A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer

// Lorenz Jahn 1 , Renate S. Hagedoorn 1 , Dirk M. van der Steen 1 , Pleun Hombrink 1, 2 , Michel G.D. Kester 1 , Marjolein P. Schoonakker 1 , Daniëlle de Ridder 1 , Peter A. van Veelen 3 , J.H. Frederik Falkenburg 1 , Mirjam H.M. Heemskerk 1 1 Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 2 Department of Hematopoiesis, Sanquin Research, 1006 AD Amsterdam, The Netherlands 3 Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands Correspondence to: Lorenz Jahn, email: l.jahn@lumc.nl Mirjam H.M. Heemskerk, email: m.h.m.heemskerk@lumc.nl Keywords: CD22, TCR gene transfer, immunotherapy, acute lymphoblastic leukemia, allogeneic HLA Received: June 13, 2016 Accepted: September 19, 2016 Published: September 26, 2016 ABSTRACT 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 (CD22 RPF ) 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. CD22 RPF -specific T-cell clone 9D4 was isolated from a healthy HLA-B * 07:02 neg 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 CD22 neg hematopoietic cell subsets but weakly lysed CD22 low -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.