Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

中文翻译：

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GPC1特异性CAR-T细胞根除已建立的实体瘤而无不良影响，并与抗PD-1 Ab协同作用

当前的异种小鼠模型无法评估靶向肿瘤外的不良反应，从而阻碍了针对实体瘤的嵌合抗原受体（CAR）T细胞疗法的发展，原因是CAR /严重移植物抗体的人/小鼠交叉反应性有限。人体T细胞诱导的抗宿主疾病 我们已经评估了针对多种实体瘤中过表达的Glypican-1（GPC1）的CAR-T细胞的安全性和抗肿瘤功效。由我们原始的抗人/小鼠GPC1抗体产生的GPC1特异性人和鼠CAR-T细胞分别在异种和同种小鼠模型中显示出强大的抗肿瘤作用。重要的，鼠CAR-T细胞通过抗原扩散机制增强了对非GPC1肿瘤抗原的内源性T细胞应答，并显示了与抗PD-1抗体的协同抗肿瘤作用，而在同源模型中没有任何不利影响。我们的研究表明，GPC1作为实体瘤的CAR-T细胞靶标的潜力以及同系和异种模型对评估其安全性和有效性的重要性。