a Department of Medical Oncology , Poitiers University Hospital , Poitiers , France.
b Department of Cancer biology , Poitiers University Hospital , Poitiers , France.
Expert Opin Biol Ther. 2018 May;18(5):561-573. doi: 10.1080/14712598.2018.1445222. Epub 2018 Feb 28.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC.
This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed.
As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a 'nonimmunogenic' neoplasm into an 'immunogenic' neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.
结直肠癌（CRC）是全球第三大常见癌症，在过去二十年中，随着靶向治疗的出现，其临床疗效有了显著提高。免疫系统在癌症中起着重要作用，尤其是针对肿瘤抗原的 CD8+T 细胞。然而，肿瘤可以通过不同的机制逃避免疫反应，包括上调抑制性免疫检查点受体，如众所周知的程序性细胞死亡蛋白 1（PD-1）/程序性细胞死亡配体 1（PD-L1）相互作用，导致 CD8+T 细胞进入无能状态。免疫疗法，即所谓的免疫检查点抑制剂（CPIs），由于其延长的疾病控制和可接受的毒性，最近已被批准用于治疗多种癌症。最近在错配修复缺陷（dMMR）的转移性 CRC 中使用抗 PD-1 CPIs 的突破性成功令人鼓舞，目前正在进行多项试验。为了确定我们应该如何、何时以及为哪些患者在 CRC 中使用这些 CPIs，还面临着重大挑战。
本文重点介绍了 CRC 个性化免疫治疗的一些前景和挑战。介绍了初步结果和正在进行的突破性试验。还讨论了生物标志物在选择患者中的关键作用。
到目前为止，dMMR 和 POLE 突变（DNA 聚合酶 ε）具有超突变表型是 CPIs 疗效的最有力预测生物标志物。最具挑战性的问题是 pMMR mCRC，以及如何将“非免疫原性”肿瘤转化为“免疫原性”肿瘤，CPIs 与放疗或 MEK 抑制剂联合可能是最相关的策略。下一代测序（NGS）检测来量化突变负荷可能是比 PD-L1 表达或免疫评分更可靠的 CPIs 疗效预测生物标志物。
