Abstract
Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR(+) CTLs produced interferon-gamma (IFNgamma) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 +/- 104 to 1034 +/- 304 spot-forming cells [SFCs]/10(5) T cells) and lysed primary B-ALL blasts in (51)Cr-release assays (mean, 66% +/- 5% specific lysis; effector-target [E/T] ratio, 40:1) and the CD19(+) Raji cell line (mean, 78% +/- 17%) in contrast to nontransduced controls (8% +/- 8% and 3% +/- 2%). CB-derived CAR(+) CTLs showed similar antiviral and antitumor function and both PB and CB CAR(+) CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / immunology
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Adoptive Transfer*
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Adult
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Antigens, CD19 / immunology
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Antigens, Viral / immunology
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Blood Cells / immunology
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Cell Line, Transformed
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Cell Line, Tumor / immunology
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Cells, Cultured / immunology
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Cells, Cultured / transplantation
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Coxsackie and Adenovirus Receptor-Like Membrane Protein
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Cytomegalovirus / immunology
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Feasibility Studies
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Fetal Blood / cytology*
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Humans
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In Vitro Techniques
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Interferon-gamma / biosynthesis
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Leukemia, B-Cell / immunology*
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Leukemia, B-Cell / pathology
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Neoplastic Stem Cells / immunology
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Postoperative Complications / prevention & control*
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Postoperative Complications / virology
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Receptors, Antigen, T-Cell, alpha-beta / immunology
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Receptors, Virus / genetics
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Receptors, Virus / physiology*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / immunology
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Recurrence
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Single-Chain Antibodies / genetics
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Single-Chain Antibodies / immunology*
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / transplantation
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / transplantation
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Virus Diseases / immunology
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Virus Diseases / prevention & control*
Substances
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Antigens, CD19
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Antigens, Viral
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CLMP protein, human
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Coxsackie and Adenovirus Receptor-Like Membrane Protein
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Virus
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Recombinant Fusion Proteins
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Single-Chain Antibodies
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Interferon-gamma