肿瘤细胞治疗研究
英文原题：Persistence of activated anti-mesothelin hYP218 chimeric antigen receptor T cells in the tumour is associated with efficacy in gastric and colorectal carcinomas.
使用 TCGA 数据库中的人胃癌（n = 408）和结肠癌肿瘤（n = 275）进行 GEPIA 分析，以评估间皮素的 mRNA 表达，并与正常组织进行比较。
晚期胃癌和结直肠癌患者的治疗选择有限。鉴于间皮素在这两类肿瘤中高表达，我们评估了抗间皮素hYP218 CAR T细胞单独使用，以及与抗PD-1抗体帕博利珠单抗联合使用的治疗获益。我们利用GEPIA分析癌症基因组图谱（TCGA）数据库中408例胃癌和275例结肠癌肿瘤，评估间皮素mRNA表达并与正常组织比较；采用流式细胞术分析5种胃癌和结直肠癌细胞系中的间皮素表达。通过细胞毒性和细胞因子释放实验检测hYP218 CAR T细胞的体外疗效。在携带人胃癌（HGC27）和结直肠癌（SW48）异种移植瘤的NSG小鼠中，评估hYP218 CAR T细胞单独使用及与帕博利珠单抗联合使用的体内抗肿瘤疗效。此外，还研究hYP218 CAR-T细胞持续存在、活化及耗竭标志物表达。与正常组织相比，胃癌和结肠癌活检样本中的间皮素表达显著较高（p<0.005）。胃癌和结肠癌细胞系的间皮素表达范围为每个细胞10,000至70,000个分子。hYP218 CAR T细胞在较低效靶比下仍表现出强效细胞毒活性，效靶比为0.24至1.0。在NSG小鼠模型中，hYP218 CAR T细胞具有抗肿瘤疗效；治疗后第40天仍以功能状态存在于肿瘤微环境中，表达活化标志物CD39和CD69，产生更多IFN-γ和TNF-α，并且从肿瘤中分离后仍能在体外杀伤肿瘤细胞。其PD-1表达增加。在携带大体积HGC27肿瘤的NSG小鼠中，hYP218 CAR T细胞联合帕博利珠单抗可减缓肿瘤生长；对小体积肿瘤未见此效果。hYP218 CAR T细胞的抗肿瘤疗效源于肿瘤内活化CAR T细胞积聚增加；联合帕博利珠单抗可进一步改善对已建立大体积肿瘤的抗肿瘤活性。 要点：间皮素在胃癌和结直肠癌中的表达显著高于正常组织。hYP218 CAR T细胞对间皮素阳性胃癌和结直肠癌具有强效抗肿瘤活性。活化的hYP218 CAR T细胞可持续存在于肿瘤微环境中并保持细胞毒活性。在大体积肿瘤中加入帕博利珠单抗可增强CAR T细胞疗效。
Patients with advanced gastric and colorectal cancers have limited treatment options. Since mesothelin is highly expressed in these tumour types, we evaluated the therapeutic benefits of anti-mesothelin hYP218 CAR T cells alone, and in combination with anti-PD1 antibody, pembrolizumab. GEPIA analysis was performed using human gastric (n = 408) and colon cancer tumours (n = 275) in TCGA database, to evaluate mRNA expression of mesothelin, compared to normal tissues. Mesothelin expression in gastric and colorectal cancer cell-lines (n = 5) was analysed using flow cytometry. In vitro efficacy by hYP218 CAR T cells was tested by cytotoxicity and cytokine release assays. In vivo anti-tumour efficacy of hYP218 CAR T cells alone, and in combination with pembrolizumab, was evaluated in NSG mice bearing human gastric (HGC27) and colorectal (SW48) tumour xenografts. Additionally, hYP218 CAR-T cell persistence, activation and exhaustion marker-expression were studied. Mesothelin expression was significantly higher in gastric and colon cancer biopsies compared to normal tissues (p < .005). Mesothelin expression in gastric and colon cancer cell lines ranged from 10 000 to 70 000 molecules per cell. hYP218 CAR T cells demonstrated strong cytotoxic activity at low effector to target ratio, ranging from 0.24 to 1.0. In NSG mouse-models, hYP218 CAR T cells demonstrated anti-tumour efficacy and persisted in the tumour microenvironment in a functional state at day 40 posttreatment with expression of activation markers CD39 and CD69, increased production of IFN- and TNF- and ability to kill tumour cells in vitro when isolated from tumours. There was increased PD1 expression. In combination with pembrolizumab, hYP218 CAR T cells led to slower tumour growth in NSG mice bearing large but not small HGC27 tumours. Anti-tumour efficacy of hYP218 CAR T cells is due to increased accumulation of activated CAR T cells in the tumour and combination with pembrolizumab resulted in improvement in anti-tumour activity of large established tumours. HIGHLIGHTS: Mesothelin expression is significantly higher in gastric and colorectal cancers than normal tissues. hYP218 CAR T cells demonstrate strong anti-tumour activity against mesothelin-positive gastric and colorectal carcinomas. Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity. Addition of pembrolizumab in larger tumours enhance CAR T cell efficacy.
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