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A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells
Published on: October 16, 2018
Aggressive Lymphoma after CD19 CAR T-Cell Therapy.
Guido Kobbe1, Monika Brüggemann1, Ben-Niklas Baermann1
1From the Department of Hematology, Oncology and Clinical Immunology (G.K., B.-N.B., P.-M.B., N.L., A.R., M. Seifert, C.S., U.G., R.-P.C., K.N., P.J., T.U., S.D.), the Institute of Pathology (M. Seidel, I.E.), the Institute for Transplantation Diagnostics and Cellular Therapy (J.C.F., J.M.R.), the Departments of Nuclear Medicine (F.G.), Rheumatology (J.H.W.D.), and Neurology (S.G.M.), and the Hiller Research Center (J.H.W.D.), University Hospital Düsseldorf, the Center for Integrated Oncology, Aachen-Bonn-Cologne-Düsseldorf (G.K., B.-N.B., P.-M.B., N.L., A.R., M. Seifert, C.S., U.G., R.-P.C., K.N., P.J., T.U., S.D.), and the Department of Diagnostic and Interventional Radiology, University Düsseldorf (G.A.), Düsseldorf, Medical Department II, Hematology and Oncology (M.B., H.T.), and the Department of Pathology (I.I.), University Medical Center Schleswig-Holstein, Kiel, the Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin (L.W., F.D.), Berlin Institute of Health, Charité Universitätsmedizin Berlin (S.Y., S.H.), and Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (S.Y., S.H.), Berlin, the Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases Heidelberg (N.P.), the Innovation and Service Unit for Bioinformatics and Precision Medicine (D.H.), German Cancer Research Center, the European Molecular Biology Laboratory, Molecular Medicine Partnership Unit (D.F.), German Cancer Consortium (D.H., S.H., F.D.), the Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (D.H.), the Medical Faculty of Heidelberg (J.L.) and the Department of Medicine V (S.D.), Heidelberg University, German Cancer Consortium, partner site Berlin, and German Cancer Research Center (S.H., F.D.), Heidelberg, the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (R.K.), and the Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen (M.J.) - all in Germany; and Biomedical Research, Novartis (S.L., P.U.), and Novartis Pharma (H.D.M., H.J.M., J.G.) - both in Basel, Switzerland.
A rare CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) developed post-treatment. Genetic analysis revealed clonal hematopoiesis contributed to this fatal lymphoma development.
Area of Science:
- Oncology
- Hematology
- Immunotherapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is a powerful tool for treating hematologic malignancies.
- Relapsed primary central nervous system lymphoma presents significant treatment challenges.
Purpose of the Study:
- To investigate the etiology of a fatal CD4-CD8- CAR+ peripheral T-cell lymphoma (PTCL) that developed after CAR T-cell therapy.
- To determine the role of clonal hematopoiesis in lymphomagenesis in this context.
Main Methods:
- Case study analysis of a patient treated with tisagenlecleucel.
- Detection of clonal T-cell receptor rearrangement in lymphoma, apheresis product, and autotransplant.
- Somatic mutation analysis (DNMT3A, TET2) in CD34+ stem cells and progeny across different specimens.
Main Results:
- A fatal, clonal, CD4-CD8- CAR+ PTCL emerged one month after tisagenlecleucel treatment.
- Clonal T-cell receptor rearrangement was present in the CAR T-cell manufacturing product and autotransplant.
- Somatic DNMT3A and TET2 mutations were identified in the PTCL, apheresis specimen, and autotransplant.
- An additional TET2 mutation, present at low frequencies in the CAR T-cell product, indicated clonal hematopoiesis contribution.
Conclusions:
- Clonal hematopoiesis, evidenced by specific somatic mutations, can contribute to lymphomagenesis following CAR T-cell therapy.
- This case highlights a rare but serious potential complication of CAR T-cell therapy.
- Further research is needed to understand and mitigate risks associated with CAR T-cell therapy and underlying clonal hematopoiesis.
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