ABSTRACT

Introduction

Immunotherapy with checkpoint inhibition has shown potent antitumor activity in patients with microsatellite instability (MSI) metastatic cancer. Microsatellite stable (MSS) colorectal cancer has long been considered resistant to immunotherapy.

Areas covered

In this review, we provide an overview of current progress on strategies to overcome the resistance to immunotherapy in MSS colorectal cancer.

Expert opinion

Emerging evidence suggest that combination of immune modulators such as regorafenib may improve the responsiveness of MSS colorectal cancer to checkpoint blockade. In addition, signs of clinical activity have also been observed in other combination strategies, such as the combination of checkpoint blockade with Stat3 inhibitor, or bispecific T-cell engagers. Nevertheless, predictive biomarkers that can identify patients who may benefit from immunotherapy are key for its implementation in clinical setting. Metastatic disease sites may predict for the response or resistance to checkpoint blockade, with liver metastases emerging as a strong predictive biomarker of lack of benefit from PD-1 targeting, even with combination therapies. Additional efforts are required to study the mechanism of resistance and to develop novel therapeutic strategies to overcome immune resistance.

Abbreviations

CEA: carcinoembryonic antigen; CR: complete response; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DCR: disease control rate; MSI-H: microsatellite instability-high; MSS: Microsatellite stable (MSS); OS: overall survival; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand receptor 1; PR: partial response; PFS: progression-free survival; SD: stable disease; TMB: tumor mutation burden; VEGFR: vascular endothelial growth factor receptor

中文翻译：

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用免疫疗法靶向 MSS 结直肠癌：我们正在转机吗？

摘要

介绍

检查点抑制的免疫疗法在微卫星不稳定性 (MSI) 转移性癌症患者中显示出有效的抗肿瘤活性。微卫星稳定型 (MSS) 结直肠癌长期以来一直被认为对免疫治疗具有抗药性。

涵盖的领域

在这篇综述中，我们概述了克服 MSS 结直肠癌免疫治疗耐药性策略的当前进展。

专家意见

新出现的证据表明，瑞戈非尼等免疫调节剂的组合可能会提高 MSS 结直肠癌对检查点阻断的反应性。此外，在其他组合策略中也观察到了临床活性的迹象，例如检查点阻断与 Stat3 抑制剂或双特异性 T 细胞接合剂的组合。然而，可以识别可能从免疫治疗中受益的患者的预测性生物标志物是其在临床环境中实施的关键。转移性疾病部位可以预测对检查点阻断的反应或抗性，肝转移作为一种强有力的预测生物标志物，即使在联合治疗中也无法从 PD-1 靶向中获益。

缩写

CEA：癌胚抗原；CR：完全响应；CTLA-4：细胞毒性 T 淋巴细胞相关蛋白 4；DCR：疾病控制率；MSI-H：微卫星不稳定性-高；MSS：微卫星稳定（MSS）；OS：总生存期；PD-1：程序性细胞死亡蛋白1；PD-L1：程序性死亡配体受体 1；PR：部分反应；PFS：无进展生存期；SD：疾病稳定；TMB：肿瘤突变负荷；VEGFR：血管内皮生长因子受体