文章：

机制驱动的生物标志物在癌症治疗中指导免疫检查点阻断

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

原文发布日期：2016-04-15

DOI: 10.1038/nrc.2016.36

类型: Review Article

开放获取: 否

要点：

1. Exploration for biomarkers for drugs that block immune checkpoints should be rationally conducted based on knowledge of the mechanism of action of the targeted pathway. The programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated antigen 4 (CTLA4) pathways are unique, and there are special considerations based on mechanisms of action for developing biomarkers for drugs blocking each of these pathways.
2. Biomarkers for immune checkpoint-blocking drugs currently fall into three major categories: immunological, genetic and virological. Future work may reveal additional markers related to metabolism and the microbiome.
3. Immunological biomarkers offer the advantage of applicability across multiple tumour types amenable to immune checkpoint blockade. In the case of anti-PD1 drugs, tumour PD1 ligand 1 (PDL1) expression is a pretreatment biomarker that predicts a greater likelihood of response to therapy. Despite technical pitfalls that make clinical application challenging, two PDL1 immunohistochemistry tests are currently approved by the US Food and Drug Administration for guiding treatment decisions in patients with non-small-cell lung cancer and melanoma.
4. Although no specific oncogene or driver mutation has yet been correlated with clinical response to immune checkpoint blockade, overall tumour mutational burden reflecting neoantigenic diversity may have predictive value. This is exemplified by the high anti-PD1 response rate in DNA mismatch repair deficient colorectal cancers (which have a large mutational burden and which account for ∼15% of all colon cancers), whereas mismatch repair proficient colon cancers are unlikely to respond.
5. Virus-associated cancers, which account for more than 20% of cancers worldwide, express viral neoantigens that are strongly immunogenic. Early evidence demonstrates expression of PD1–PDL1 in these cancers, and suggests responsiveness to anti-PD1 therapies.
6. Combination treatment regimens based on immune checkpoint-blocking drugs are emerging as the next step in clinical development to improve efficacy and response durability. Biomarker considerations for these regimens are complex and are likely to involve multifactorial assessments.

要点翻译：

1. 针对免疫检查点阻断药物的生物标志物探索，应基于对靶向通路作用机制的深入理解进行合理开展。程序性细胞死亡蛋白1（PD1）与细胞毒性T淋巴细胞相关抗原4（CTLA4）通路具有独特性，在开发阻断这些通路的药物生物标志物时，需根据其作用机制采取特殊考量。
2. 目前免疫检查点阻断药物的生物标志物主要分为三大类：免疫学标志物、遗传学标志物和病毒学标志物。未来研究可能揭示与代谢及微生物组相关的其他标志物。
3. 免疫学生物标志物的优势在于其适用于多种适合免疫检查点阻断的肿瘤类型。对于抗PD1药物而言，肿瘤PD1配体1（PDL1）表达可作为预测治疗反应概率的预处理生物标志物。尽管存在技术难点使临床应用面临挑战，目前美国食品药品监督管理局已批准两种PDL1免疫组织化学检测方法，用于指导非小细胞肺癌和黑色素瘤患者的治疗决策。
4. 虽然尚未发现特定癌基因或驱动突变与免疫检查点阻断的临床反应相关，但反映新抗原多样性的总体肿瘤突变负荷可能具有预测价值。典型例证是DNA错配修复缺陷型结直肠癌对抗PD1疗法的高应答率（该类肿瘤具有高突变负荷，约占所有结肠癌的15%），而错配修复正常型结肠癌则难以产生应答。
5. 病毒相关癌症占全球癌症的20%以上，其表达的病毒新抗原具有强免疫原性。早期证据显示这类癌症中存在PD1-PDL1通路表达，提示其对抗PD1疗法可能产生应答。
6. 以免疫检查点阻断药物为基础的联合治疗方案正成为临床发展的新方向，旨在提升疗效并延长应答持续时间。这些治疗方案的生物标志物考量较为复杂，很可能需要涉及多因素综合评估。

英文摘要：

With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.

摘要翻译： 

随着多种阻断细胞毒性T淋巴细胞相关抗原4（CTLA4）和程序性细胞死亡蛋白1（PD1）的治疗性抗体获批用于黑色素瘤、非小细胞肺癌和肾癌，以及更多免疫检查点进入临床靶向研究，关于如何最佳使用这些阻断检查点通路的药物，仍有许多问题亟待解决。定义可预测治疗效果和不良事件的生物标志物，是一项关键任务，这一点也因近期两项PDL1诊断测试获批而凸显。在此，我们基于免疫学、遗传学和病毒学标准，探讨抗PD1治疗的生物标志物。与PD1相比，CTLA4免疫检查点具有独特的生物学特性，因此其生物标志物的开发需采取不同策略。相关研究带来的机制性洞见，可能为指导基于免疫检查点阻断的协同联合治疗方案设计提供方向。

原文链接：

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy