肿瘤细胞治疗研究
英文原题：Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity.
Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity.
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嵌合抗原受体（CAR）T细胞疗法应用于实体瘤时，可能因靶向肿瘤抗原同时杀伤低水平表达该抗原的非恶性细胞（靶向肿瘤外毒性）而引发危及生命的毒性。间皮素（MSLN）在肿瘤细胞中高表达、在间皮细胞中表达有限，因此被确立为间皮瘤、肺癌、卵巢癌及其他癌症CAR-T 治疗的靶抗原。
然而，多项临床试验已报告高亲和力MSLN靶向CAR-T 细胞造成致命的肿瘤外毒性。本研究利用单域纳米抗体的突变变体构建CAR，这些变体以不同亲和力结合人和小鼠MSLN；研究者在小鼠模型中考察肿瘤应答及靶向肿瘤外相互作用导致的毒性。具有低纳摩尔级亲和力（平衡解离常数KD）的CAR-T 细胞出现显著全身扩增，却未见明显肿瘤浸润。随着CAR亲和力逐步降低至微摩尔级KD，CAR-T 细胞扩增逐渐局限于肿瘤。临床前研究显示，高亲和力MSLN CAR与致命的靶向肿瘤外毒性相关；通过调节亲和力可使T细胞对MSLN高表达肿瘤具有更强选择性。
The application of chimeric antigen receptor (CAR) T cell therapy in solid tumors is hindered by life-threatening toxicities resulting from on-target, off-tumor killing of nonmalignant cells that express low levels of the target antigen. Mesothelin (MSLN) has been identified as a target antigen for CAR T cell treatment of mesothelioma, lung, ovarian, and other cancers because of its high expression on tumor cells and limited expression on mesothelial cells.
However, fatal off-tumor toxicity of high-affinity MSLN-targeting CAR T cells has been reported in multiple clinical trials. In this study, we constructed CARs using mutant variants of a single-domain nanobody that bind both human and mouse MSLN with a wide range of affinities and examined tumor responses and their toxicities from on-target, off-tumor interactions in mouse models.
CAR T cells with low nanomolar affinity (equilibrium dissociation constant, KD) exhibited profound systemic expansion with no apparent infiltration into the tumor. With a gradual reduction of CAR affinity toward the micromolar KD, the expansion of CAR T cells became more restricted to tumors.
Our preclinical studies demonstrated that high-affinity MSLN CARs were associated with fatal on-target, off-tumor toxicity and that affinity-tuned CARs rendered T cells more selective for MSLN-high tumors.
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