Treatment with T cells expressing chimeric antigen receptors (CAR) is a promising anticancer therapy. However, this approach has several limitations and has not yet been effectively applied to treat solid tumors. The study by Panowski and colleagues represents the first comparative analysis of multiple single chain fragment variable (scFv)-based anti-CD70 CAR T-cell clones for the development of a clinical product to treat renal cell carcinoma (RCC). Despite the risk of T-cell fratricide due to CD70 expression on T cells, CD70 CAR T cells were produced successfully thanks to the protective CD70 masking phenomenon. Two distinct classes of CAR T cells were identified with different memory phenotypes, activation statuses, and cytotoxic activity. CD70 CAR T cells presented high cytotoxic activity against RCC both in vitro in RCC cell lines and in vivo in patient-derived xenograft mouse models. The off-target effects expected on the lymphoid compartment were confirmed by tissue cross-reactivity staining and in a cynomolgus monkey preclinical model with CD3-CD70 bispecific antibody treatment. The efficacy and the toxicity profile of the lead CD70 CAR T-cell candidate instigated the researchers to proceed with upscaled clinical production. This article emphasizes the influence of the scFv of the CARs on their efficacy:toxicity balance. Ultimately, they successfully managed to develop a highly effective CAR T-cell candidate to treat a solid tumor by an allogeneic approach, thereby overcoming two major hurdles to broaden application of CAR T-cell therapy. See related article by Panowski et al., p. 2610

中文翻译：

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抗肿瘤CAR T细胞筛选平台：叫的多，选的少

使用表达嵌合抗原受体（CAR）的 T 细胞进行治疗是一种有前途的抗癌疗法。然而，这种方法有一些局限性，尚未有效应用于治疗实体瘤。Panowski 及其同事的研究首次对多个基于单链片段可变 (scFv) 的抗 CD70 CAR T 细胞克隆进行比较分析，用于开发治疗肾细胞癌 (RCC) 的临床产品。尽管T细胞上表达CD70存在T细胞自相残杀的风险，但由于保护性CD70掩蔽现象，CD70 CAR T细胞仍能成功生产。两类不同的 CAR T 细胞被鉴定出具有不同的记忆表型、激活状态和细胞毒活性。CD70 CAR T 细胞在体外 RCC 细胞系和体内患者来源的异种移植小鼠模型中均表现出针对 RCC 的高细胞毒活性。通过组织交叉反应染色和在使用 CD3-CD70 双特异性抗体治疗的食蟹猴临床前模型中证实了预期对淋巴室的脱靶效应。主要候选 CD70 CAR T 细胞的功效和毒性特征促使研究人员继续扩大临床生产规模。本文强调了CAR的scFv对其功效的影响：毒性平衡。最终，他们成功开发出一种高效的 CAR T 细胞候选物，通过同种异体方法治疗实体瘤，从而克服了扩大 CAR T 细胞疗法应用的两大障碍。请参阅 Panowski 等人的相关文章，p。2610