@article{822489e1c61b49f0a870a10a4b1f018b,
title = "CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression",
abstract = "Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(−) disease. We report that CD19(−) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(−) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(−) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.",
author = "Kristen Fousek and Junji Watanabe and Joseph, {Sujith K.} and Ann George and Xingyue An and Byrd, {Tiara T.} and Morris, {Jessica S.} and Annie Luong and Mart{\'i}nez-Paniagua, {Melisa A.} and Khaled Sanber and Navai, {Shoba A.} and Gad, {Ahmed Z.} and Salsman, {Vita S.} and Mathew, {Pretty R.} and Kim, {Hye Na} and Wagner, {Dimitrios L.} and Lorenzo Brunetti and Albert Jang and Baker, {Matthew L.} and Navin Varadarajan and Meenakshi Hegde and Kim, {Yong Mi} and Nora Heisterkamp and Hisham Abdel-Azim and Nabil Ahmed",
note = "Funding Information: Acknowledgements This research was supported by the William Lawrence and Blanche Hughes Foundation, Kure It Cancer Research Foundation, and the Stand Up to Cancer–St Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NA was supported by NIH PHS grants U54-CA23256. HA-A was supported by NIH CA225629, Kure It Cancer Research Foundation, St Baldrick{\textquoteright}s-PBMTF, and Gateway Foundation grants. NH was supported by NIH PHS grants CA172040 and CA090321. YMK was supported by NIH CA172896. In addition, KF and TTB were supported by NIH T32 training grants T32GM088129 and 5T32HL092332 from the National Institute of General Medical Sciences and National Heart, Lung and Blood Institute, respectively, and SAN was supported by a K12 award 5K12CA090433. NV and XA were supported by NIH (R01CA174385), CPRIT (RP180466), MRA Award (509800), Owens foundation, CDMRP (CA160591), and NSF (1705464). We would like to acknowledge the Cytometry and Cell Sorting Core at Baylor College of Medicine and the FACS2 Lab of the Saban Research Institute of Children Hospital Los Angeles for their assistance and technical support with flow cytometry and cell sorting experiments, Jing Zhou and Sean Mackay (IsoPlexis Corporation, Branford, CT) for their assistance and technical support for the single-cell polyfunctionality assays. We also would like to thank Dr. Laurence Cooper for generously providing the FMC63-specific antibody for flow cytometry detection of the CD19CAR on T-cells. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2021",
month = jan,
doi = "10.1038/s41375-020-0792-2",
language = "English (US)",
volume = "35",
pages = "75--89",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "1",
}