Immuno-oncology combinations: raising the tail of the survival curve.
Immuno-oncology combinations: raising the tail of the survival curve.
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DOI：
10.20892/j.issn.2095-3941.2016.0015
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发表时间：
2016-06
影响因子：
5.5
通讯作者：
Yap TA
中科院分区：
文献类型：
--
作者：
Harris SJ;Brown J;Lopez J;Yap TA
近年来，通过免疫检查点抑制剂的研发，免疫肿瘤学取得了指数级的进展。免疫检查点抑制剂已被美国食品药品监督管理局批准用于晚期黑色素瘤和非小细胞肺癌，在多种其他肿瘤类型中似乎也具有显著的抗肿瘤活性。免疫疗法令人兴奋的一个方面是观察到的抗肿瘤反应的持久性，一些患者实现了多年的疾病控制。然而，并非所有患者都受益，因此现在应致力于通过联合用药方法以及反应和耐药的预测性生物标志物来提高免疫疗法的疗效。以免疫疗法为基础有多种潜在的合理组合，包括现有的治疗方法，如放疗、化疗或分子靶向药物，以及其他免疫治疗药物。此类抗肿瘤策略的目的将是通过增加长期幸存者的数量来提高生存曲线的尾部，同时控制免疫疗法联合用药可能产生的任何相加或协同毒性。基于对肿瘤生物学和药物药理学的清晰理解进行合理的试验设计仍然至关重要。本文综述了免疫肿瘤学的生物学基础，讨论了目前正在研发的现有和新型免疫治疗组合、反应和耐药预测性生物标志物面临的挑战以及免疫肿瘤学对早期临床试验设计的影响。
There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.