肿瘤细胞治疗研究
英文原题：Immunotherapy in GI Cancers: Lessons from Key Trials and Future Clinical Applications.
Immunotherapy in GI Cancers: Lessons from Key Trials and Future Clinical Applications.
免疫治疗已成为胃肠道（GI）癌症的一种变革性方法，解决了晚期疾病历史上生存率低的问题。
免疫治疗已成为胃肠道（GI）癌症的一种变革性方法，解决了晚期疾病历史上生存率低的问题。靶向 PD-1/PD-L1 轴的免疫检查点抑制剂（ICIs）在错配修复缺陷（dMMR）或高度微卫星不稳定（MSI-H）的结直肠癌中显示出显著疗效，NICHE-2 等试验实现了极高的病理缓解率。然而，重大局限性仍然存在，包括部分 dMMR/MSI-H 肿瘤的耐药、错配修复正常（pMMR）肿瘤中疗效甚微，以及由于肿瘤异质性和免疫逃逸机制导致大多数 GI 恶性肿瘤的总体缓解率较低。肿瘤突变负荷（TMB）和 PD-L1 表达等预测性生物标志物对于优化患者选择至关重要，而伴有 POLE 突变的高突变 pMMR 肿瘤代表了新兴的治疗机会。在生存率仍然极低的胰腺腺癌中，与化疗联合的策略以及癌症疫苗等新方法显示出前景，但缺乏变革性突破。食管胃癌受益于 ICIs 联合化疗，尤其是在 MSI-H 和 HER2 阳性肿瘤中，而肝细胞癌通过 atezolizumab-bevacizumab 和 durvalumab-tremelimumab 等联合方案取得了显著进展，超越了传统疗法。胆道癌在 durvalumab-化疗联合方案中显示出适度改善。尽管取得了这些进展，免疫治疗仍面临重大挑战，包括免疫相关不良事件、通过癌症免疫编辑产生的获得性耐药，以及需要以生物标志物驱动的方法来克服肿瘤微环境障碍。本综述讨论了关键临床试验、治疗进展以及包括CAR T细胞疗法和联合策略在内的新兴模式，强调迫切需要解决耐药机制并完善精准医学方法，以充分发挥免疫疗法在GI恶性肿瘤中的潜力。
Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab-bevacizumab and durvalumab-tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab-chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy's potential in GI malignancies.
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