Jessurun Charissa A C, Vos Julien A M, Limpens Jacqueline, Luiten Rosalie M
Department of Dermatology and Netherlands Institute for Pigment Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Medical Library, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Front Oncol. 2017 Sep 27;7:233. doi: 10.3389/fonc.2017.00233. eCollection 2017.
Immune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20-40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking.
Here, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients.
To identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria.
Blood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes.
This review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.
靶向细胞毒性T淋巴细胞相关抗原4（CTLA-4）或程序性死亡受体1（PD-1）分子的免疫检查点抑制剂（ICI）已显示出令人瞩目的治疗效果。然而，只有20%-40%的晚期黑色素瘤患者对ICI有持久反应，并且这些积极效果必须与严重的脱靶免疫毒性和高昂成本相权衡。这促使开发用于ICI反应的预测生物标志物，以选择可能从治疗中获得临床益处的患者。尽管存在许多候选生物标志物，但缺乏对生物标志物及其效用的系统概述。
在此，我们系统回顾ICI治疗临床数据的当前文献，以概述黑色素瘤患者中ICI的候选预测生物标志物。
为了识别关于黑色素瘤患者对ICI治疗的临床反应或生存的生物标志物的研究，我们在OVID MEDLINE中进行了系统检索，检索到429篇出版物，其中67篇符合纳入标准。
血液和基因组生物标志物主要针对CTLA-4 ICI进行研究，而肿瘤组织标志物则针对CTLA-4和PD-1 ICI进行分析。血液细胞学和可溶性因子与总生存期（OS）的相关性比与反应的相关性更频繁，表明它们具有预后而非预测性质。全身T细胞反应和调节标志物与反应相关，但未分析无进展生存期或OS。肿瘤组织分析揭示了与突变负荷、新抗原负荷、免疫相关基因表达以及侵袭边缘处CD8+ T细胞浸润的反应相关性。程序性死亡配体1（PD-L1）的预测价值各不相同，这可能是由于T细胞浸润对肿瘤PD-L1表达的影响。基因组生物标志物研究涉及CTLA-4和其他免疫相关基因。
本综述概述了所有已发表的ICI治疗生物标志物，并突出了未来研究的潜在候选标志物。迄今为止，PD-L1是针对PD-1 ICI反应研究最多的生物标志物。尚未确定最有前景的ICI反应候选预测生物标志物。结果参数、统计效能和分析的差异阻碍了结果的总结。建议使用标准化的目标和结果测量方法在更大的患者队列中进一步研究生物标志物。
