TY - JOUR
T1 - The Art and Science of Selecting a CD123-Specific Chimeric Antigen Receptor for Clinical Testing
AU - Riberdy, Janice M.
AU - Zhou, Sheng
AU - Zheng, Fei
AU - Kim, Young In
AU - Moore, Jennifer
AU - Vaidya, Abishek
AU - Throm, Robert E.
AU - Sykes, April
AU - Sahr, Natasha
AU - Bonifant, Challice L.
AU - Ryu, Byoung
AU - Gottschalk, Stephen
AU - Velasquez, Mireya Paulina
N1 - Funding Information:
We would like to acknowledge the St. Jude Children's Research Hospital Scientific Writing Department for their help with manuscript editing. Preclinical imaging was performed by the Center for In Vivo Imaging and Therapeutics, which is supported in part by NIH grants P01CA096832 and R50CA211481. Preclinical procedures were performed in collaboration with the St. Jude Animal Resource Center. This project was supported in part by The Leukemia Lymphoma Society, St. Baldrick's Foundation, Assisi Foundation of Memphis, Cancer Prevention & Research Institute of Texas (RP101335), and American Lebanese Syrian Associated Charities. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We would like to acknowledge the St. Jude Children’s Research Hospital Scientific Writing Department for their help with manuscript editing. Preclinical imaging was performed by the Center for In Vivo Imaging and Therapeutics, which is supported in part by NIH grants P01CA096832 and R50CA211481 . Preclinical procedures were performed in collaboration with the St. Jude Animal Resource Center. This project was supported in part by The Leukemia Lymphoma Society , St. Baldrick's Foundation , Assisi Foundation of Memphis , Cancer Prevention & Research Institute of Texas ( RP101335 ), and American Lebanese Syrian Associated Charities . The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9/11
Y1 - 2020/9/11
N2 - Chimeric antigen receptor (CAR) T cells targeting CD123, an acute myeloid leukemia (AML) antigen, hold the promise of improving outcomes for patients with refractory/recurrent disease. We generated five lentiviral vectors encoding CD20, which may serve as a target for CAR T cell depletion, and 2nd or 3rd generation CD123-CARs since the benefit of two costimulatory domains is model dependent. Four CARs were based on the CD123-specific single-chain variable fragment (scFv) 26292 (292) and one CAR on the CD123-specific scFv 26716 (716), respectively. We designed CARs with different hinge/transmembrane (H/TM) domains and costimulatory domains, in combination with the zeta (z) signaling domain: 292.CD8aH/TM.41BBz (8.41BBz), 292.CD8aH/TM.CD28z (8.28z), 716.CD8aH/TM.CD28z (716.8.28z), 292.CD28H/TM. CD28z (28.28z), and 292.CD28H/TM.CD28.41BBz (28.28.41BBz). Transduction efficiency, expansion, phenotype, and target cell recognition of the generated CD123-CAR T cells did not significantly differ. CAR constructs were eliminated for the following reasons: (1) 8.41BBz CARs induced significant baseline signaling, (2) 716.8.28z CAR T cells had decreased anti-AML activity, and (3) CD28.41BBz CAR T cells had no improved effector function in comparison to CD28z CAR T cells. We selected the 28.28z CAR since CAR expression on the cell surface of transduced T cells was higher in comparison to 8.28z CARs. The clinical study (NCT04318678) evaluating 28.28z CAR T cells is now open for patient accrual.
AB - Chimeric antigen receptor (CAR) T cells targeting CD123, an acute myeloid leukemia (AML) antigen, hold the promise of improving outcomes for patients with refractory/recurrent disease. We generated five lentiviral vectors encoding CD20, which may serve as a target for CAR T cell depletion, and 2nd or 3rd generation CD123-CARs since the benefit of two costimulatory domains is model dependent. Four CARs were based on the CD123-specific single-chain variable fragment (scFv) 26292 (292) and one CAR on the CD123-specific scFv 26716 (716), respectively. We designed CARs with different hinge/transmembrane (H/TM) domains and costimulatory domains, in combination with the zeta (z) signaling domain: 292.CD8aH/TM.41BBz (8.41BBz), 292.CD8aH/TM.CD28z (8.28z), 716.CD8aH/TM.CD28z (716.8.28z), 292.CD28H/TM. CD28z (28.28z), and 292.CD28H/TM.CD28.41BBz (28.28.41BBz). Transduction efficiency, expansion, phenotype, and target cell recognition of the generated CD123-CAR T cells did not significantly differ. CAR constructs were eliminated for the following reasons: (1) 8.41BBz CARs induced significant baseline signaling, (2) 716.8.28z CAR T cells had decreased anti-AML activity, and (3) CD28.41BBz CAR T cells had no improved effector function in comparison to CD28z CAR T cells. We selected the 28.28z CAR since CAR expression on the cell surface of transduced T cells was higher in comparison to 8.28z CARs. The clinical study (NCT04318678) evaluating 28.28z CAR T cells is now open for patient accrual.
KW - AML
KW - CAR
KW - CD123
KW - T cell therapy
KW - chimeric antigen receptor
KW - immunotherapy
KW - leukemia
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UR - http://www.scopus.com/inward/citedby.url?scp=85088655205&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2020.06.024
DO - 10.1016/j.omtm.2020.06.024
M3 - Article
C2 - 32775492
AN - SCOPUS:85088655205
SN - 2329-0501
VL - 18
SP - 571
EP - 581
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -