytes of the adaptive immune system are difficult to modify using CRISPR-enhanced homology-directed repair because of inefficient or toxic delivery of donor templates using transient transfection methods. Read More

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Retrovirology 2021 Feb 23;18(1). Epub 2021 Feb 23.

Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA.

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