Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.
Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.
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DOI：
10.1182/bloodadvances.2022008327
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发表时间：
2023-07-25
期刊：
影响因子：
7.5
通讯作者：
June, Carl H.
中科院分区：
文献类型：
--
作者：
Watanabe, Keisuke;Gomez, Angela M.;Kuramitsu, Shunichiro;Siurala, Mikko;Da, Tong;Agarwal, Sangya;Song, Decheng;Scholler, John;Rotolo, Antonia;Posey Jr, Avery D.;Rook, Alain H.;Haun, Paul L.;Ruella, Marco;Young, Regina M.;June, Carl H.
CCR 4 CAR对T细胞淋巴瘤有活性。由CCR 4 CAR诱导的杀兄弟选择性地消耗Th 2、Th 17和Treg，同时保留Th 1。当用嵌合抗原受体（CAR）T细胞疗法靶向T细胞淋巴瘤时的挑战是靶抗原通常在T细胞和肿瘤细胞之间共享，导致CAR T细胞之间的自相残杀和对正常T细胞的靶细胞毒性。CC趋化因子受体4（CCR 4）在许多成熟T细胞恶性肿瘤中高度表达，如成人T细胞白血病/淋巴瘤（ATLL）和皮肤T细胞淋巴瘤（CTCL），并且在正常T细胞中具有独特的表达谱。CCR 4主要由2型和17型辅助性T细胞（Th 2和Th 17）和调节性T细胞（Treg）表达，但很少由其他T辅助性（Th）亚群和CD 8+细胞表达。尽管CAR T细胞中的自相残杀通常被认为对抗癌功能有害，但在这项研究中，我们证明了抗CCR 4 CAR T细胞特异性地耗尽了Th 2和Tcl 3，同时保留了CD 8+和Th 1 T细胞。此外，杀兄弟增加了最终产物中CAR+ T细胞的百分比。CCR 4-CAR T细胞的特征在于高转导效率、稳健的T细胞扩增以及在CAR转导和扩增期间CCR 4阳性T细胞的快速自相残杀消耗。此外，基于mogamulizumab的CCR 4-CAR T细胞在植入人T细胞淋巴瘤细胞的小鼠中诱导了上级抗肿瘤功效和长期缓解。总之，CCR 4耗尽的抗CCR 4 CAR T细胞富含Th 1和CD 8 + T细胞，并对表达CCR 4的T细胞恶性肿瘤表现出高抗肿瘤功效。
CCR4 CAR is active against T-cell lymphoma. Fratricide induced by CCR4 CAR selectively depletes Th2, Th17, and Treg while sparing Th1. A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4–depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4–expressing T-cell malignancies.
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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
DOI：
10.1084/jem.20130762
发表时间：
2013-10-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bos PD;Plitas G;Rudra D;Lee SY;Rudensky AY
通讯作者：
Rudensky AY
DOI：
10.1084/jem.20101876
发表时间：
2011-03-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
De Monte L;Reni M;Tassi E;Clavenna D;Papa I;Recalde H;Braga M;Di Carlo V;Doglioni C;Protti MP
通讯作者：
Protti MP
影响因子：
32.4
作者：
Kawalekar, Omkar U.;O'Connor, Roddy S.;June, Carl H.
通讯作者：
June, Carl H.
影响因子：
12.4
作者：
Gomes-Silva, Diogo;Atilla, Erden;Mamonkin, Maksim
通讯作者：
Mamonkin, Maksim