ROR1-targeting switchable CAR-T cells for cancer therapy.
ROR1-targeting switchable CAR-T cells for cancer therapy.
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DOI：
10.1038/s41388-022-02416-5
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发表时间：
2022-08
期刊：
影响因子：
8
通讯作者：
Rader, Christoph
中科院分区：
文献类型：
--
作者：
Peng, Haiyong;Nerreter, Thomas;Mestermann, Katrin;Wachter, Jakob;Chang, Jing;Hudecek, Michael;Rader, Christoph
嵌合抗原受体T细胞（CAR-T）疗法在治疗恶性血液病中的成功促进了许多CAR-T技术的发展，包括将通用CAR-T与双特异性衔接子蛋白组合的联合收割机的可切换CAR-T（sCAR-T）系统。由于它们的可控性和多功能性，sCAR-Ts受到了相当大的关注。为了探索靶向受体酪氨酸激酶ROR 1（在血液和实体恶性肿瘤中表达）的sCAR-Ts的治疗效用，并鉴定有效介导通用CAR-T接合的双特异性衔接蛋白，在表达ROR 1的癌症的体外和体内模型中比较了一组基于具有不同表位和亲和力的ROR 1靶向Fab的开关。对于靶向重叠或相同表位的开关，效力与亲和力相关。然而，令人惊讶的是，我们鉴定了靶向具有低亲和力但介导体外和体内有效和选择性抗肿瘤活性的独特表位的开关。转换为常规CAR-T后，相同的抗ROR 1 mAb（324）的性能优于基于抗ROR 1 mAb（R12）的临床研究常规CAR-T，亲和力高约200倍。因此，sCAR-T本身证明了治疗效用，也有助于更高通量的筛选，以鉴定用于临床前和临床研究的常规CAR-T候选物。
The success of chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies has prompted the development of numerous CAR-T technologies, including switchable CAR-T (sCAR-T) systems that combine a universal CAR-T with bispecific adapter proteins. Owing to their controllability and versatility, sCAR-Ts have received considerable attention. To explore the therapeutic utility of sCAR-Ts targeting the receptor tyrosine kinase ROR1, which is expressed in hematologic and solid malignancies, and to identify bispecific adaptor proteins that efficiently mediate universal CAR-T engagement, a panel of switches based on ROR1-targeting Fabs with different epitopes and affinities was compared in in vitro and in vivo models of ROR1-expressing cancers. For switches targeting overlapping or identical epitopes, potency correlated with affinity. Surprisingly, however, we identified a switch targeting a unique epitope with low affinity but mediating potent and selective antitumor activity in vitro and in vivo. Converted to a conventional CAR-T, the same anti-ROR1 mAb (324) outperformed a clinically investigated conventional CAR-T that is based on an anti-ROR1 mAb (R12) with ~200-fold higher affinity. Thus, demonstrating therapeutic utility on their own, sCAR-Ts also facilitate higher throughput screening for the identification of conventional CAR-T candidates for preclinical and clinical studies.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
影响因子：
7
作者：
Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
20.3
作者：
Hudecek, Michael;Schmitt, Thomas M.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
4.6
作者：
Acevedo-Rocha, Carlos G.;Reetz, Manfred T.;Nov, Yuval
通讯作者：
Nov, Yuval