Department of Medical Oncology, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester, United Kingdom.
Clin Cancer Res. 2010 Mar 1;16(5):1662-72. doi: 10.1158/1078-0432.CCR-09-2870. Epub 2010 Feb 23.
Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity.
This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated.
Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative) lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity.
Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.
细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）是 T 细胞激活的关键负调节剂，抗体 tremelimumab 可靶向该蛋白从而释放潜在的抗肿瘤活性。
本Ⅱ期临床试验旨在研究 tremelimumab 作为转移性胃和食管腺癌二线治疗药物的疗效。tremelimumab 每 3 个月给药 1 次，直至出现症状性疾病进展。评估安全性、临床疗效和免疫活性。
18 例患者接受了 tremelimumab 治疗。大多数药物相关毒性为轻度；但有 1 例因结肠炎并发肠穿孔导致死亡。4 例患者有临床获益的稳定疾病，1 例患者在接受 8 个周期（25.4 个月）后获得部分缓解，目前在研究中已 32.7 个月仍病情稳定。在接受 tremelimumab 治疗后 1 个月内，CD4+CD25+高淋巴细胞中的调节表型标志物叉头框蛋白 3 和 CTLA4 短暂加倍，然后恢复至基线。相反，在整个治疗周期中，CD4+CD25（低/阴性）淋巴细胞中的 CTLA4 持续增加。在 18 例患者中有 8 例检测到针对肿瘤相关抗原 5T4（8 of 18 patients）和癌胚抗原（5 of 13）的新的增殖反应。与无反应者（4.7 个月）相比，治疗后癌胚抗原增殖反应患者的中位生存时间为 17.1 个月（P = 0.004）。T 细胞激活后白细胞介素-2 释放较高的患者有更好的临床获益和毒性反应。
尽管 tremelimumab 的缓解率令人失望，但对于这种预后不良的疾病，1 例患者仍获得了显著持久的获益。体外证据表明，针对相关肿瘤相关抗原的增殖反应增强提示 CTLA4 阻断与抗原靶向治疗联合可能值得进一步研究。
