Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors
Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors
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新抗原识别策略使难治性实体瘤的个性化免疫治疗成为可能
DOI：
10.1172/jci99538
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Liu, Baorui
中科院分区：
文献类型：
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作者：
Chen, Fangjun;Zou, Zhengyun;Liu, Baorui
背景。最近基因组学和生物信息学技术的进步，使剖析由肿瘤特异性突变编码的个体化新抗原的免疫反应成为可能。然而，及时有效地识别新抗原仍然是个体化基于新抗原的癌症免疫治疗的主要障碍。本研究建立了两种不同的新抗原鉴定管道：(a)对难治实体瘤患者进行临床级靶向测序，并重新合成具有高变异等位基因频率和预测的高hla结合亲和力的突变肽。(b)构建目录共享的常见实体瘤新抗原肽库，并将患者的热点突变与新抗原肽库进行匹配。候选新表位是通过体外回忆T细胞反应确定的。随后，对6例患者进行了新抗原负载树突状细胞疫苗和新抗原反应性T细胞的个性化免疫治疗。免疫原性新表位在使用从头合成模式的4例患者中有3例被自身T细胞识别，在使用共享新抗原肽库的13例患者中有6例被自身T细胞识别。一名转移性胸腺瘤患者在治疗29个月后获得了完全和持久的缓解。在另一名转移性胰腺癌患者中观察到免疫相关的部分反应。其余4例患者实现了疾病的长期稳定，中位无进展生存期为8.6个月。本研究为新抗原鉴定提供了可行的途径。实施这些策略来单独定制新抗原可以促进基于新抗原的转化免疫治疗研究。
BACKGROUND. Recent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations. However, timely and efficient identification of neoantigens is still a major obstacle to personalized neoantigen-based cancer immunotherapy.METHODS. Two different pipelines of neoantigen identification were established in this study: (a) Clinical-grade targeted sequencing was performed in patients with refractory solid tumor, and mutant peptides with high variant allele frequency and predicted high HLA-binding affinity were synthesized de novo. (b) An inventory-shared neoantigen peptide library of common solid tumors was constructed, and patients' hotspot mutations were matched to the neoantigen peptide library. The candidate neoepitopes were identified by recalling memory T cell responses in vitro. Subsequently, neoantigen-loaded dendritic cell vaccines and neoantigen-reactive T cells were generated for personalized immunotherapy in 6 patients.RESULTS. Immunogenic neoepitopes were recognized by autologous T cells in 3 of 4 patients who used the de novo synthesis mode and in 6 of 13 patients who used the shared neoantigen peptide library. A metastatic thymoma patient achieved a complete and durable response beyond 29 months after treatment. Immune-related partial response was observed in another patient with metastatic pancreatic cancer. The remaining 4 patients achieved prolonged stabilization of disease with a median progression-free survival of 8.6 months.CONCLUSION. The current study provides feasible pipelines for neoantigen identification. Implementing these strategies to individually tailor neoantigens could facilitate neoantigen-based translational immunotherapy research.