Sharma Samantha, Singh Naresh, Turk Anita Ahmed, Wan Isabella, Guttikonda Akshay, Dong Julia Lily, Zhang Xinna, Opyrchal Mateusz
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
World J Gastroenterol. 2024 Apr 7;30(13):1815-1835. doi: 10.3748/wjg.v30.i13.1815.
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
结直肠癌（CRC）是一种病因多样、临床结局各异的复杂疾病。尽管CRC治疗学取得了长足进展，但晚期转移性CRC（mCRC）的诊断和管理仍面临挑战。特别是，由于mCRC目前很少能治愈，其五年生存率非常低。在过去十年中，随着癌症免疫疗法的引入，尤其是免疫检查点抑制剂，癌症治疗有了显著改善。旨在阻断免疫检查点（如PD-1、PD-L1和CTLA-4）的疗法靶向免疫系统的抑制途径，从而增强抗肿瘤免疫力。因此，这些疗法单独或联合使用在许多临床试验中都显示出了有前景的结果。免疫疗法单独或与CRC联合使用的疗效和安全性已在多项临床试验中进行了研究。包括KEYNOTE-164和CheckMate 142在内的临床试验分别导致美国食品药品监督管理局批准了PD-1抑制剂帕博利珠单抗和纳武利尤单抗用于治疗不可切除或转移性微卫星高度不稳定或错配修复缺陷的CRC患者。不幸的是，这些药物仅使一小部分患者受益，免疫疗法对绝大多数CRC患者的益处仍然难以捉摸。为此，对免疫疗法的原发性和继发性耐药仍然是一个重大问题，需要进一步研究以优化免疫疗法在CRC中的使用并确定预测反应的生物标志物。本综述全面概述了涉及CRC中免疫检查点抑制剂的临床试验。讨论了其基本原理、面临的挑战以及改善该领域预后和提高成功试验可能性的潜在未来步骤。
