个体化 RNA 突变组疫苗激发针对癌症的多特异性治疗性免疫
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
针对肿瘤突变产生的新抗原（肿瘤特有、正常组织没有的蛋白片段）的 T 细胞是抗癌免疫的关键，但人体自发识别这些突变效率很低。本研究首次在人体中应用“个体化突变组疫苗”概念：对每位黑色素瘤患者全面鉴定其肿瘤突变、用计算机预测新抗原，并设计制造专属的 RNA 疫苗。结果显示所有患者都产生了针对多个疫苗新抗原的 T 细胞反应；在两名患者接种后切除的转移灶中，可见疫苗诱导的 T 细胞浸润和特异性杀伤肿瘤细胞。接种后转移事件累积发生率显著下降，无进展生存期持续延长；5 名转移性疾病患者中 2 名出现疫苗相关客观缓解，其中 1 名因肿瘤细胞 β2-微球蛋白缺失而晚期复发，另 1 名联合 PD-1 阻断治疗后完全缓解。该研究证明可利用个体突变开展个体化癌症免疫治疗。
为什么推荐给您：个体化 RNA 新抗原疫苗概念首次用于人体，属全新治疗模态里程碑。
不需要生物学背景，多打比方
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免疫系统里的T细胞能够识别肿瘤突变产生的新表位，从而发动攻击。
在两名患者的术后转移灶中，看到疫苗诱导的T细胞浸润和肿瘤特异性杀伤。
这项研究招募的是黑色素瘤患者，特别是已经出现转移的患者。
摘要Abstract
T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.