在一项晚期胃癌和胃食管交界癌患者的 1 期研究中，评估zolbetuximab 联合唑来膦酸和白细胞介素-2 多次给药的免疫效应和活性。
Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer.
机构信息
Department of Oncology, Gastroenterology, Hepatology, and Pulmonology, Comprehensive Cancer Center Central Germany (CCCG), University of Leipzig Medical Center, Liebigstraße 22, 04103, Leipzig, Germany.
Department of Hematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
出版信息
J Cancer Res Clin Oncol. 2023 Aug;149(9):5937-5950. doi: 10.1007/s00432-022-04459-3. Epub 2023 Jan 6.
PURPOSE
Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity.
METHODS
This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma.
RESULTS
Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%).
CONCLUSIONS
Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect.
TRIAL REGISTRATION
NCT01671774.
目的
Zolbetuximab（IMAB362）经过工程改造后可诱导抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性。我们评估了 ADCC 活性，以及将免疫调节药物唑来膦酸（ZA）和白细胞介素-2（IL-2）作为佐剂与 zolbetuximab 联合治疗对相关免疫细胞群和 ADCC 溶解活性的影响。
方法
这是一项多中心、开放标签的 1 期临床试验，研究了 zolbetuximab 单药（n=5）或联合 ZA（n=7）或联合 ZA 加两种不同剂量的 IL-2（低剂量：100 万国际单位 [mIU] [n=9]；中剂量：3 mIU [n=7]）在既往治疗的晚期胃和胃食管交界处（G/GEJ）腺癌患者中的免疫效应和活性、安全性、耐受性和抗肿瘤活性。
结果
28 例经治的晚期 G/GEJ 腺癌患者（CLDN18.2 表达）入组了 4 个治疗组。zolbetuximab+ZA+IL-2 治疗在给药后 2 天内诱导 ADCC 介导的细胞群（即γ9δ2 T 细胞和自然杀伤细胞）的短暂扩增和激活；中剂量 IL-2 的作用更明显。两种 IL-2 剂量治疗均导致调节性 T 细胞适度且短暂的扩增和激活。单独使用 zolbetuximab 观察到强烈的 ADCC 活性。在接受中剂量 IL-2 治疗的一些患者中观察到短暂的 ADCC 活性，但低剂量 IL-2 则没有。在临床疗效人群中，最佳确认的反应为疾病稳定（n=11/19；58%）。
结论
Zolbetuximab 介导预处理晚期 G/GEJ 癌症患者的有效 ADCC。佐剂 ZA+IL-2 联合治疗并未进一步改善这种效果。
试验注册
NCT01671774。
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