肿瘤细胞治疗研究
英文原题：Autologous T-cell antigen coupler targeting HER2 (TAC01-HER2) in advanced or metastatic solid tumors.
我们证明，TAC T细胞治疗安全、可行且耐受性良好。对于既往接受过大量治疗的HER2阳性胃、GEJ或食管腺癌患者，TAC01-HER2显示出可控的毒性和早期疗效。这些结果提示，TAC可能提供一种通过细胞疗法控制T细胞活性的有前景的方法。
T细胞抗原偶联剂（TAC）是一种新型基因工程受体，在识别抗原后能招募天然T细胞受体。TAC T细胞的下游激活在临床前模型中对肿瘤有效，且比CAR-T 细胞更安全。人表皮生长因子受体2（HER2）是癌症靶向治疗中经过验证的生物标志物，但细胞治疗方法遇到了难以控制的毒性。
我们设计了一项针对HER2阳性晚期实体瘤患者的TAC01-HER2的I期临床试验，TAC01-HER2是一种靶向HER2的自体T细胞产品。该试验包括剂量递增阶段和在推荐的II期剂量（RP2D）进行的剂量扩展。
本研究共纳入23例HER2阳性实体瘤患者。最常见的治疗相关不良事件（AEs）为细胞因子释放综合征（n = 14，60.9%）、贫血（n = 5，21.7%）和丙氨酸氨基转移酶升高（n = 5，21.7%）。RP2D为6-8 × 10 6 cells/kg。未报告治疗相关死亡或导致研究终止的AEs。9例胃癌和胃食管结合部（GEJ）癌患者中有2例达到部分缓解（PR），18例可评估肿瘤患者的疾病控制率（稳定疾病或PR）为61.1%。中位无进展生存期为2.6个月（范围0.8-12.4），6个月总生存率为57.9%（95%置信区间36.3%至76.9%）。所有患者在外周血中均观察到TAC T细胞持续存在，直至首次输注后至少第29天。
BACKGROUND: The T-cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T-cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and is safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. PATIENTS AND METHODS: We designed a phase I clinical trial of TAC01-HER2, an autologous T-cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and dose expansion at the recommended phase II dose (RP2D). RESULTS: A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events (AEs) were cytokine release syndrome (n = 14, 60.9%), anemia (n = 5, 21.7%), and increased alanine aminotransferase (n = 5, 21.7%). The RP2D was 6-8 × 10 6 cells/kg. No treatment-related deaths or AEs leading to study discontinuation were reported. Two of nine patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses (PRs), and the disease control rate (stable disease or PR) was 61.1% in the 18 patients with evaluable tumors. The median progression-free survival was 2.6 months (range 0.8-12.4), and the overall survival rate at 6 months was 57.9% (95% confidence interval 36.3% to 76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. CONCLUSION: We demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ, or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T-cell activity through cellular therapy.
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