Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy.

Autor: Atilla PA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA., McKenna MK; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA., Watanabe N; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA., Mamonkin M; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA., Brenner MK; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA., Atilla E; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. Electronic address: erdenatilla@gmail.com.
Jazyk: angličtina
Zdroj: Cytotherapy [Cytotherapy] 2022 Mar; Vol. 24 (3), pp. 282-290. Date of Electronic Publication: 2021 Dec 23.
DOI: 10.1016/j.jcyt.2021.10.007
Abstrakt: Background Aims: Efforts to safely and effectively treat acute myeloid leukemia (AML) by targeting a single leukemia-associated antigen with chimeric antigen receptor (CAR) T cells have met with limited success, due in part to heterogeneous expression of myeloid antigens. The authors hypothesized that T cells expressing CARs directed toward two different AML-associated antigens would eradicate tumors and prevent relapse.
Methods: For co-transduction with the authors' previously optimized CLL-1 CAR currently in clinical study (NCT04219163), the authors generated two CARs targeting either CD123 or CD33. The authors then tested the anti-tumor activity of T cells expressing each of the three CARs either alone or after co-transduction. The authors analyzed CAR T-cell phenotype, expansion and transduction efficacy and assessed function by in vitro and in vivo activity against AML cell lines expressing high (MOLM-13: CD123 high, CD33 high, CLL-1 intermediate), intermediate (HL-60: CD123 low, CD33 intermediate, CLL-1 intermediate/high) or low (KG-1a: CD123 low, CD33 low, CLL-1 low) levels of the target antigens.
Results: The in vitro benefit of dual expression was most evident when the target cell line expressed low antigen levels (KG-1a). Mechanistically, dual expression was associated with higher pCD3z levels in T cells compared with single CAR T cells on exposure to KG-1a (P < 0.0001). In vivo, combinatorial targeting with CD123 or CD33 and CLL-1 CAR T cells improved tumor control and animal survival for all lines (KG-1a, MOLM-13 and HL-60); no antigen escape was detected in residual tumors.
Conclusions: Overall, these findings demonstrate that combinatorial targeting of CD33 or CD123 and CLL-1 with CAR T cells can control growth of heterogeneous AML tumors.
Competing Interests: Declaration of Competing Interest MKB is a co-founder and equity holder of and receives fees from AlloVir, Marker Therapeutics and Tessa Therapeutics. MKB is a scientific advisory board member of and reports personal fees from Allogene Therapeutics, Abintus Bio, Bellicum Pharmaceuticals, Coya Therapeutics, Athenex/Kuur Therapeutics, Marker Therapeutics, Memgen, Tessa Therapeutics, Turnstone Biologics, TScan Therapeutics and Walking Fish Therapeutics. MKB also has stock options from Allogene Therapeutics, Abintus Bio, Coya Therapeutics, TScan Therapeutics and Walking Fish Therapeutics.
(Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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