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 responses^9,10,11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies^1,2,3,4. 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.

靶向 CD19 的嵌合抗原受体 (CAR) 修饰的 T 细胞在复发/难治性急性淋巴细胞白血病 (ALL) ^1,2,3,4,5中表现出无与伦比的反应，但毒性，包括细胞因子释放综合征 (CRS) 和神经毒性，限制更广泛的应用。此外，由于 CAR T 细胞持久性差或 CD19 ^-克隆的出现，40-60% 的患者会复发。一些因素，包括单链间隔子⁶和细胞外⁷以及共刺激域^8的选择, 对 CAR T 细胞的功能和持久性有深远的影响。然而，关于 CAR 结合亲和力的影响知之甚少。有证据表明，免疫受体亲和力的增加可能会对 T 细胞反应产生不利影响^9,10,11。我们生成了一种亲和力低于 FMC63 的新型 CD19 CAR (CAT)，FMC63 是许多临床研究中使用的高亲和力粘合剂^1,2,3,4. 与 FMC63 CAR T 细胞相比，CAT CAR T 细胞在体外显示出增殖和细胞毒性增加，并且具有增强的增殖和体内抗肿瘤活性。在一项临床研究 (CARPALL, NCT02443831) 中，12/14 名接受 CAT CAR T 细胞治疗的复发/难治性小儿 B 细胞急性淋巴细胞白血病患者获得了分子缓解。在最后一次随访时，14 名患者中有 11 名表现出持久性，与公布的数据相比，CAR T 细胞扩增增强。毒性低，没有严重的 CRS。一年总生存率和无事件生存率分别为 63% 和 46%。