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A novel and efficient tandem CD19- and CD22-directed CAR for B cell ALL
Molecular Therapy ( IF 12.4 ) Pub Date : 2021-09-01 , DOI: 10.1016/j.ymthe.2021.08.033
Samanta Romina Zanetti 1 , Talia Velasco-Hernandez 2 , Francisco Gutierrez-Agüera 2 , Víctor M Díaz 3 , Paola Alejandra Romecín 2 , Heleia Roca-Ho 1 , Diego Sánchez-Martínez 2 , Néstor Tirado 2 , Matteo Libero Baroni 1 , Paolo Petazzi 2 , Raúl Torres-Ruiz 4 , Oscar Molina 2 , Alex Bataller 5 , José Luis Fuster 6 , Paola Ballerini 7 , Manel Juan 8 , Irmela Jeremias 9 , Clara Bueno 10 , Pablo Menéndez 11
Affiliation  

CD19-directed chimeric antigen receptor (CAR) T cells have yielded impressive response rates in refractory/relapse B cell acute lymphoblastic leukemia (B-ALL); however, most patients ultimately relapse due to poor CAR T cell persistence or resistance of either CD19+ or CD19 B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19 relapses. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T cells showed similar in vitro expansion to CD19-CAR T cells with no increase in tonic signaling. CRISPR-Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples, and patient-derived xenografts (PDXs). Strikingly, the robust antileukemic activity of the Tan-CAR was slightly more effective in controlling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.



中文翻译:

一种用于 B 细胞 ALL 的新型高效串联 CD19 和 CD22 定向 CAR

CD19 定向嵌合抗原受体 (CAR) T 细胞在难治性/复发性 B 细胞急性淋巴细胞白血病 (B-ALL) 中产生了令人印象深刻的反应率;然而,由于 CAR T 细胞持久性差或 CD19 +或 CD19 - B-ALL 克隆的耐药性,大多数患者最终会复发。CD22 是一种泛 B 标记,其表达在 CD19 +和 CD19 -中均保持不变复发。CD22-CAR T细胞已在临床上用于B-ALL患者,尽管也会出现复发。用在单个构建体中包含 CD19 和 CD22 scFv 的串联 CAR (Tan-CAR) 改造的 T 细胞可能有利于实现更高的缓解率和/或防止抗原丢失。我们使用内部开发的新型 CD19 和 CD22 scFvs 使用尖端检测生成了基于 4-1BB 的 CD22/CD19 Tan-CAR 并对其进行了功能验证。表达 Tan-CAR 的 T 细胞显示出与 CD19-CAR T 细胞相似的体外扩增,而强直信号没有增加。CRISPR-Cas9 编辑的 B-ALL 细胞证实了 Tan-CAR 的双特异性。Tan-CAR在体外体内与 CD19-CAR 一样有效使用 B-ALL 细胞系、患者样本和患者来源的异种移植物 (PDX)。引人注目的是,在长期随访 PDX 模型中,Tan-CAR 强大的抗白血病活性在控制疾病方面稍微更有效。这种 Tan-CAR 结构需要进行临床评估,以测试同时靶向 CD19 和 CD22 是否能增强白血病根除并降低/延迟复发率和抗原丢失。

更新日期:2021-09-01
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