TY - JOUR
T1 - Human chimeric antigen receptor macrophages for cancer immunotherapy
AU - Klichinsky, Michael
AU - Ruella, Marco
AU - Shestova, Olga
AU - Lu, Xueqing Maggie
AU - Best, Andrew
AU - Zeeman, Martha
AU - Schmierer, Maggie
AU - Gabrusiewicz, Konrad
AU - Anderson, Nicholas R.
AU - Petty, Nicholas E.
AU - Cummins, Katherine D.
AU - Shen, Feng
AU - Shan, Xinhe
AU - Veliz, Kimberly
AU - Blouch, Kristin
AU - Yashiro-Ohtani, Yumi
AU - Kenderian, Saad S.
AU - Kim, Miriam Y.
AU - O’Connor, Roddy S.
AU - Wallace, Stephen R.
AU - Kozlowski, Miroslaw S.
AU - Marchione, Dylan M.
AU - Shestov, Maksim
AU - Garcia, Benjamin A.
AU - June, Carl H.
AU - Gill, Saar
N1 - Funding Information:
We acknowledge technical support from the University of Pennsylvania (UPenn) Cell and Vaccine Production Facility, UPenn Human Immunology Core, UPenn Stem Cell and Xenograft Core, UPenn Microscopy Core, UPenn Small Animal Imaging Facility, UPenn Flow Cytometry Core, Wistar Institute Flow Cytometry Core and Baylor Vector Development Laboratory. The Vpx plasmid was a kind gift of N. Landau (Department of Microbiology, New York University). Funding was provided by Abramson Cancer Center and Carisma Therapeutics, Inc. M.K. was partially supported by NIH T32 #T32GM008076. Drawings were created with BioRender (www.biorender.com). We thank S. Kelly, B. Peacock, D. Mitchell, N. Minutolo, A. Smole and L. Sepgyr for review of the manuscript.
Funding Information:
M.K. and S.G. are scientific cofounders and Scientific Advisory Board members and hold equity in Carisma Therapeutics. C.J. is a member of the Scientific Advisory Board of Carisma Therapeutics. M.K., S.G. and C.J. are inventors on intellectual property related to this work. S.G. has received research funding from Carisma Therapeutics. A.B., M.Z., M.S., K.G., N.A., Y.O. and M.K. are employees of Carisma Therapeutics. Carisma Therapeutics is a company pursuing the commercial development of this technology.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082120880&partnerID=8YFLogxK
U2 - 10.1038/s41587-020-0462-y
DO - 10.1038/s41587-020-0462-y
M3 - Article
C2 - 32361713
AN - SCOPUS:85082120880
SN - 1087-0156
VL - 38
SP - 947
EP - 953
JO - Nature Biotechnology
JF - Nature Biotechnology
IS - 8
ER -