Oncotarget

Research Papers:

Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies

Lorenz Jahn, Dirk M. van der Steen, Renate S. Hagedoorn, Pleun Hombrink, Michel G.D. Kester, Marjolein P. Schoonakker, Daniëlle de Ridder, Peter A. van Veelen, J.H. Frederik Falkenburg and Mirjam H.M. Heemskerk _

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Oncotarget. 2016; 7:77021-77037. https://doi.org/10.18632/oncotarget.12778

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Abstract

Lorenz Jahn1, Dirk M. van der Steen1, Renate S. Hagedoorn1, Pleun Hombrink1,2, Michel G.D. Kester1, Marjolein P. Schoonakker1, Daniëlle de Ridder1, Peter A. van Veelen3,4, J.H. Frederik Falkenburg1, Mirjam H.M. Heemskerk1

1Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

2Department of Hematopoiesis, Sanquin Research, 1006 AD Amsterdam, The Netherlands

3Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

4Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Correspondence to:

Lorenz Jahn, email: [email protected]

Mirjam H.M. Heemskerk, email: [email protected]

Keywords: CD20, TCR gene transfer, monoclonal antibodies, immunotherapy, B-cell leukemia and lymphoma

Received: August 20, 2016     Accepted: October 13, 2016     Published: October 20, 2016

ABSTRACT

Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20. We isolated CD8+ T-cell clones binding to peptide-MHC-tetramers composed of HLA-A*02:01 and CD20-derived peptide SLFLGILSV (CD20SLF) from HLA-A*02:01neg healthy individuals to overcome tolerance towards self-antigens such as CD20. High avidity T-cell clones were identified that readily recognized and lysed primary HLA-A2pos B-cell leukemia and lymphoma in the absence of reactivity against CD20-negative but HLA-A2pos healthy hematopoietic and nonhematopoietic cells. The T-cell clone with highest avidity efficiently lysed malignant cell-lines that had insufficient extracellular CD20 to be targeted by CD20 mAbs. Transfer of this TCR installed potent CD20-specificity onto recipient T-cells and led to lysis of CD20low malignant cell-lines. Moreover, our approach facilitates the generation of an off-the-shelf TCR library with broad applicability by targeting various HLA alleles. Using the same methodology, we isolated a T-cell clone that efficiently lysed primary HLA-B*07:02pos B-cell malignancies by targeting another CD20-derived peptide. TCR gene transfer of high affinity CD20-specific TCRs can be a valuable addition to current treatment options for patients suffering from CD20low B-cell malignancies.


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