title: Modification of hematopoietic stem/progenitor cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy.
abstract: Chimeric antigen receptors (CARs) against CD19 have been shown to direct T-cells to specifically target B-lineage malignant cells in animal models and clinical trials, with efficient tumor cell lysis. However, in some cases, there has been insufficient persistence of effector cells, limiting clinical efficacy. We propose gene transfer to hematopoietic stem/progenitor cells (HSPC) as a novel approach to deliver the CD19-specific CAR, with potential for ensuring persistent production of effector cells of multiple lineages targeting B-lineage malignant cells. Assessments were performed using in vitro myeloid or natural killer (NK) cell differentiation of human HSPCs transduced with lentiviral vectors carrying first and second generations of CD19-specific CAR. Gene transfer did not impair hematopoietic differentiation and cell proliferation when transduced at 1-2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive cells, with second-generation CAR including CD28 domains being more efficient in NK cells. Our results provide evidence for the feasibility and efficacy of the modification of HSPC with CAR as a strategy for generating multiple lineages of effector cells for immunotherapy against B-lineage malignancies to augment graft-versus-leukemia activity.
authors: 1 Division of Hematology/Oncology, Department of Pediatrics, University of California-Los Angeles , Los Angeles, CA 90095.
authors: Satiro Nakamura
authors: SN
authors: De Oliveira
authors: Christine
authors: C
authors: Ryan
authors: Francesca
authors: F
authors: Giannoni
authors: Cinnamon L
authors: CL
authors: Hardee
authors: Irena
authors: I
authors: Tremcinska
authors: Behrod
authors: B
authors: Katebian
authors: Jennifer
authors: J
authors: Wherley
authors: Arineh
authors: A
authors: Sahaghian
authors: Andy
authors: A
authors: Tu
authors: Tristan
authors: T
authors: Grogan
authors: David
authors: D
authors: Elashoff
authors: Laurence J N
authors: LJ
authors: Cooper
authors: Roger P
authors: RP
authors: Hollis
authors: Donald B
authors: DB
authors: Kohn
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D011946:Receptors, Antigen / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D018941:Antigens, CD19; D011946:Receptors, Antigen
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