Modulation of Lymphocyte Regulation for Cancer Therapy: A Phase II Trial of Tremelimumab in Advanced Gastric and Esophageal Adenocarcinoma
Modulation of Lymphocyte Regulation for Cancer Therapy: A Phase II Trial of Tremelimumab in Advanced Gastric and Esophageal Adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-09-2870
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发表时间：
2010-03-01
影响因子：
11.5
通讯作者：
Thistlethwaite, Fiona C.
中科院分区：
文献类型：
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作者：
Ralph, Christy;Elkord, Eyad;Thistlethwaite, Fiona C.
目的：细胞毒性T淋巴细胞抗原4（CTLA 4），一个关键的负调节T细胞活化，是有针对性的抗体tremelimumab释放潜在有用的抗肿瘤activity.Experimental Design：这个II期试验研究tremelimumab作为二线治疗转移性胃癌和食管腺癌患者。曲美木单抗每3个月给药一次，直到有症状的疾病进展。安全性，临床疗效和免疫活性进行了evaluated.Results：18例患者接受曲美木单抗。大多数药物相关毒性是轻度的;然而，有一个死亡，由于肠穿孔并发结肠炎。4例患者病情稳定，具有临床获益; 1例患者在8个周期（25.4个月）后获得部分缓解，并在32.7个月时保持良好的研究状态。在曲美木单抗治疗后的第一个月内，调节表型标志物叉头盒蛋白3和CTLA 4在CD 4（+）CD 25（高）淋巴细胞中瞬时加倍，然后恢复到基线水平。相反，在整个治疗周期中，CD 4 + CD 25（低/阴性）淋巴细胞中的CTLA 4增加。检测到对肿瘤相关抗原5 T4（18例患者中的8例）和癌胚抗原（13例中的5例）的新生增殖反应。治疗后有癌胚抗原增殖反应的患者中位生存期为17.1个月，而无反应者为4.7个月（P = 0.004）。基线白细胞介素-2释放后T细胞活化是较高的患者的临床效益和toxicity.Conclusion：尽管tremelimumab的反应率令人失望，一个病人有一个显着持久的利益，这种预后不良的疾病。对相关肿瘤相关抗原的增殖反应增强的体外证据表明，将CTLA 4阻断与抗原靶向治疗相结合可能需要进一步研究。临床癌症研究; 16（5）; 1662-72。(C)2010年AACR。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusion: 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. Clin Cancer Res; 16(5); 1662-72. (C) 2010 AACR.