Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours.

确定一种对非炎症性肿瘤具有强效的策略对于癌症免疫治疗至关重要。ERY974 是一种人源化 IgG4 双特异性 T 细胞重定向抗体，可识别 glypican-3 和 CD3。在这里，我们检查了 ERY974 和化疗（紫杉醇、顺铂和卡培他滨）在异种移植模型中治疗非炎症肿瘤的联合作用。ERY974 单一疗法对非发炎的 NCI-H446 异种移植肿瘤显示出轻微的抗肿瘤作用，因为 ERY974 重定向 T 细胞的浸润仅限于肿瘤-基质边界。然而，联合疗法通过促进 T 细胞浸润到肿瘤中心并增加 ERY974 在肿瘤中的分布来提高疗效。ERY974 通过 ERY974 诱导的 T 细胞中的 IFNγ 和 TNFα 诱导非炎症 MKN45 肿瘤中的胸苷磷酸化酶表达，促进卡培他滨转化为其活性形式，从而增加卡培他滨诱导的细胞毒性。我们表明，ERY974 与化疗协同和互惠地增加抗肿瘤功效，根除非炎症性肿瘤。