Human chimeric antigen receptor macrophages for cancer immunotherapy
By M. Klichinsky, M. Ruella, O. Shestova, X. Lu, Andrew Best, Martha E. Zeeman, Maggie Schmierer, Konrad Gabrusiewicz, Nicholas R. Anderson, Nicholas E. Petty and 16 more. Nature Biotechnology, 2020
1,262 citations recorded by the source corpus.
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. Primary macrophages engineered to express chimeric antigen receptors have anti-tumor activity in humanized mice.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/10e85b102cbcc35e9c10acf93066d1a6c26335e5
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Citations in the corpus
- CAR-NK cells: A promising cellular immunotherapy for cancer (2020, background): “[8] For better recognition and killing of tumour cells, immune cells including T cells, [9,10] NK cells, [11] gdT cells, [12] NKT cells, [13] and even macrophages, [14] are engineered to express antigen-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs).”
- Macrophages in immunoregulation and therapeutics (2023, background): “In contrast, substances that hinder M2 polarization, such as CSF1R inhibitors, corosolic acid, omeprazole, Gpr132 inhibitors, MEK/STAT3 inhibitors, fast-mimicking diets, and antibodies against IL-4, IL-4Rα, and IL-13, are also able to diminish the amount of tumor burden.(372) Cancer therapy, immunom”
- Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma (2021, background): “Another approach not yet tried against MPM is the genetic modification with an anti-MSLN CAR of other types of immune cells such as macrophages [147] and natural killer cells [148,149].”