A CD22-specific T-cell receptor enables effective adoptive T-cell therapy for B-cell malignancies

CD19 chimeric antigen receptor (CAR) T-cell therapy has become the standard of care in relapse and/or refractory B-cell malignancies. 30-60% of patients experience relapsed disease due to the emergence of CD19low or CD19negative tumor cell clones. Although bispecific CD19/CD22 CAR-T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 in relapsing patients have compromised their efficacy. A comprehensive analysis of CD22 expression revealed that CD22 is ubiquitously expressed across all subgroups of B-cell lymphomas and B-cell leukemias, establishing CD22 as a valuable immunotherapeutic target. Using a humanized mouse model with a diverse human TCR repertoire, we identified a high-affinity T-cell receptor (TCR) targeting a CD22 epitope presented by HLA-A*02:01. In-vitro, this TCR demonstrated high specificity and efficacy in both CD22-positive cell lines and primary patient-derived tumor samples. Importantly, CD22 TCR-T cells outperformed CD22 CAR-T cells in recognizing cells with low CD22 surface expression, including CD22low Nalm6 cells that emerged after in-vivo CD19 T cell treatment. Unlike CD22 CAR-T cells, CD22 TCR-T cells effectively recognized tumor cells that predominantly express intracellular CD22. Notably, in-vivo validation in a Nalm6 B-cell leukemia model confirmed the superior activity of CD22 TCR-T cells against CD22low cells compared to CD22 CAR-T cells. In conclusion, our findings provide strong preclinical evidence supporting CD22 TCR-based therapy as a potent treatment option for CD22low B-cell malignancies, including patients who relapsed following CD19 CAR-T therapy.