免疫检查点抑制剂在胃肠道恶性肿瘤新辅助治疗中的应用研究进展

Advances in application of immune checkpoint inhibitors in neoadjuvant therapy for gastrointestinal malignancies

胃肠道恶性肿瘤的主要治疗方法仍是外科手术辅以放化疗,但术后高复发率和5年低生存率等特点成为影响患者生命健康的重大问题。相对于外科手术辅以放化疗的传统常规疗法,新辅助治疗是将放疗、化疗、介入治疗、靶向治疗、免疫治疗等前移至手术前的治疗方式,具有提高根治率、延长生存时间和改善生存质量等优良特点。由于胃肠道恶性肿瘤患者难以通过传统常规疗法显著延长生存期,近年来,新辅助治疗所展现的优势在各种恶性肿瘤的治疗中愈发明显,逐渐纳入最新权威诊疗指南的推荐治疗标准。免疫检查点抑制剂(ICIs)是一类通过阻断免疫检查点来激活免疫系统攻击肿瘤细胞的新型抗肿瘤免疫治疗药物,包括程序性细胞死亡蛋白1(PD-1)及其配体(PD-L1)抑制剂与细胞毒性T淋巴细胞相关蛋白4(CTAL-4)抑制剂,其研发和应用给无数恶性肿瘤患者带来生命的曙光,在医学肿瘤领域具有划时代的意义。ICIs已经在胃肠道恶性肿瘤的综合治疗中得到广泛应用,化疗免疫组合治疗和免疫治疗更是在晚期不可切除/转移性胃肠道恶性肿瘤患者中展现出显著的效果,并且成为晚期胃肠道恶性肿瘤患者进行一、二线治疗的选择之一,从而为ICIs新辅助治疗在局部进展期可切除/潜在可切除胃肠道恶性肿瘤患者中的应用提供了良好的机遇。近期的Ⅰ/Ⅱ期临床研究结果表明,以ICIs为基础的新辅助免疫疗法在胃肠道恶性肿瘤治疗中极具潜力,患者的肿瘤分期明显降低、病理学缓解率和完全切除率显著提升、安全性可控,但生存时间仍然需要进一步观察,更多的Ⅲ期研究或将阐明ICIs在胃肠道恶性肿瘤新辅助治疗中的应用效果。笔者就ICIs在胃肠道恶性肿瘤新辅助治疗中的临床应用现状、最新临床研究结果和可能的作用机制等方面进行分析和讨论。

The main treatment approach for gastrointestinal malignancies still involves surgical procedures complemented by radiotherapy and chemotherapy.However,the high recurrence and low 5-year survival rates after surgery have become significant issues affecting the life and health of patients.In contrast to traditional conventional treatments involving surgery followed by radiotherapy and chemotherapy,neoadjuvant therapy is a treatment method that moves radiotherapy,chemotherapy,interventional therapy,targeted therapy,and immunotherapy to preoperative period.It offers advantages such as improving radical resection rate,prolonging survival,and enhancing the quality of life.Because it is difficult to significantly extend the survival of patients with gastrointestinal malignancies through traditional conventional treatments,the advantages of neoadjuvant therapy have become increasingly apparent in the treatment of various malignant tumors.It is gradually being included in the recommended treatment standards of the latest authoritative clinical guidelines.Immune checkpoint inhibitors(ICIs)are a new class of anti-tumor immunotherapy drugs that activate the immune system to attack tumor cells by blocking immune checkpoints.This category includes programmed cell death protein 1(PD-1)and its ligand(PD-L1)inhibitors,as well as cytotoxic T-lymphocyte-associated protein 4(CTAL-4)inhibitors.The development and application of ICIs have brought new hope to countless cancer patients and are considered groundbreaking in the field of medical oncology.ICIs have been widely used in the comprehensive treatment of gastrointestinal malignancies.The combination of chemotherapy and immunotherapy,as well as immunotherapy alone,has shown significant effects in patients with advanced,unresectable,or metastatic gastrointestinal malignancies.It has become one of the treatment choices for these patients.This provides a promising opportunity for the use of ICIs in the neoadjuvant treatment of locally resectable or potentially resectable gastrointestinal malignancies.Recent results from phase I/Ⅱclinical trials indicate that neoadjuvant immunotherapy based on ICIs holds great potential in the treatment of gastrointestinal malignancies.It significantly reduces tumor stage,and increases the pathological remission and complete resection rates,with controllable safety.However,the long-term survival outcomes still require further observation,and more phaseⅢstudies are needed to elucidate the effectiveness of ICIs in neoadjuvant treatment of gastrointestinal malignancies.Here,the authors analyze and discuss the current clinical applications of ICIs in the neoadjuvant treatment of gastrointestinal malignancies,recent clinical research findings,and potential mechanisms of action.