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mRNA疫苗：胰腺癌个性化治疗新曙光
DOI: 10.12449/JCH250404
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：王新景、王蔚负责资料收集，分析数据及撰写文章；沈柏用负责文章框架构思，指导文章撰写并修改。
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摘要: 胰腺癌作为恶性程度最高的实体肿瘤之一，其5年生存率长期维持在约13%，且80%的患者在确诊时已失去手术机会。此外，传统放化疗及靶向治疗因肿瘤异质性高、免疫抑制微环境复杂而效果有限。近年来，mRNA疫苗凭借其独特的技术优势，成为肿瘤免疫治疗的新焦点。基于非整合性mRNA模板，mRNA疫苗可精准编码肿瘤新抗原，在宿主体内高效表达并诱导多维度免疫应答。针对胰腺癌，研究热点集中在肿瘤相关抗原疫苗及肿瘤特异性抗原疫苗的研发与优化。当前研究主要关注基于测序的新抗原表位优化、靶向递送技术和人工智能驱动的免疫应答预测模型，以期推动mRNA疫苗在胰腺癌精准治疗中的应用。未来研究需进一步突破肿瘤微环境中关键免疫抑制分子的靶向阻断，精准识别肿瘤特异性抗原表位，开发高效新型疫苗，为胰腺癌患者带来新的治疗希望。Abstract: Pancreatic cancer is currently recognized as one of the most malignant solid tumors， with a 5-year survival rate of 13% over a long period of time， and 80% of the patients have lost the opportunity for surgery at the time of confirmed diagnosis. In addition， the efficacy of conventional radiochemotherapy and targeted therapy is limited by high tumor heterogeneity and the complex immunosuppressive microenvironment. In recent years， mRNA vaccines have become a new focus of tumor immunotherapy due to their unique technical advantages. Based on non-integrating mRNA templates， mRNA vaccines enable precise encoding of tumor neoantigens， which are efficiently expressed in the host and can induce multifaceted immune responses. As for pancreatic cancer， current studies mainly focus on the development and optimization of tumor-associated antigen vaccines and tumor-specific antigen vaccines， as well as next-generation sequencing-guided neoantigen epitope optimization， innovative targeted delivery systems， and artificial intelligence-powered predictive models for immune response， thereby promoting the application of mRNA vaccines in the precise treatment of pancreatic cancer. Further studies should make breakthroughs in the targeted blockade of critical immunosuppressive molecules within the tumor microenvironment， the precise identification of tumor-specific antigenic epitopes， and the development of highly efficient vaccines， so as to bring new hopes for patients with pancreatic cancer.
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Key words:
- Pancreatic Neoplasms /
- mRNA Vaccine /
- Immunotherapy， Active
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注： a，mRNA疫苗：串联多个个性化肿瘤新抗原序列的mRNA被脂质纳米颗粒或其他递送系统包裹后成药。b，抗原递呈细胞端的新抗原翻译、加工和T淋巴细胞激活：mRNA被抗原递呈细胞内吞后，经过内逃逸进入细胞质，被翻译成包含多个肿瘤新抗原氨基酸片段的融合蛋白。融合蛋白经蛋白酶体切割后，成为突变新抗原肽，被匹配的人类白细胞抗原（HLA）递呈到细胞表面，随后引起抗原特异性T淋巴细胞的激活和扩增。c，肿瘤细胞端的T淋巴细胞激活、扩增和杀伤：激活的T淋巴细胞迁移至肿瘤组织中，识别肿瘤细胞表面被呈递的突变抗原-HLA复合物，进一步激活T淋巴细胞下游通路后不断扩增的同时，活化并释放大量细胞因子，起到杀伤肿瘤细胞的效果。
图 1 肿瘤mRNA疫苗的作用机制
Figure 1. Mechanism map of tumor mRNA vaccine
表 1 胰腺癌mRNA疫苗的临床试验汇总
Table 1. Summary of clinical trials of pancreatic cancer mRNA vaccine
疫苗名称 所属公司 类别 机制 适应证 阶段 试验号 BNT122 BioNTech/Genentech 个性化 20种患者特异性抗原，联用PD-L1 胰腺癌术后 Ⅱ期 NCT05968326 BNT122 BioNTech/Genentech 个性化 20种患者特异性抗原，联用PD-1 包括胰腺癌在内的晚期实体肿瘤 Ⅰ期 NCT03289962 mRNA-0217/S001 上海交通大学附属瑞金医院 个性化 1～20种个性化肿瘤新抗原 包括胰腺癌在内的晚期实体肿瘤 IIT NCT05916248 LK101 立康生命 个性化 mRNA疫苗+树突状细胞载体 包括胰腺癌在内的晚期实体肿瘤 Ⅰ期 NCT06054932 XP-004 上海交通大学附属瑞金医院 个性化 1～20种个性化肿瘤新抗原 胰腺癌术后 IIT NCT06496373 PANC-IIT-RGL 复旦大学附属肿瘤医院 个性化 个性化肿瘤新抗原 胰腺癌术后 IIT NCT06156267 mRNA-5671 Moderna 通用型 多个KRAS突变抗原串联 晚期非小细胞肺癌、结肠、胰腺癌 Ⅰ期 NCT03948763 mRNA-4359 Moderna 通用型 靶向免疫检查点IDO/PD-L1 包括胰腺癌在内的晚期实体肿瘤 Ⅰ/Ⅱ期 NCT05533697 GRT-C903/GRT-R904 Gritstone 通用型 16～20个固定抗原/单独靶向KRAS，联用PD-1/CTLA-4 包括胰腺癌在内的晚期实体肿瘤 Ⅰ/Ⅱ期 NCT03953235 ABO2102 上海交通大学附属瑞金医院 通用型 多个KRAS突变抗原串联 晚期胰腺癌 IIT NCT06577532 注：PD-L1，程序性死亡配体；PD-1，程序性死亡受体；IDO，吲哚胺2，3-双加氧酶；CTLA-4，细胞毒性T淋巴细胞相关抗原4；IIT，研究者发起的临床试验。
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