新辅助免疫治疗对微卫星高度不稳定胃肠肿瘤的有效性和安全性病例探讨

Efficacy and safety of neoadjuvant immunotherapy in patients with microsatellite instability-high gastrointestinal malignancies:a case series

目的:免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)现已被批准用于不可切除胃肠肿瘤的晚期姑息治疗。然而新辅助形式的免疫治疗的有效性和安全性还未被阐明。错配修复缺陷(deficient mismatch repair,dMMR)或微卫星高度不稳定(mic⁃rosatellite instability-high,MSI-H)患者群体是否能从术前ICIs联合手术治疗中获益,有待进一步探索。方法:选取2018年1月至2020年2月于北京大学肿瘤医院接受治疗,患有高分期、可切除、MSI-H胃肠肿瘤的6例患者,均接受了新辅助免疫治疗和后续手术。所有患者在治疗前和治疗后均接受完整临床评估和影像学检查。每例患者的活检标本均通过二代测序(next-generation se⁃quencing,NGS)、免疫组织化学染色(immunohistochemistry,IHC)和原位杂交(in situ hybridization,ISH)检测以获得各自的分子病理学信息。结果:新辅助免疫治疗dMMR/MSI-H胃肠肿瘤是安全且有效的。在6例患者均观察到病理学缓解,其中包括5例(83%)完全缓解,另1例患者也被证实在ICIs治疗后肿瘤TNM分期下降。3例患者(50%)发生了1~2度不良反应。所有纳入研究的患者均及时接受了手术,无特殊的围手术期或手术后并发症发生。截止到目前尚无肿瘤复发者。结论:新辅助免疫治疗在MSI-H胃肠肿瘤的患者中有良好的病理学缓解率和轻微的不良反应(trAEs)。这种术前治疗措施并不会妨碍手术治疗,需要开展大样本临床试验,以便于进一步验证新辅助免疫治疗在可切除dMMR/MSI-H胃肠肿瘤中的作用。

Objective:Immune checkpoint inhibitors(ICIs) have been approved for the late-line treatment of unresectable gastrointestinal tumors,but their efficacy and safety in the neoadjuvant setting have not been described.Whether DNA mismatch repair-deficient/microsatellite instability-high(d MMR/MSI-H) populations benefit from preoperative ICI treatment plus surgery remains unclear.Methods:From January 2018 to February 2020,six consecutive patients enrolled in Peking University Cancer Hospital & Institute received neoadjuvant ICIs and underwent surgery for advanced,resectable,MSI-H gastrointestinal tumors.All patients underwent thorough clinical evaluations and radiographic investigations before and during treatment.For molecular profiling,next-generation sequencing(NGS),immunohistochemical staining(IHC),and in situ hybridization(ISH) were performed using biopsy specimens.Results:Neoadjuvant immunotherapy was efficient and well-tolerated in patients with dMMR/MSI-H gastrointestinal tumors.Pathological responses were observed in 6/6(100%) dMMR/MSI-H tumors,with 5/6(83%) tumors showing complete responses.The remaining patient was also confirmed to demonstrate TNM downstaging after ICI treatment.Three patients(50%) developed grade Ⅰ/Ⅱ adverse events.All enrolled patients underwent timely operations without the occurrence of unexpected perioperative or postoperative complications.No disease recurrence was identified during follow-up.Conclusions:Neoadjuvant immunotherapy leads to a favorable pathological response and minor treatment-related adverse events(trAEs) among patients with MSI-H gastrointestinal tumors.This preoperative measure does not compromise subsequent surgery.Clinical trials with large cohorts are required to examine the utility of neoadjuvant ICI treatment for resectable,dMMR/MSI-H gastrointestinal malignancies.