期刊
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
卷 26, 期 8, 页码 1377-1385出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2020.04.006
关键词
Adult T cell leukemia; Cytotoxic T cells; Human T cell lymphotropic virus type-1; Tax; T cell immunotherapy
资金
- Japan Society for the Promotion of Science KAKENHI [JP26290058]
- Japanese Initiative for Progress of Research on Infectious Disease for Global Epidemic from the Japan Agency of Medical Research and Development [JP17fm0208015]
Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by infection with human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains extremely poor. Tax, the most important regulatory protein for HTLV-1, is associated with the aggressive proliferation of host cells and is also a major target antigen for CD8(+) cytotoxic T cells (CTLs). Based on our previous findings that Tax-specific CTLs with a T cell receptor (TCR) containing a unique amino-acid sequence motif exhibit strong HLA-A*24:02-restricted, Tax(301-309) -specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-alpha/beta genes were cloned from a previously established CTL clone and transduced into peripheral blood mononuclear cells (PBMCs) of healthy volunteers using a retroviral siTCR vector. Then the cytotoxic efficacy against HTLV-1-infected T cells or primary ATL cells was assessed both in vitro and in vivo. The redirected CTLs (Tax-siCTLs) produced a large amount of cytokines and showed strong killing activity against ATL/HTLV-1-infected T cells in vitro, although they did not have universal activity against ATL cells. Next, in a xenograft mouse model using an HTLV-1-infected T cell line (MT-2), in all mice treated with Tax-siCTLs, the tumor rapidly diminished and finally disappeared without normal tissue damage, although all mice that were untreated or treated with non-gene-modified PBMCs died because of tumor progression. Our findings confirm that Tax-siCTLs can exert strong anti-ATL/HTLV-1 effects without a significant reaction against normal cells and have the potential to be a novel immunotherapy for ATL patients. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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