T 细胞抗原偶联剂 (TAC) 是一种嵌合受体，在缺乏强直信号传导的情况下，通过选择内源性 T 细胞受体复合物来促进 T 细胞的肿瘤抗原特异性激活。先前的数据表明，TAC 使 T 细胞能够在血液学和实体瘤的临床前模型中诱导持久且安全的抗肿瘤反应。在这里，我们描述了自体 Claudin 18.2 (CLDN18.2) 导向的 TAC T 细胞疗法 TAC01-CLDN18.2 的临床前药理学和安全性，为 CLDN18.2 阳性受试者的 I/II 期临床研究做准备实体瘤。在筛选假定的 TAC 构建体后，使用胃、胃食管和胰腺肿瘤模型以及源自人类的细胞，在体外和体内评估了表达最终 CLDN18.2-TAC 受体的 TAC T 细胞的特异性、活性和细胞毒性。来自正常组织。在与天然表达 CLDN18.2 的各种 2D 肿瘤培养物以及肿瘤球体共培养时，观察到 CLDN18.2-TAC T 细胞的 CLDN18.2 特异性活性和细胞毒性。这些效应发生在低抗原水平的模型中，并且与 CLDN18.2 表达的增加呈正相关。在没有观察到脱靶或中靶/脱肿瘤效应的情况下，CLDN18.2-TAC T细胞有效地根除小鼠体内已建立的肿瘤异种移植物，在递归杀伤和肿瘤再攻击实验中产生持久功效，并且在与人类共培养中保持不反应性细胞代表重要器官。因此，数据表明，CLDN18.2-TAC T细胞可以在各种CLDN18.2阳性实体瘤模型中诱导特异性且持久的抗肿瘤反应，且没有显着的TAC依赖性毒性，支持TAC01-CLDN18的临床开发.2.

The T cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T cell receptor complex in the absence of tonic signaling. Previous data demonstrates that TAC affords T cells with the ability to induce durable and safe anti-tumor responses in preclinical models of hematological and solid tumors. Here, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T cell therapy, TAC01-CLDN18.2, in preparation for a Phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and was positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting anti-tumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.