Ali and Giannakopolou et al. developed a T cell-based therapy to target TdT, an intracellular antigen upregulated transiently during lymphocyte development, but overexpressed in many leukemias. Through mass spectrometry, they found TdT-derived peptides capable of binding the common HLA-A2 allele, then identified reactive TCR clones. T cells transduced with these TCRs recognized only cells expressing both TdT and HLA-A2, spared normal lymphocytes and progenitors, and effectively treated NSG mice engrafted with HLA-A2+TdT+ leukemia lines or primary xenograft B-ALL, even when the T cells and ALL were non HLA-matched.
Contributed by Alex Najibi
ABSTRACT: Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
Author Info: (1) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute
Author Info: (1) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (2) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (3) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (4) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. (5) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. (6) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (7) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (8) Charit - Universittsmedizin Berlin, Institute of Immunology, Berlin, Germany. (9) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (10) Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (12) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (13) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (14) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (15) Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. (17) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. (18) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (19) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (20) K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (21) Department of Haematology, Oslo University Hospital and KG Jebsen Center for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (22) Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway. (23) Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. (24) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. (25) Department of Immunology, Oslo University Hospital, Oslo, Norway. (26) Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway. (27) Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (28) Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands. (29) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (30) Charit - Universittsmedizin Berlin, Institute of Immunology, Berlin, Germany. David and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USA. German Cancer Consortium, partner site Berlin, Berlin, Germany. German Cancer Research Center, Heidelberg, Germany. (31) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Karolinska University Hospital, Stockholm, Sweden. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. (32) Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. (33) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no.
