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. Up to 30% to 60% of patients experience relapsed disease because of the emergence of CD19low or CD19- tumor cell clones. Although bispecific CD19/CD22 CAR T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 have compromised their efficacy in relapsing patients. 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 T-cell receptor (TCR) repertoire, we identified a high-affinity TCR targeting a CD22 epitope presented by HLA-A∗02:01. In vitro, this TCR demonstrated high specificity and efficacy in both CD22+ 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 after CD19 CAR T-cell therapy.

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Publication Details

Journal
Blood
Published
2025-10-16
DOI
https://doi.org/10.1182/blood.2025029329
Citations
1
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
1.05

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article

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

Frank Konietschke, Sarah Al-Tabatabaee, Antonio Pezzutto, Matthias Leisegang et al.
1 citations
Blood
CAR-T cell therapy research
1.05
article

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

Frank Konietschke, Sarah Al-Tabatabaee, Antonio Pezzutto, Matthias Leisegang, Ulrich Bernd Keller, Thomas J. F. Blankenstein, Corinna Grunert, Simone Rhein, Nazli Serin, Stefanos Timiliotis, Cäcilia Freund, Gerald Willimsky, Elisa Kieback, Sarah K. Tasian, Neşe Çakmak-Görür, Bjoern Chapuy, Luisa Ohlmeier, Antonia Busse
article en
1 citations

Abstract

CD19 chimeric antigen receptor (CAR) T-cell therapy has become the standard of care in relapse and/or refractory B-cell malignancies. Up to 30% to 60% of patients experience relapsed disease because of the emergence of CD19low or CD19- tumor cell clones. Although bispecific CD19/CD22 CAR T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 have compromised their efficacy in relapsing patients. 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 T-cell receptor (TCR) repertoire, we identified a high-affinity TCR targeting a CD22 epitope presented by HLA-A∗02:01. In vitro, this TCR demonstrated high specificity and efficacy in both CD22+ 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 after CD19 CAR T-cell therapy.

BloodVol. 147(10)
Helmholtz Association of German Research Centres (DE), Children's Hospital of Philadelphia (US), German Cancer Research Center (DE), Max Delbrück Center (DE), Heidelberg University (DE), Humboldt-Universität zu Berlin (DE), University of Chicago (US), MSB Medical School Berlin (DE), Silence Therapeutics (Germany) (DE), German Centre for Cardiovascular Research (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), BioTez (Germany) (DE), Franklin University (US), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US)
Leukemia and Lymphoma Society, Children's Hospital of Philadelphia, European Commission, Deutsche Krebshilfe, Berlin Institute of Health
Openalex Percentile: Top 17%
CAR-T cell therapy research
1.05
DOIOpen Access PDFOpenAlex
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