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Publications

Journal Article Ppublish

PubMed: 40203088 DOI: 10.1126/sciadv.adq4297

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

Sci Adv 11(15):eadq4297

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

Affiliations

  • 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.

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.

MeSH

Cells, Biological Science Disciplines, Leukemia