Toh James W T, de Souza Paul, Lim Stephanie H, Singh Puneet, Chua Wei, Ng Weng, Spring Kevin J
Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Discipline of Surgery, Sydney Medical School, The University of Sydney, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Colorectal Surgery, Westmead Hospital, Westmead, New South Wales, Australia.
Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia.
Clin Colorectal Cancer. 2016 Dec;15(4):285-291. doi: 10.1016/j.clcc.2016.07.007. Epub 2016 Jul 22.
Colorectal cancers (CRCs) have been identified as potential targets for immunotherapy with programmed cell death (PD)-1 inhibitors. English-language publications from MedLine and Embase that evaluated PD-1/PD ligand 1 (PD-L1) in the CRC tumor microenvironment and clinical trials that assessed PD-1 inhibitors were included. Sixteen abstracts were screened. Fifteen met the inclusion criteria. After review of the full texts, this resulted in a final reference list of 8 studies eligible for review. Five studies that assessed PD-1/PD-L1 in CRC and 3 trials that assessed PD-1 inhibitors were included. PD-1-positive (PD-1) tumor-infiltrating lymphocytes and PD-L1 cancer cells featured more prominently in high-level microsatellite instability (MSI-H) CRCs compared with microsatellite stable (MSS) CRCs, except in 1 study in which PD-L1 expression was higher in MSS CRCs. In the 3 trials that assessed PD-1 inhibitor, all 3 studies recruited patients with metastatic CRC (mCRC). One study also included patients with recurrent CRC. The objective response according to the Response Evaluation Criteria in Solid Tumors criteria was 0% (19 CRC patients with unknown microsatellite instability status) in the nivolumab study. In the pembrolizumab study, the objective response to PD-1 inhibitor was 40% and 0% in patients with MSI-H and MSS mCRC, respectively (10 patients in the MSI-H group, 18 patients in the MSS group). Seventy-eight percent of the patients in the MSI-H mCRC group compared with 11% in the MSS mCRC group (P < .005) showed no further disease progression at 12 weeks. In the nivolumab with or without ipilimumab study, objective partial response at 12 weeks to PD-1 inhibitor with or without cytotoxic T-lymphocyte-associated protein 4 inhibitor was 25.5% to 33.3% and 5% in the MSI-H and MSS groups, respectively (100 patients in the MSI-H group, 20 patients in the MSS group). Clinical trials that assessed PD-1 inhibitor immunotherapy in patients with CRC have recruited only small cohorts of patients with mCRC. Studies on the tumor microenvironment have been on the basis of archival specimens with different antibody PD-1 and PD-L1 preparations for immunohistochemistry, independent from immunotherapy trials. Immunotherapy with PD-1 therapy has potential benefit for immunogenic MSI-H CRCs whereas there is no evidence to date to suggest immunotherapy benefit in MSS CRCs. The available data are limited, and there is no information on non-mCRCs. Future trials are under way to determine its benefits.
结直肠癌（CRC）已被确定为程序性细胞死亡（PD）-1抑制剂免疫治疗的潜在靶点。纳入了来自MedLine和Embase评估CRC肿瘤微环境中PD-1/PD配体1（PD-L1）的英文出版物以及评估PD-1抑制剂的临床试验。筛选了16篇摘要。15篇符合纳入标准。在审阅全文后，最终得到8项符合审查条件的研究参考文献列表。其中包括5项评估CRC中PD-1/PD-L1的研究和3项评估PD-1抑制剂的试验。与微卫星稳定（MSS）的CRC相比，高水平微卫星不稳定（MSI-H）的CRC中PD-1阳性（PD-1）肿瘤浸润淋巴细胞和PD-L1癌细胞更为突出，但有1项研究显示MSS CRC中PD-L1表达更高。在评估PD-1抑制剂的3项试验中，所有3项研究均招募了转移性CRC（mCRC）患者。1项研究还纳入了复发性CRC患者。根据实体瘤疗效评价标准，纳武单抗研究中的客观缓解率为0%（19例微卫星不稳定状态未知的CRC患者）。在帕博利珠单抗研究中，MSI-H和MSS mCRC患者对PD-1抑制剂的客观缓解率分别为40%和0%（MSI-H组10例患者，MSS组18例患者）。MSI-H mCRC组78%的患者与MSS mCRC组11%的患者（P <.005）在12周时无疾病进展。在纳武单抗联合或不联合伊匹木单抗的研究中，MSI-H组和MSS组在12周时对联合或不联合细胞毒性T淋巴细胞相关蛋白4抑制剂的PD-1抑制剂的客观部分缓解率分别为25.5%至33.3%和5%（MSI-H组100例患者，MSS组20例患者）。评估CRC患者PD-1抑制剂免疫治疗的临床试验仅招募了少量mCRC患者队列。关于肿瘤微环境的研究基于存档标本，使用不同的抗体PD-1和PD-L1制剂进行免疫组织化学检测，独立于免疫治疗试验。PD-1治疗免疫疗法对免疫原性MSI-H CRC具有潜在益处，而迄今为止尚无证据表明对MSS CRC有免疫治疗益处。现有数据有限，且尚无关于非mCRC的信息。未来的试验正在进行以确定其益处。
