A CD22-specific T-cell receptor enables effective adoptive T-cell therapy for B-cell malignancies
Abstract
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.
Article Details
Authors (18)
Simone Rhein
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Neşe Çakmak-Görür
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Corinna Grunert
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Sarah Al-Tabatabaee
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Nazli Serin
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Matthias Leisegang
5Institute of Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Stefanos Timiliotis
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Luisa Ohlmeier
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Cäcilia Freund
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Gerald Willimsky
Frank Konietschke
Elisa Kieback
9T-Knife Therapeutics GmbH, Berlin, Germany
Sarah K. Tasian
Björn Chapuy
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Ulrich Keller
Thomas Blankenstein
Antonio Pezzutto
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Antonia Busse