CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
抗原结合域亲和力对 CAR-T 细胞抗肿瘤疗效的影响：中等更好
英文原题：The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better.
查看英文原题
The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better.
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中文摘要
尽管研究人员已深入探索多抗原靶向、增强迁移、降低持续性信号及改善肿瘤微环境等策略，嵌合抗原受体工程化T细胞（CAR-T）治疗实体瘤的总体疗效仍有限。另一方面，抗原结合结构域（ABD）的亲和力及结合动力学如何影响CAR-T 疗效，尚未得到充分研究。本文首先分析已发表的38项实体瘤CAR-T 临床试验，并考察缓解率与ABD亲和力的关系。不出所料，多数试验（25项）使用高亲和力ABD，但总体缓解率仅5.7%。相比之下，采用中等亲和力ABD构建的CAR-T 治疗后，35%的患者出现临床应答。
因此，中等亲和力ABD构建的CAR-T 不仅脱靶毒性较低，疗效也更佳。本文随后综述ABD亲和力对CAR-T 生物学特性和功能的影响，进一步支持中等亲和力ABD可能更适合CAR-T 开发。
最后，作者提出，在实体瘤中，CAR-T 与靶点快速结合并快速解离（Kon和Koff均较高），可能足以产生杀伤肿瘤细胞所需的信号，同时避免细胞陷入耗竭。研究ABD亲和力及CAR-T 与肿瘤相互作用的动力学，可能是设计有效实体瘤CAR-T 的关键。
展开英文摘要原文
The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART's efficacy has not been carefully investigated.
In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5. 7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses.
Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective.
We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high K on and K off ) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion.
We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.
论文信息
- 作者
- Mao R、Kong W、He Y
- 单位
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.United States
- 文献类型
- 综述 · 非美国政府资助研究
- 期刊
- Frontiers in immunology2022
- 原文标识
- PubMed 36325345 · DOI 10.3389/fimmu.2022.1032403
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