Big opportunities for small molecules in immuno-oncology
Big opportunities for small molecules in immuno-oncology
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DOI：
10.1038/nrd4596
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发表时间：
2015-09-01
影响因子：
120.1
通讯作者：
Hoos, Axel
中科院分区：
文献类型：
--
作者：
Adams, Jerry L.;Smothers, James;Hoos, Axel
2011年ipilimumab（Yerlime）的监管批准开创了具有持久临床效果的癌症免疫疗法的新时代。这些突破性药物中的大多数是单克隆抗体，它们阻断T细胞检查点受体及其同源配体之间的蛋白质-蛋白质相互作用。此外，基因工程自体T细胞疗法最近也在血液癌症中显示出显著的临床反应。这类疗法中明显缺少传统的小分子药物，这些药物以前一直是靶向癌症治疗的支柱。通过小分子方法调节免疫系统提供了几个独特的优势，这些优势与生物学方法互补并可能协同。这篇综述强调了小分子药物可以最好或唯一靶向的免疫肿瘤学途径和机制。针对这些机制的药物-调节免疫反应，运输到肿瘤微环境和细胞浸润-有望显着扩大免疫肿瘤学应用的范围，并增加与肿瘤靶向药物和生物免疫疗法组合的机会。
The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms - modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration - are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.