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CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses

  1. Author:
    Nguyen, Kilyna A [ORCID]
    Liu, Zhihui [ORCID]
    Davies, John S [ORCID]
    McIntosh, Crystal P
    Draper, Lindsey M [ORCID]
    Norberg, Scott M [ORCID]
    Rae, Zachary
    Achar, Sooraj R [ORCID]
    Altan-Bonnet, Gregoire [ORCID]
    Zhang, Ling
    Wu,Xiaolin [ORCID]
    Meyer, Thomas J [ORCID]
    Kelly, Michael C [ORCID]
    Taylor, Naomi [ORCID]
    Hinrichs, Christian S [ORCID]
    Ishii, Kazusa [ORCID]

  2. Author Address

    Center for Immuno-Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA., Pediatric Oncology Branch, CCR, NCI, NIH, Bethesda, MD, USA., Department of Safety Assessment, Genentech Inc., South San Francisco, CA, USA., Single Cell Analysis Facility, CCR, NCI, NIH, Bethesda, MD, USA., Laboratory of Integrative Cancer Immunology, CCR, NCI, NIH, Bethesda, MD, USA., Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, MD, USA., CCR Collaborative Bioinformatics Resource, CCR, NCI, NIH, Bethesda, MD, USA., Duncan and Nancy MacMillan Center of Excellence in Cancer Immunotherapy and Metabolism, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,
    1. Year: 2025
    2. Date: Apr 11
    3. Epub Date: 2025 04 09
  2. Journal: Science Advances
    1. 11
    2. 15
    3. Pages: eadq4297
  4. Type of Article: Article
  5. Article Number: eadq4297
  1. Abstract:

    Chimeric antigen receptor (CAR) T cells effectively treat B cell malignancies. However, CAR-T cells cause inflammatory toxicities such as cytokine release syndrome (CRS), which is in contrast to T cell receptor (TCR)-engineered T cells against various antigens that historically have rarely been associated with CRS. To study whether and how differences in receptor types affect the propensity for eliciting inflammatory responses in a model system wherein TCR and CAR target equalized sources of clinically relevant antigen, we discovered a CD22-specific TCR and compared it to CD22 CAR. Both CD22 TCR-T and CD22 CAR-T cells eradicated leukemia in xenografts, but only CD22 CAR-T cells induced dose-dependent systemic inflammation. Compared to TCR-T cells, CAR-T cells disproportionately upregulated inflammatory pathways without concordant augmentation in pathways involved in direct cytotoxicity upon antigen engagement. These differences in antileukemia responses comparing TCR-T and CAR-T cells highlight the potential opportunity to improve therapeutic safety by using TCRs.

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External Sources

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  2. DOI: 10.1126/sciadv.adq4297
  3. PMID: 40203088
  4. PMCID: PMC11980841

Library Notes

  1. Fiscal Year: FY2024-2025
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