小柯机器人

英国伦敦大奥蒙德街儿童医院Persis J. Amrolia小组宣布，他们使用低亲和力CD19 CAR细胞治疗儿童患者后，体内的CAR T细胞都获得了增强扩增，持续时间也获得延长。 相关论文2019年9月2日在线发表于《自然—医学》。

嵌合抗原受体(CAR)修饰的靶向CD19的T细胞在复发/难治性急性淋巴细胞白血病(ALL)中表现出了强烈的反应，但包括细胞因子释放综合征(CRS)和神经毒性在内的毒性，限制了其更广泛的应用。此外，40-60%的患者复发是由于CAR T细胞持久性差或CD19克隆的出现。一些因素，包括单链间隔的选择、细胞外和共刺激域的选择，对CAR T细胞的功能和持久性有深刻的影响。然而，人们对CAR结合亲和力的影响知之甚少。有证据表明，在一个上限以上，增加免疫受体亲和力可能会对T细胞的反应产生不利影响。

该研究组制备了一种新的CD19 CAR (CAT)，其亲和力低于许多临床研究中使用的高亲和力结合剂FMC63。与FMC63 CAR T细胞相比，CAT CAR T细胞在体外的增殖和细胞毒性增强，在体内和体外的抗肿瘤活性增强。在一项临床研究(CARPALL, NCT02443831)中，14例复发/难治性儿童B细胞急性淋巴母细胞白血病患者应用CAT CAR T细胞治疗后，12例获得了分子缓解。在最后一次随访中，14例患者中有11例表现出持续性，与公布的数据相比，CAR T细胞扩增增强，毒性低，无严重CRS。一年的总体生存率和无事件生存率分别为63%和46%。

附：英文原文

Title: Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR

Author: Sara Ghorashian, Anne Marijn Kramer, Shimobi Onuoha, Gary Wright, Jack Bartram, Rachel Richardson, Sarah J. Albon, Joan Casanovas-Company, Fernanda Castro, Bilyana Popova, Krystle Villanueva, Jenny Yeung, Winston Vetharoy, Aleks Guvenel, Patrycja A. Wawrzyniecka, Leila Mekkaoui, Gordon Weng-Kit Cheung, Danielle Pinner, Jan Chu, Giovanna Lucchini, Juliana Silva, Oana Ciocarlie, Arina Lazareva, Sarah Inglott, Kimberly C. Gilmour, Gulrukh Ahsan, Mathieu Ferrari, Somayya Manzoor, Kim Champion, Tony Brooks, Andre Lopes, Allan Hackshaw, Farzin Farzaneh, Robert Chiesa, Kanchan Rao, Denise Bonney, Sujith Samarasinghe, Nicholas Goulden, Ajay Vora, Paul Veys, Rachael Hough, Robert Wynn, Martin A. Pule, Persis J. Amrolia

Issue&Volume: 2019-09-02

Abstract: Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1,2,3,4,5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40–60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19− clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9,10,11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1,2,3,4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.

DOI: 10.1038/s41591-019-0549-5

Source: https://www.nature.com/articles/s41591-019-0549-5

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