T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
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DOI：
10.1038/s41587-021-01089-x
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发表时间：
2022-04
影响因子：
46.9
通讯作者：
Olweus, Johanna
中科院分区：
文献类型：
--
作者：
Ali, Muhammad;Giannakopoulou, Eirini;Li, Yingqian;Lehander, Madeleine;Culleton, Stina Virding;Yang, Weiwen;Knetter, Cathrine;Odabasi, Mete Can;Bollineni, Ravi Chand;Yang, Xinbo;Foldvari, Zsofia;Boschen, Maxi-Lu;Taraldsrud, Eli;Stronen, Erlend;Toebes, Mireille;Hillen, Amy;Mazzi, Stefania;de Ru, Arnoud H.;Janssen, George M. C.;Kolstad, Arne;Tjonnfjord, Geir Erland;Lie, Benedicte A.;Griffioen, Marieke;Lehmann, Soren;Osnes, Liv Toril;Buechner, Jochen;Garcia, K. Christopher;Schumacher, Ton N.;van Veelen, Peter A.;Leisegang, Matthias;Jacobsen, Sten Eirik W.;Woll, Petter;Olweus, Johanna
与嵌合抗原受体不同，T细胞受体（TCR）可以识别人类白细胞抗原（HLA）分子上呈递的细胞内靶标。在这里，我们证明了T细胞表达TCR特异性肽从细胞内淋巴细胞特异性酶末端脱氧核苷酸转移酶（TdT），在HLA-A*02：01的背景下，具体消除原发性急性淋巴细胞白血病（ALL）细胞的T细胞和B细胞来源的体外和三个小鼠模型的播散性B-ALL。相比之下，该治疗在体外和人源化小鼠体内保留了正常的外周T细胞和B细胞库以及正常的骨髓细胞。TdT是一种有吸引力的癌症靶标，因为它在80-94%的B-和T-ALL中高度且均匀地表达，但在正常淋巴分化期间仅瞬时表达，限制了TdT特异性T细胞的靶向毒性。靶向TdT的TCR修饰的T细胞可能是一种有前途的B-ALL和T-ALL免疫疗法，保留了正常淋巴细胞。工程化T细胞杀死白血病细胞，几乎没有脱靶毒性。
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes. Engineered T cells kill leukemic cells with little off-target toxicity.
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影响因子：
11.4
作者：
Cooper ML;Choi J;Staser K;Ritchey JK;Devenport JM;Eckardt K;Rettig MP;Wang B;Eissenberg LG;Ghobadi A;Gehrs LN;Prior JL;Achilefu S;Miller CA;Fronick CC;O'Neal J;Gao F;Weinstock DM;Gutierrez A;Fulton RS;DiPersio JF
通讯作者：
DiPersio JF
影响因子：
64.5
作者：
Birnbaum ME;Mendoza JL;Sethi DK;Dong S;Glanville J;Dobbins J;Ozkan E;Davis MM;Wucherpfennig KW;Garcia KC
通讯作者：
Garcia KC
影响因子：
14.8
作者：
Ali, Muhammad;Foldvari, Zsofia;Olweus, Johanna
通讯作者：
Olweus, Johanna
影响因子：
2.4
作者：
DREXLER, HG;MENON, M;MINOWADA, J
通讯作者：
MINOWADA, J
影响因子：
82.9
作者：
Linnemann, Carsten;Heemskerk, Bianca;Schumacher, Ton N. M.
通讯作者：
Schumacher, Ton N. M.