肿瘤新抗原疫苗的设计与优化策略

Strategies for the design and optimization of tumor neoantigen vaccines

随着免疫检查点抑制剂和嵌合抗原受体T细胞疗法在不同适应证中的研究和临床应用,免疫治疗已经彻底改变了多种肿瘤的治疗方式。肿瘤新抗原疫苗作为一种前景广阔的免疫治疗方法,旨在激发针对新抗原的特异性T细胞反应。新抗原具有高度特异性,能够诱导和扩展肿瘤特异性T细胞库,即表位扩展。初步临床研究表明,通过快速、经济、高效的合成生物学技术,新抗原肿瘤疫苗已经展现出强大的肿瘤特异性免疫原性和抗肿瘤活性的初步证据。本文详细探讨了肿瘤新抗原的来源、发现与鉴定,以及新抗原疫苗的分类和免疫接种方案。还总结了肿瘤新抗原疫苗的优化策略,包括对预测算法、疫苗结构、免疫原性、给药方式和递送系统等方面的优化,以及联合佐剂、放化疗、免疫检查点抑制剂等方式,为个性化免疫疗法的发展提供了新的思路。

With the research progress and clinical application of immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies,immunotherapy has substantially changed the treating modalities for various tumors.Tumor neoantigen vaccines,as a promising immunotherapy method,aim to trigger a novel T cell response against neoantigens.Neoantigens,with their high specificity,can induce and expand the tumor-specific T cell receptor repertoire,which were discovered through the second-generation sequencing of DNA extracted from both the patient’s tumor and non-tumor tissue samples.The sequences and HLA types are then analyzed for alignment to pinpoint tumor-specific mutations.To validate the significance of these mutations,RNA sequencing data are integrated with the results.Subsequently,bioinformatics platforms are employed for the prediction and analysis of neoantigens encoded by mutated genes and HLA types,enabling the identification of potential immunogenic neoantigens.Finally,the immunogenicity of these neoantigens is assessed through techniques such as ELISPOT and tetramer assays.Tumor vaccines can be categorized as peptide-based,DNA-based,RNA-based,and DC-based products.Viruses,lipid nanoparticles,and nano delivery systems can activate antigen-presenting cells,enhancing their ability to recognize and present tumor-associated antigens,thus promoting the activation of CD8+T cells.Neoantigen vaccines can be administered through various routes,including subcutaneous injection,intramuscular injection,intraperitoneal injection,intradermal injection,intravenous injection,or intralymphatic injection.Preliminary clinical studies have shown that neoantigen tumor vaccines have demonstrated evidence of strong tumor-specific immunogenicity and antitumor activity.In this review,we summarize in detail the source,prediction,and identification of tumor neoantigens,as well as the classification and immunization scheme of neoantigen vaccines.In addition,we highlight strategies for optimizing tumor neoantigen vaccines,including prediction algorithms,expressing multiple epitope structures,increasing immunogenicity,administration methods and delivery systems,and combining adjuvants and various treatments,providing new insights for the development of personalized immunotherapy.