免疫核對點抑制劑在非小細胞肺癌的治療

Immune Checkpoint Inhibitors for the Treatment of Non-Small Cell Lung Cancer

郭弘揚(Hung-Yang Kuo) ； 施金元(Jin-Yuan Shih) ； 廖唯昱(Wei-Yu Laio) ； 余忠仁(Chong-Jen Yu)

《台灣醫學》 18卷6期 (2014/11) Pp. 681-687

https://doi.org/10.6320/FJM.2014.18(6).08

摘要

鉑金類化學藥物以及表皮生長因子接受器酪胺酸晦抑制劑(epidermal growth factor receptor tyrosine kinase inhibitor, ＂EGFR-TKI＂)乃目前治療晚期非小細胞肺癌患者的第一線標準治療，然因腫瘤多樣性及抗藥性的產生，患者的存活期仍無法大幅增加。目前已知可藉由阻斷免疫核對點(immune checkpoint)，如cytotoxic T lymphocyte-associated autigen-4(CTLA-4)、programmed cell death-1(PD-1)及PD-ligand 1(PD-L1)，來解除腫瘤對於T淋巴球所產生的抑制作用。自2010年ipilimumab（CTLA-4抗體）被證實可增加晚期惡性黑色素細胞瘤病人的存活期後，便正式開啟了免疫療法的新時代。在Anti-PD-1（如nivolumab、pembrolizumab)及Anti-PD-L1（如MPDL3280A、MEDI4736）抗體的初步臨床試驗結果中，可見其整體反應率約17-24%，反應率亦與腫瘤上的PD-L1表現程度（免疫化學染色）成正相關。較特別的是在此類臨床試驗中已可見少數腫瘤呈長期穩定之個案（超過80週），此為晚期肺癌患者中較罕見之情形。另外常見的免疫相關不良反應包含了疲憊、關節痛及皮疹等，而嚴重肺炎的比率則約1-6%。目前已有數種藥物進入第三期臨床試驗階段，並將嘗試合併使用不同抗體，或將抗體與化療藥物或標靶藥物結合的治療方式，希望能找出最佳組合。本篇文章將介紹此類藥物的作用機轉，並藉由最新的臨床試驗成果來介紹目前最被寄予厚望的肺癌治療新曙光。

關鍵字

免疫核對點抑制劑 ； 肺癌 ； 免疫治療 ； 臨床試驗

並列摘要

Platinum-based chemotherapy and tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (＂EGFR＂) developed in the last decade are the cornerstones of the treatment of advanced non-small cell lung cancer. Tumor heterogeneity and inevitable drug resistance limit the survival of these patients. Recent studies established that cancer cells can inhibit T lymphocytes through the interactions of immune checkpoints. In 2010, ipilimumab was announced to successfully increase the median survival of metastatic melanoma and this started the era of immunotherapy. The preliminary results of clinical trials revealed that the overall response rate of anti-PD-1 (eg. nivolumab, pembrolizumab) or anti-PD-L1 (eg. MPDL3280A, MEDI4736) antibodies is around 17-24%. The response rates are associated with the PD-L1 expression in tumor cells by immunohistochemistry staining. Surprisingly, there were some patients with durable response (more than 80 weeks) to anti-PD-1 antibodies and it is rare in advanced lung cancer. Common immune-related toxicities include fatigue, arthralgia, and skin rash. Severe pneumonitis was also reported in 1-6% of all patients. Several phase III clinical trials of anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab and MPDL3280A) are ongoing, and investigators also try to find the best regimen by combining anti-PD-1 antibodies with CTLA-4 antibody, chemotherapy, or EGFR-TKI. Here we will introduce the mechanism of these immune checkpoint inhibitors and summarize updated results of clinical trials in recent years.

並列關鍵字

immune checkpoint inhibitor ； lung cancer ； immunotherapy ； clinical trial