CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.
CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.
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DOI：
10.1002/advs.202207394
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发表时间：
2023-09
期刊：
影响因子：
15.1
通讯作者：
Sun, Jie
中科院分区：
文献类型：
--
作者：
Liao, Chan;Wang, Yajie;Huang, Yanjie;Duan, Yanting;Liang, Yan;Chen, Jiangqing;Jiang, Jie;Shang, Kai;Zhou, Chun;Gu, Ying;Liu, Nan;Zeng, Xun;Gao, Xiaofei;Tang, Yongmin;Sun, Jie
关键词：
CD 38在T细胞急性淋巴细胞白血病（T-ALL）母细胞中的稳健和稳定表达使CD 38嵌合抗原受体（CAR）-T/自然杀伤细胞（NK）成为T-ALL的潜在治疗方法。然而，正常T/NK细胞中的CD 38表达导致CD 38 CAR-T/NK细胞的自相残杀。在这里，开发了一种“二合一”基因编辑策略，以产生抗杀兄弟基因座特异性CAR-T/NK细胞。CD 38特异性CAR通过CRISPR/Cas9整合到破坏的CD 38基因座中，CAR置于内源性CD 38启动子（CD 38 KO/KI）或外源性EF 1 α启动子（CD 38 KO/KIEF 1 α）的控制下。CD 38敲除减少了自相残杀，并允许CAR-T细胞的扩增。同时，在CAR-T和CAR-NK细胞中，CD 38 KO/KIEF 1 α导致比CD 38 KO/KI更高的CAR表达。在小鼠T-ALL模型中，CD 38 KO/KIEF 1 α CAR-T细胞比CD 38 KO/KI CAR-T细胞更好地根除肿瘤。令人惊讶的是，CD 38 KO/KI CAR-NK细胞显示出比CD 38 KO/KIEF 1 α CAR-NK细胞更好的上级肿瘤控制。进一步的研究表明，NK细胞中的内源性调节元件导致CD 38 CAR的表达高于T细胞，CAR的表达水平不同地影响CAR-T和CAR-NK细胞的治疗结果。因此，这些结果支持了CD 38 CAR-T/NK对T-ALL的疗效，并证明了“二合一”策略可以解决自相残杀并增强肿瘤根除，为临床转化铺平了道路。开发了一种新的“二合一”策略，通过CRISPR/Cas9在CD 38位点插入CD 38嵌合抗原受体（CAR），这可以解决自相残杀并增强肿瘤根除。在CD 38基因座上使用不同的启动子，作者意外地发现CAR-T中的EF 1 α启动子更好，而CAR-自然杀伤细胞（NK）中的CD 38内源性启动子上级。
The robust and stable expression of CD38 in T‐cell acute lymphoblastic leukemia (T‐ALL) blasts makes CD38 chimeric antigen receptor (CAR)‐T/natural killer (NK) a potential therapy for T‐ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR‐T/NK cells. Here a “2‐in‐1” gene editing strategy is developed to generate fratricide‐resistant locus‐specific CAR‐T/NK cells. CD38‐specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38 KO/KI) or exogenous EF1α promoter (CD38 KO/KIEF1α). CD38 knockout reduces fratricide and allows the expansion of CAR‐T cells. Meanwhile, CD38 KO/KIEF1α results in higher CAR expression than CD38 KO/KI in both CAR‐T and CAR‐NK cells. In a mouse T‐ALL model, CD38 KO/KIEF1α CAR‐T cells eradicate tumors better than CD38 KO/KI CAR‐T cells. Surprisingly, CD38 KO/KI CAR‐NK cells show superior tumor control than CD38 KO/KIEF1α CAR‐NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR‐T and CAR‐NK cells differently. Therefore, these results support the efficacy of CD38 CAR‐T/NK against T‐ALL and demonstrate that the “2‐in‐1” strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation. A new “2‐in‐1” strategy is developed to insert CD38 chimeric antigen receptor (CAR) at the CD38 locus by CRISPR/Cas9, which can resolve fratricide and enhance tumor eradication. With different promoters at the CD38 locus, the authors unexpectedly discover that the EF1α promoter in CAR‐T is better, while CD38 endogenous promoter in CAR‐natural killer (NK) is superior.
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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：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
12.4
作者：
Duan, Yanting;Chen, Jiangqing;Sun, Jie
通讯作者：
Sun, Jie
影响因子：
24.1
作者：
Ju, Ying;Hou, Nan;Ma, Chunhong
通讯作者：
Ma, Chunhong
影响因子：
11.4
作者：
Blaeschke, Franziska;Willier, Semjon;Feuchtinger, Tobias
通讯作者：
Feuchtinger, Tobias