Global Clinical Research, Oncology, Bristol-Myers Squibb Co, Wallingford, CT 06492, USA.
Semin Oncol. 2010 Oct;37(5):533-46. doi: 10.1053/j.seminoncol.2010.09.015.
Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.
细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）被鉴定为 T 细胞活性的关键负调控因子，这促使开发了完全人源化的单克隆抗体伊匹单抗，以阻断 CTLA-4 并增强抗肿瘤 T 细胞反应。动物研究首次提供了关于抗 CTLA-4 抗体引起肿瘤消退的能力的见解，特别是在联合治疗方案中。早期临床研究确定了伊匹单抗的药代动力学和联合应用的可能性。在晚期黑色素瘤的 II 期临床试验中，伊匹单抗显示出客观反应，但更多的患者病情稳定。在一项 III 期试验中，伊匹单抗是首个在先前治疗的晚期黑色素瘤患者中提高总生存期的药物。与伊匹单抗相关的不良事件谱主要与免疫相关。不良事件可能很严重且危及生命，但大多数情况下可通过治疗指南进行逆转。伊匹单抗单药治疗在晚期黑色素瘤中表现出常规和新的活性模式，Kaplan-Meier 生存曲线的分离较晚。伊匹单抗观察到的一些新的反应模式，这些模式无法用标准反应标准来捕捉，这导致了用于评估实体瘤免疫治疗的新标准。总体而言，从伊匹单抗的开发中吸取的经验教训为癌症免疫治疗的新临床范式做出了贡献，该范式由癌症免疫治疗联盟发展而来。
