title: Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.
abstract: Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (>60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs.
authors.affiliation: Department of Haematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan. kmmihara@hiroshima-u.ac.jp
authors.forename: Keichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Misato
authors.initials: M
authors.lastname: Takigahira
authors.forename: Akira
authors.initials: A
authors.lastname: Kitanaka
authors.forename: Chihaya
authors.initials: C
authors.lastname: Imai
authors.forename: Joyeeta
authors.initials: J
authors.lastname: Bhattacharyya
authors.forename: Takanori
authors.initials: T
authors.lastname: Kubo
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takei
authors.forename: Shin'ichiro
authors.initials: S
authors.lastname: Yasunaga
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.forename: Akiro
authors.initials: A
authors.lastname: Kimura
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016923:Cell Death; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D000069283:Rituximab; D013601:T-Lymphocytes / Q000637:transplantation*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D011946:Receptors, Antigen; D000069283:Rituximab; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1