Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin lymphoma.
T-cell-mediated immunotherapy with a chimeric antigen receptor (CAR) is expected to become a powerful treatment for cancer. CD38, highly expressed in B-cell non-Hodgkin lymphoma (B-NHL) cells, is an attractive target in immunotherapy for B-NHL. We retrovirally transduced a T-cell line, Hut78, expressing little CD38, with an anti-CD38-CAR. Hut78 cells with the anti-CD38-CAR were cocultured with B-NHL cell lines bearing CD38 and also B-NHL cells from patients. Four days later most of the lymphoma cells were killed (the level of cytotoxicity was >95%). By contrast, there was undetectable cytotoxicity against CD38-negative cell lines. Then, we introduced the anti-CD38-CAR into human peripheral T cells. However, the recovery of viable cells was very low, presumably because of an autolytic reaction caused by the association of the anti-CD38-CAR with CD38 on the cell surface. The addition of an anti-CD38 antibody increased the yield of viable transduced T cell probably by blocking the autolytic reaction. We cocultured human peripheral T cells bearing anti-CD38-CAR with B-NHL cells. The median specific cytotoxicity was greater than 90%. These cells were injected 4 times into NOD/SCID mice, which were inoculated with B-NHL cells luciferase. Luciferase activity was not detectable even 30 days after the inoculation in 5 of 6 mice injected. By contrast, it increased in all of the mice injected with the mock vector-transduced T cell. In conclusion, T cell with the anti-CD38-CAR showed powerful cytotoxicity against B-NHL cells in vitro and in vivo. These findings may provide an important clue for improving the methodology of T-cell-mediated immunotherapy.
Mihara
Keichiro
K
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan. kmmihara@hiroshima-u.ac.jp
Yanagihara
Kazuyoshi
K
Takigahira
Misato
M
Imai
Chihaya
C
Kitanaka
Akira
A
Takihara
Yoshihiro
Y
Kimura
Akiro
A
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020014:K562 Cells; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; D051997:ADP-ribosyl Cyclase 1