Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I/II study
Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I/II study
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DOI：
10.1245/aso.2005.03.536
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发表时间：
2005-12-01
影响因子：
3.7
通讯作者：
Rosenberg, SA
中科院分区：
文献类型：
--
作者：
Maker, AV;Phan, GQ;Rosenberg, SA
背景：细胞毒性T淋巴细胞相关抗原(CTLA)-4可抑制T细胞反应，参与自身抗原耐受。我们之前报道了使用CTLA-4阻滞剂治疗的转移性黑色素瘤患者的自身免疫表现和客观的癌症消退。CTLA-4阻滞剂在激活肿瘤反应性T细胞的同时消除抑制活性的可能性激发了人们将抗CTLA-4抗体与其他癌症免疫疗法结合使用以改善临床结果的兴趣。在这项研究中，我们评估了CTLA-4阻滞剂联合免疫激活刺激因子IL-2对转移性黑色素瘤患者的抗肿瘤活性和自身免疫毒性。每个队列中有3名患者接受了1、3、1.0和2.0 mg/kg的剂量。24例患者给予3.0 mg/kg。所有患者接受IL-2治疗(每8小时720,000 IU/kg，最多15次)。结果：8例(22%)患者出现了客观的肿瘤反应(3例完全，5例部分)，包括肺、淋巴结、纵隔和皮下组织的转移。8名患者中有6名在11至19个月时有持续的客观反应。5例患者(14%)继发于抗CTLA-4治疗后出现III/IV级自身免疫毒性反应，其中4例为小肠结肠炎，1例为关节炎和葡萄膜炎。结论：没有证据支持CTLA-4阻断和IL-2治疗的协同作用，因为22%的客观有效率是这两种药物单独治疗的预期结果。在接受这种联合治疗的患者中，可以看到持久的癌症消退。
Background: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.Methods: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses).Results: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.Conclusions: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.