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Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia

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Last modified
  • 06/25/2025
Type of Material
Authors
    Gianna Branella, Emory UniversityJasmine Y. Lee, Emory UniversityJennifer Okalova, Emory UniversityKiran K. Parwani, Emory UniversityJordan Shields Alexander, Emory UniversityRaquel F. Arthuzo, Emory UniversityAndrew Fedanov, Emory UniversityBing Yu, Expression Therapeutics Inc.David McCarty, Expression Therapeutics Inc.Harrison C. Brown, Expression Therapeutics Inc.Shanmuganathan Chandrakasan, Emory UniversityBrian G. Petrich, Expression Therapeutics Inc.Christopher Doering, Emory UniversityH. Trent Spencer, Emory University
Language
  • English
Date
  • 2023-11-13
Publisher
  • Frontiers
Publication Version
Copyright Statement
  • © 2023 Branella, Lee, Okalova, Parwani, Alexander, Arthuzo, Fedanov, Yu, McCarty, Brown, Chandrakasan, Petrich, Doering and Spencer
License
Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 14
Start Page
  • 1294555
Grant/Funding Information
  • The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from Curing Kids Cancer and the National Institutes of Health under an R21 grant (5R21CA223300 to HS) and an F31 grant awarded to Emory University (5F31CA265249-02 to GB).
Supplemental Material (URL)
Abstract
  • The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αβ T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.
Author Notes
Keywords
Research Categories
  • Health Sciences, Immunology
  • Biology, Cell
  • Health Sciences, Oncology

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