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

鉑金類化學藥物以及表皮生長因子接受器酪胺酸酶抑制劑（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 antigen-4 （LTLA-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。

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.