CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses
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.
Authors
- Naomi Taylor (ORCID: https://orcid.org/0000-0002-2459-4558)
- Zhihui Liu (ORCID: https://orcid.org/0000-0002-5876-0614)
- Xiaolin Wu (ORCID: https://orcid.org/0000-0002-6432-1300)
- Michael C. Kelly (ORCID: https://orcid.org/0000-0003-0654-2778)
- Grégoire Altan‐Bonnet (ORCID: https://orcid.org/0000-0002-7283-3162)
- Scott M. Norberg (ORCID: https://orcid.org/0000-0001-5232-2448)
- Kazusa Ishii (ORCID: https://orcid.org/0000-0002-1915-6334)
- Zachary Rae
- Sooraj Achar (ORCID: https://orcid.org/0000-0003-3425-7501)
- John Davies (ORCID: https://orcid.org/0000-0002-9482-1066)
- Kilyna A. Nguyen (ORCID: https://orcid.org/0000-0001-7767-3260)
- Thomas J. Meyer (ORCID: https://orcid.org/0000-0002-7185-5597)
- Christian S. Hinrichs (ORCID: https://orcid.org/0000-0001-5597-2841)
- Lindsey M. Draper (ORCID: https://orcid.org/0009-0006-1107-5640)
- Ling Zhang (ORCID: https://orcid.org/0009-0008-8096-3072)
- Crystal P. McIntosh
Institutions
- National Institutes of Health (US)
- Macmillan Cancer Support (GB)
- Frederick National Laboratory for Cancer Research (US)
- Laboratoire d’immunologie intégrative du cancer (FR)
- Center for Cancer Research (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1126/sciadv.adq4297
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.05