title: Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.
abstract: The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.|Division of Neurosurgery, Koujunkai Daido Hospital, Nagoya, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kuramitsu
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.|Division of Neurosurgery, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Ohka
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shiina
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yamamichi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tanahashi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Motomura
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Kondo
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.affiliation: Division of Cancer Biology, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Senga
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Natsume
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005910:Glioma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D054992:Immunological Synapses / Q000187:drug effects* / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D000077269:Lenalidomide; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C507942:Il2rg protein, mouse; D007155:Immunologic Factors; D053631:Interleukin Receptor Common gamma Subunit; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C410723:epidermal growth factor receptor VIII; D013792:Thalidomide; D007371:Interferon-gamma; D066246:ErbB Receptors; D000077269:Lenalidomide