Bispecific targeting of CD20 and CD19 increases polyfunctionality of chimeric antigen receptor T-cell products in B-cell malignancies |
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| Affiliation: | 1. Blood and Marrow Transplant and Cellular Therapy Program, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;2. Lentigen Technology Inc, Gaithersburg, Maryland, USA;3. Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;1. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada;2. Centre for Journalology, Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada;3. School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada;4. Department of Anesthesiology and Pain Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada;5. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada;6. Neonatology, Department of Pediatrics, Children''s Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada;1. Center for Cancer and Immunology Research, Children''s National Hospital, Washington, DC, USA;2. Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA;3. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA;4. Genomics Shared Resource, Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA;5. George Washington University Cancer Center, George Washington University, Washington, DC, USA;1. The Emmes Company, LLC, Rockville, Maryland, USA;2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA;3. Moffitt Cancer Center, Tampa, Florida, USA;4. Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA;5. Molecular and Cellular Therapeutics, University of Minnesota, Saint Paul, Minnesota, USA;1. Medical Affairs and Innovation, Héma-Québec, Québec City, Canada;2. Cord Blood Bank, Héma-Québec, Montréal, Canada;3. Centre for Innovation, Canadian Blood Services, Ottawa, Canada;4. Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, Canada |
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| Abstract: | Background aimsSelective immune pressure contributes to relapse due to target antigen downregulation in patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells. Bispecific lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells may prevent progression/relapse due to antigen escape. Highly polyfunctional T cells within a CAR T-cell product have been associated with response in single-antigen-targeted anti-CD19 CAR T cells.MethodsThe authors performed a single-cell proteomic analysis to assess polyfunctional cells in our LV20.19 CAR T-cell product. Analysis was limited to those treated at a fixed dose of 2.5 × 106 cells/kg (n = 16). Unused pre-infusion CAR T cells were thawed, sorted into CD4/CD8 subsets and stimulated with K562 cells transduced to express CD19 or CD20. Single-cell production of 32 individual analytes was measured and polyfunctionality and polyfunctional strength index (PSI) were calculated.ResultsFifteen patients had adequate leftover cells for analysis upon stimulation with CD19, and nine patients had adequate leftover cells for analysis upon stimulation with CD20. For LV20.19 CAR T cells, PSI was 866–1109 and polyfunctionality was 40–45%, which were higher than previously reported values for other CAR T-cell products.ConclusionsStimulation with either CD19 or CD20 antigens resulted in similar levels of analyte activation, suggesting that this product may have efficacy in CD19– patient populations. |
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