Relation of clinical culture method to T-cell memory status and efficacy in xenograft models of adoptive immunotherapy |
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| Institution: | 1. Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania, USA;2. Division of Oncology, Children''s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;3. Department of Pathology, Children''s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;1. Division of Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR;2. Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR;1. Department of Virology, Pasteur Institute of Iran, Tehran, Iran;2. School of Advanced Technologies in Medicine, Department of Medical Biotechnology, Tehran University of Medical Sciences, Tehran, Iran;3. Endocrinology and Metabolic Research Institute of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran;4. Medical Genetics Department, Tehran University of Medical Sciences, Tehran, Iran;5. Department of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran;6. National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran;1. Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;2. Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Japan;1. Experimental Transplantation and Immunology Branch, National Cancer Institute,;2. Biostatistics and Data Management, National Cancer Institute, and;3. Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD;4. The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and;5. University of Pennsylvania, Abramson Family Cancer Research Center, Philadelphia, PA;1. Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA;2. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;1. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich 81675, Germany;2. Focus Group “Clinical Cell Processing and Purification”, Institute for Advanced Study, TUM, Munich 81675, Germany;3. Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA;4. Department of Medicine, University of Washington, Seattle, WA 98109, USA;5. National Center for Infection Research (DZIF), Munich 81675, Germany |
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| Abstract: | Background aimsCytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies are effective in pre-clinical models, and this efficacy has translated to success in several clinical trials. Many early trials were disappointing in large part because of the lack of proliferation and subsequent persistence of transferred cells. Recent investigations have pointed to the importance of delivering highly proliferative cells, whether of naive or early memory phenotypes.MethodsWe investigated the influence of two common cell culturing methods used in early trials and their relationship to T-cell phenotype and pre-clinical efficacy.ResultsWe observed that stimulation with soluble anti-CD3 antibody OKT-3 and high-dose interleukin-2 produces more effector memory-type T cells with shorter average telomeres when compared with cells generated with the use of CD3/CD28 beads. When used in xenograft models of leukemia, bead-stimulated cells proliferated earlier and to a higher degree than those generated with the use of OKT-3/IL2 and resulted in better disease control despite no difference in distribution or migration throughout the mouse. Inclusion of the known successful clinical 4-1BB endodomain in the CAR could not rescue the function of OKT-3/IL-2–cultured cells. T cells isolated from animals that survived long-term (>120 days) retained a central memory–like phenotype and demonstrated a memory response to a large re-challenge of CD19-positive leukemia.ConclusionsIn summary, we confirm that cells with a younger phenotype or higher proliferative capacity perform better in pre-clinical models and that cell culturing influences cell phenotype seemingly independent of the 4-1BB endodomain in the CAR structure. |
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| Keywords: | CD19 chimeric antigen receptor leukemia T-cell memory T lymphocytes |
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