恶性胸膜间皮瘤免疫检查点抑制剂临床治疗进展

Progress in clinical researches of immunotherapy for malignant pleural mesothelioma in regards of immunological checkpoint inhibitor

恶性胸膜间皮瘤(MPM)是一种主要与石棉暴露相关的罕见的高度侵袭性肿瘤,尽管应用不同的方式治疗(如化疗、放疗和手术)患者的疗效仍很差,预后也极差。近年来免疫治疗逐渐成为肿瘤治疗的热点,突破性进展是发现阻断T细胞免疫检测点分子可激活T细胞对肿瘤细胞的杀伤作用。免疫检查点抑制剂改变了肿瘤治疗的临床实践。2011年,CTLA-4抑制剂易普利姆玛(ipilimumab)获得美国食品药品监督管理局(FDA)的批准,成为首个上市的免疫检查点抑制剂。2014年,纳武单抗(nivolumab)获准成为全球首个上市的PD-1抑制剂。之后数年内,包括PD-1/PD-L1抗体在内的多个免疫检查点抑制剂获准用于包括非小细胞肺癌、胃癌和肝癌等在内的多个癌种的适应证。从DETERMINE研究、KEYNOTE-028研究到The PROMISE-Meso研究,都显示免疫检查点抑制剂单药对MPM治疗具有临床疗效和较好的安全性。免疫检查点抑制剂作为一线治疗与化疗的对比研究也在进行中,联合治疗(包括联合应用免疫检查点抑制剂和免疫检查点抑制剂联合化疗)的研究也在不断开展。免疫检查点抑制剂的生物标志物的研究推动了MPM的精准免疫治疗。

Malignant pleural mesohelioma is a rare type of highly invasive cancer that is mainly related to asbestos exposure. Despite application of different modalities such as chemotherapy, radiotherapy and surgery, the therapies remain ineffective.and the prognoses remain very poor. Immunotherapy has gradually become a hot spot in cancer treatment in recent years. The breakthrough finding is that blocking T cell immunologic checkpoint molecules can reactivate the killing effect of T cells on tumor cells. Immunological checkpoint inhibitors have changed the clinical practice of cancer therapy. In 2011, the CTLA-4 inhibitor ipilimumab was approved by the US FDA and became the first immune checkpoint inhibitor in market. In 2014, nivolumab was approved to become the world＇s first PD-1 inhibitor to open to market. Several years later, multiple immune checkpoint inhibitors, including PD-1/PD-L1 antibodies, were approved to be adaptable to multiple cancers, including non-small cell lung cancer, gastric cancer, and liver cancer. From the study of DETERMINE, KEYNOTE-028 to the PROMISE-Meso study, immune checkpoint blockades monotherapy has been proved to be effective and relatively safe for the treatment of MPM. A comparative study of immunological checkpoint inhibitors as first-line treatment and chemotherapy is also under way, combined treatment （including the combination of immunological checkpoint inhibitors treatment and chemotherapy） research is also ongoing. The study of biomarkers of immune checkpoint inhibitors has promoted the precise immunotherapy of MPM.