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

• DOI: 10.1126/sciadv.adq4297
• Publication Date: 2025-04-09T17:58:41Z
• 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-Bo...; Ling Zhang; Xiaolin Wu; Thomas J. Meyer; Michael C. Kelly; Naomi Taylor; Christian S. Hinr...; Kazusa Ishii

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.