讲座

联合抗血管生成、免疫检查点抑制剂与化疗在局部进展期胃癌新辅助治疗中的临床意义

展开
  • 上海交通大学医学院附属瑞金医院外科 上海消化外科研究所上海市胃肿瘤重点实验室,上海 200025
朱正纲,E-mail: zzg1954@hotmail.com

收稿日期: 2024-03-04

  网络出版日期: 2024-07-01

Clinical significance of combination of anti-angiogenesis, immune checkpoint inhibitors and chemotherapy in the neoadjuvant treatment of locally advanced gastric cancer

Expand
  • Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received date: 2024-03-04

  Online published: 2024-07-01

摘要

联合抗血管生成、免疫检查点抑制剂(ICIs)与化疗(靶-免-化)方案在胃癌的综合治疗中已取得初步成效。实验研究表明,在肿瘤免疫治疗的各种决定因素中,肿瘤微环境(TME)影响ICIs疗效至关重要。导致免疫抑制性TME生物学机制是多因素且十分复杂,但其中较明确和重要的机制之一是肿瘤异常新血管生成的影响。使用小剂量靶向肿瘤血管生成药物(抗VEGF/VEGFR单抗等)有望促使肿瘤血管正常化,逆转免疫抑制性TME为免疫支持性TME,以更好地发挥ICI与化疗药物的协同、互补与增效抗肿瘤作用。对局部进展期胃癌(LAGC)病人开展积极的围术期综合治疗,已成为胃癌外科综合治疗中不可或缺的重要手段。近年来,临床上联合抗血管生成、免疫检查点抑制剂与化疗(靶-免-化)方案应用在LAGC围术期治疗上,初步疗效[病理完全缓解(pCR)、主要病理缓解(MPR)、肿瘤退缩分级(TRG)与治疗相关不良事件(TRAEs)等]显示出令人鼓舞的结果。本文复习有关临床研究结果,作汇总与分析。

本文引用格式

朱正纲 . 联合抗血管生成、免疫检查点抑制剂与化疗在局部进展期胃癌新辅助治疗中的临床意义[J]. 外科理论与实践, 2024 , 29(02) : 132 -137 . DOI: 10.16139/j.1007-9610.2024.02.07

Abstract

The combination of anti-angiogenesis, immune checkpoint inhibitors(ICIs) and chemotherapy(target-immune-chemo) has achieved initial results in the comprehensive treatment of gastric cancer. Experimental studies have shown that among various determinants of tumor immunotherapy, tumor microenvironment (TME) plays a crucial role in affecting ICIs efficacy. The biological mechanism leading to immunosuppressive TME is multi-factorial and very complex, but one of clear and important mechanisms is the influence of abnormal neoangiogenesis in tumors. The use of low-dose targeted tumor angiogenesis drugs (such as anti-VEGF /VEGFR monoclonal antibody, etc.) is expected to make tumor vessels normalization and reverse immunosuppressive TME to immunesupportive TME, so as to play synergistic, complementary, anti-tumor effects with ICIs and chemotherapy drugs. Perioperative treatment of locally advanced gastric cancer (LAGC) has become an indispensable and important strategy in surgical comprehensive treatment of gastric cancer. In recent years, a therapeutic combination regimen of anti-angiogenesis, ICIs and chemotherapy (target-immune-chemo) has been clinically applied in the perioperative treatment of LAGC, and the preliminary efficacy [pathologic complete response(pCR), major pathological response(MPR), tumor regression grade(TRG) and treatment-related adverse events(TRAEs), etc.] has shown encouraging results. This article reviewed the relevant clinical research results and made a summary and analysis.

参考文献

[1] AJANI J A, D'AMICO T A, BENTREM D J, et al. Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2022, 20(2):167-192.
[2] LORDICK F, CARNEIRO F, CASCINU S, et al. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up[J]. Ann Oncol, 2022, 33(10):1005-1020.
[3] JAPANESE GASTRIC CANCER ASSOCIATION. Japanese gastric cancer treatment guidelines 2021 (6th edition)[J]. Gastric Cancer, 2023, 26(1):1-25.
[4] KANG Y K, YOOK J H, PARK Y K, et al. PRODIGY: a phase Ⅲ study of neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 versus surgery and adjuvant S-1 for resectable advanced gastric cancer[J]. J Clin Oncol, 2021, 39(26):2903-2913.
[5] WANG F H, ZHANG X T, TANG L, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2023[J]. Cancer Commun (Lond), 2024, 44(1):127-172.
[6] 朱正纲. 局部进展期胃癌围手术期治疗的现状与展望[J]. 中华胃肠外科杂志, 2021, 24(2):101-106.
  ZHU Z G. Current status and prospects of perioperative treatment for locally advanced gastric cancer[J]. Chin J Gastrointest Surg, 2021, 24(2):101-106.
[7] 朱正纲. 胃癌外科综合治疗的若干进展与展望[J]. 外科理论与实践, 2023, 28(1):1-6.
  ZHU Z G. Several advances and prospects in the comprehensive surgical treatment of gastric cancer[J]. J Surg Concepts Pract, 2023, 28(1):1-6.
[8] KOERNER A S, MOY R H, RYEOM S W, et al. The present and future of neoadjuvant and adjuvant therapy for locally advanced gastric cancer[J]. Cancers (Basel), 2023, 15(16):4114.
[9] YAP T A, PARKES E E, PENG W, et al. Development of immunotherapy combination strategies in cancer[J]. Cancer Discov, 2021, 11(6):1368-1397.
[10] LEE W S, YANG H, CHON H J, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity[J]. Exp Mol Med, 2020, 52(9):1475-1485.
[11] SONG Y, FU Y, XIE Q, et al. Anti-angiogenic agents in combination with immune checkpoint inhibitors: a promi-sing strategy for cancer treatment[J]. Front Immunol, 2020,11:1956.
[12] FUKUMURA D, KLOEPPER J, AMOOZGAR Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges[J]. Nat Rev Clin Oncol, 2018, 15(5):325-340.
[13] DATTA M, COUSSENS L M, NISHIKAWA H, et al. Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies[J]. Am Soc Clin Oncol Educ Book, 2019,39:165-174.
[14] SAEED A, PARK R, SUN W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials[J]. J Hematol Oncol, 2021, 14(1):13.
[15] RAHMA O E, HODI F S. The intersection between tumor angiogenesis and immune suppression[J]. Clin Cancer Res, 2019, 25(18):5449-5457.
[16] YASUDA S, SHO M, YAMATO I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo[J]. Clin Exp Immunol, 2013, 172(3):500-506.
[17] LUO Q, DONG Z, XIE W, et al. Apatinib remodels the immunosuppressive tumor ecosystem of gastric cancer enhancing anti-PD-1 immunotherapy[J]. Cell Rep, 2023, 42(5):112437.
[18] HERBST R S, ARKENAU H T, SANTANA-DAVILA R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial[J]. Lancet Oncol, 2019, 20(8):1109-1123.
[19] FUKUOKA S, HARA H, TAKAHASHI N, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ⅰb trial (REGONIVO, EPOC1603)[J]. J Clin Oncol, 2020, 38(18):2053-2061.
[20] KAWAZOE A, FUKUOKA S, NAKAMURA Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(8):1057-1065.
[21] LIN J X, TANG Y H, ZHENG H L, et al. Neoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial[J]. Nat Commun, 2024, 15(1):41.
[22] Li C, Zheng YN, Shi Z, et al. Perioperative camrelizumab combined with rivoceranib and chemotherapy versus chemotherapy for locally advanced resectable gastric or gastroesophageal junction adenocarcinoma: the first interim analysis of a randomized, phase Ⅲ trial (DRAGON Ⅳ/CAP 05)[J]. Ann Oncol, 2023, 34(suppl 2):S852-S886.
[23] XU T, WANG W, BAO R, et al. Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study[J]. J Gastrointest Oncol, 2023, 14(1):175-186.
[24] PENG Z, WEI J, WANG F, et al. Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma[J]. Clin Cancer Res, 2021, 27(11):3069-3078.
[25] XU J, ZHANG Y, JIA R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study[J]. Clin Cancer Res, 2019, 25(2):515-523.
[26] CHEN L, YE Z, LIU G, et al. 85P Tislelizumab combined with apatinib and oxaliplatin plus S1 as neoadjuvant therapy for Borrmann Ⅳ large Borrmann Ⅲ type and bulky N positive advanced gastric cancer: a single-arm multicenter trial (TAOS-3B-Trial)[J]. Immuno-Oncology Technology, 2022,16,100189.
[27] LI S, YU W, XIE F, et al. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer[J]. Nat Commun, 2023, 14(1):8.
文章导航

/