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 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.