Activated T Cell-Mediated Immunotherapy with a Chimeric Receptor Against CD38 in B-Cell Malignancies.

Abstract

CD38 is expected to be one of the most useful molecular targets on the surface of malignant B-cells. T cell-mediated immunotherapy with a chimeric receptor could provide a powerful tool for treating cancer. However, since CD38 is also expressed on effector cells such as activated T cells, NK cells, and monocytes, these cells with the chimeric receptor could be eliminated by autologous cytotoxicity through the interaction with the antigen. In this study, we developed a novel methodology for enhancing the survival and clonal expansion of T lymphocytes expressing an anti-CD38 chimeric receptor. Hut78 T cells, which express very little CD38, retrovirally transduced with the anti-CD38 chimeric receptor showed powerful cytotoxic activity against B cell lines expressing CD38, such as HT (lymphoma), RPMI8226 (myeloma), 380 (ALL-Ph1−) and OP-1 (ALL-Ph1+) cells (mean specific cytotoxicity was 97.94% ± 0.31% after four days of culture in vitro). However, in activated human T cells and Jurkat cells constitutively expressing CD38, the recovery rate of cells transduced with the chimeric receptor was extremely low, because the cells eradicated each other and/or themselves by inducing apoptosis. To block the interaction of the anti-CD38 chimeric receptor with CD38 antigen, we incubated activated T cells and Jurkat cells in medium supplemented with an anti-CD38 antibody before the transduction. The number of viable cells harvested after the transduction was dramatically increased by the antibody in a dose-dependent manner. Using this method, we prepared human peripheral T cells bearing the chimeric receptor and injected them into NOD/SCID mice, which were transplanted with HT cells labeled with luciferase. Lucuferase activity was not detectable in 13 days in five of six mice with T cells transduced with the chimeric receptor. In contrast, the activity had a rapid and steady increase in all of the mice injected with vector-transduced T cells. These results clearly showed that even though human peripheral T cells express any molecule on their surface, an antibody could protect T cells transduced with a chimeric receptor-containing vector from cytolysis, and apoptosis. These findings may provide us with a powerful tool for improving T cell-mediated targeting therapy.