A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer
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Lorenz Jahn1, Renate S. Hagedoorn1, Dirk M. van der Steen1, Pleun Hombrink1,2, Michel G.D. Kester1, Marjolein P. Schoonakker1, Daniëlle de Ridder1, Peter A. van Veelen3, 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
3Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Lorenz Jahn, email: firstname.lastname@example.org
Mirjam H.M. Heemskerk, email: email@example.com
Keywords: CD22, TCR gene transfer, immunotherapy, acute lymphoblastic leukemia, allogeneic HLA
Received: June 13, 2016 Accepted: September 19, 2016 Published: September 26, 2016
CD22 is currently evaluated as a target-antigen for the treatment of B-cell malignancies using chimeric antigen receptor (CAR)-engineered T-cells or monoclonal antibodies (mAbs). CAR- and mAbs-based immunotherapies have been successfully applied targeting other antigens, however, occurrence of refractory disease to these interventions urges the identification of additional strategies. Here, we identified a TCR recognizing the CD22-derived peptide RPFPPHIQL (CD22RPF) presented in human leukocyte antigen (HLA)-B*07:02. To overcome tolerance to self-antigens such as CD22, we exploited the immunogenicity of allogeneic HLA. CD22RPF-specific T-cell clone 9D4 was isolated from a healthy HLA-B*07:02neg individual, efficiently produced cytokines upon stimulation with primary acute lymphoblastic leukemia and healthy B-cells, but did not react towards healthy hematopoietic and nonhematopoietic cell subsets, including dendritic cells (DCs) and macrophages expressing low levels of CD22. Gene transfer of TCR-9D4 installed potent CD22-specificity onto recipient CD8+ T-cells that recognized and lysed primary B-cell leukemia. TCR-transduced T-cells spared healthy CD22neg hematopoietic cell subsets but weakly lysed CD22low-expressing DCs and macrophages. CD22-specific TCR-engineered T-cells could form an additional immunotherapeutic strategy with a complementary role to CAR- and antibody-based interventions in the treatment of B-cell malignancies. However, CD22 expression on non-B-cells may limit the attractiveness of CD22 as target-antigen in cellular immunotherapy.
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