CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.

Autor: Fousek K; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Watanabe J; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States., Joseph SK; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., George A; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States., An X; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA., Byrd TT; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Morris JS; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Luong A; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States.; University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Martínez-Paniagua MA; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA., Sanber K; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Navai SA; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Gad AZ; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Salsman VS; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Mathew PR; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Kim HN; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States.; University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Wagner DL; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Institute of Medical Immunology, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin Institute of Health-Center for Regenerative Therapies (B-CRT), Charité-Universitätsmedizin Berlin, Berlin, Germany., Brunetti L; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA., Jang A; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA., Baker ML; National Center for Macromolecular Imaging and Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA., Varadarajan N; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA., Hegde M; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Kim YM; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States.; University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Heisterkamp N; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States.; University of Southern California Keck School of Medicine, Los Angeles, CA, USA.; Department of Systems Biology, Beckman Research Institute City of Hope, Duarte, CA, United States., Abdel-Azim H; Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States. habdelazim@chla.usc.edu.; University of Southern California Keck School of Medicine, Los Angeles, CA, USA. habdelazim@chla.usc.edu., Ahmed N; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.; Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.; Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2021 Jan; Vol. 35 (1), pp. 75-89. Date of Electronic Publication: 2020 Mar 24.
DOI: 10.1038/s41375-020-0792-2
Abstrakt: 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.
Databáze: MEDLINE
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