| RRC ID |
63657
|
| 著者 |
Kawamura K, Tanaka Y, Nakasone H, Ishihara Y, Kako S, Kobayashi S, Tanaka Y, Ohmori T, Uchimaru K, Okamoto S, Mineno J, Shiku H, Nishimura S, Kanda Y.
|
| タイトル |
Development of a Unique T Cell Receptor Gene-Transferred Tax-Redirected T Cell Immunotherapy for Adult T Cell Leukemia.
|
| ジャーナル |
Biol Blood Marrow Transplant
|
| Abstract |
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, Tax301-309-specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-ɑ/β 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.
|
| 巻・号 |
26(8)
|
| ページ |
1377-1385
|
| 公開日 |
2020-8-1
|
| DOI |
10.1016/j.bbmt.2020.04.006
|
| PII |
S1083-8791(20)30215-9
|
| PMID |
32311478
|
| MeSH |
Adult
Animals
Gene Products, tax / genetics
Genes, T-Cell Receptor
Human T-lymphotropic virus 1*
Humans
Immunotherapy
Leukemia-Lymphoma, Adult T-Cell* / therapy
Leukocytes, Mononuclear
Mice
T-Lymphocytes, Cytotoxic
|
| IF |
3.853
|
| リソース情報 |
| ヒト・動物細胞 |
ATN-1(RCB1440) |
