Human chimeric antigen receptor macrophages for cancer immunotherapy

Michael Klichinsky, Marco Ruella, Olga Shestova, Xueqing Maggie Lu, Andrew Best, Martha Zeeman, Maggie Schmierer, Konrad Gabrusiewicz, Nicholas R. Anderson, Nicholas E. Petty, Katherine D. Cummins, Feng Shen, Xinhe Shan, Kimberly Veliz, Kristin Blouch, Yumi Yashiro-Ohtani, Saad S. Kenderian, Miriam Y. Kim, Roddy S. O’Connor, Stephen R. WallaceMiroslaw S. Kozlowski, Dylan M. Marchione, Maksim Shestov, Benjamin A. Garcia, Carl H. June, Saar Gill

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)947-953
Number of pages7
JournalNature biotechnology
Volume38
Issue number8
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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