{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:55:39Z","timestamp":1791932139326,"version":"4.3.4"},"reference-count":49,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>\n                    Using gene modification of hematopoietic stem cells (HSC) to create persistent generation of multilineage immune effectors to target cancer cells directly is proposed. Gene-modified human HSC have been used to introduce genes to correct, prevent, or treat diseases. Concerns regarding malignant transformation, abnormal hematopoiesis, and autoimmunity exist, making the co-delivery of a suicide gene a necessary safety measure. Truncated epidermal growth factor receptor (EGFRt) was tested as a suicide gene system co-delivered with anti-CD19 chimeric antigen receptor (CAR) to human HSC. Third-generation self-inactivating lentiviral vectors were used to co-deliver an anti-CD19 CAR and EGFRt.\n                    <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                    , gene-modified HSC were differentiated into myeloid cells to allow transgene expression. An antibody-dependent cell-mediated cytotoxicity (ADCC) assay was used, incubating target cells with leukocytes and monoclonal antibody cetuximab to determine the percentage of surviving cells.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    , gene-modified HSC were engrafted into NSG mice with subsequent treatment with intraperitoneal cetuximab. Persistence of gene-modified cells was assessed by flow cytometry, droplet digital polymerase chain reaction (ddPCR), and positron emission tomography (PET) imaging using\n                    <jats:sup>89<\/jats:sup>\n                    Zr-Cetuximab. Cytotoxicity was significantly increased (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.01) in target cells expressing EGFRt after incubation with leukocytes and cetuximab 1\u2009\u03bcg\/mL compared to EGFRt+ cells without cetuximab and non-transduced cells with or without cetuximab, at all effector:target ratios. Mice humanized with gene-modified HSC presented significant ablation of gene-modified cells after treatment (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.002). Remaining gene-modified cells were close to background on flow cytometry and within two logs of decrease of vector copy numbers by ddPCR in mouse tissues. PET imaging confirmed ablation with a decrease of an average of 82.5% after cetuximab treatment. These results give proof of principle for CAR-modified HSC regulated by a suicide gene. Further studies are needed to enable clinical translation. Cetuximab ADCC of EGFRt-modified cells caused effective killing. Different ablation approaches, such as inducible caspase 9 or co-delivery of other inert cell markers, should also be evaluated.\n                  <\/jats:p>","DOI":"10.1089\/hum.2018.180","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T10:25:52Z","timestamp":1552386352000},"page":"413-428","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":49,"title":["A Cetuximab-Mediated Suicide System in Chimeric Antigen Receptor\u2013Modified Hematopoietic Stem Cells for Cancer Therapy"],"prefix":"10.1177","volume":"30","author":[{"given":"Roy L.","family":"Kao","sequence":"first","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel C.","family":"Truscott","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ting","family":"Chiou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satiro N.","family":"De Oliveira","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-400937"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1404588"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-221606"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233151"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.01.035"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386509-0.00010-7"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233158"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-06-507178"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67930"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2012.202"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12128"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.4161\/hv.27637"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2016.1268745"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35700"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35798"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007280"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2088"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-12-580068"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.24"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3182829903"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-337360"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.208"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-2920"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84813"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.12.9873-9880.1998"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.12.9466-9474.1997"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2011.06.019"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im22f05s67"},{"key":"e_1_3_3_30_2","first-page":"21","article-title":"Clonogenic cell survival assay","volume":"110","author":"Munshi A","year":"2005","unstructured":"Munshi A, , Hobbs M, , Meyn RE. 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