Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
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DOI：
10.1038/nature23003
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发表时间：
2017-07-13
期刊：
影响因子：
64.8
通讯作者：
Tuereci, Oezlem
中科院分区：
文献类型：
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作者：
Sahin, Ugur;Derhovanessian, Evelyna;Tuereci, Oezlem
针对突变新表位的T细胞推动癌症免疫。然而，对突变的自发免疫识别效率很低。我们最近引入了个性化突变组疫苗的概念，并实施了一种基于RNA的多新表位方法来动员对一系列癌症突变的免疫(1，2)。在这里，我们报告了这一概念在人类中首次在黑色素瘤中的应用。我们建立了一个过程，包括对个体突变的全面识别，对新表位的计算预测，以及为每个患者设计和制造独特的疫苗。所有患者都对多种疫苗新表位产生了高达个位数百分比的T细胞反应。在疫苗接种后切除的2例患者的转移瘤中，显示了疫苗诱导的T细胞浸润和对自体肿瘤细胞的新表位特异性杀伤。在开始接种疫苗后，转移事件的累积发生率大大降低，导致了持续的无进展生存。五名转移性疾病患者中有两名经历了与疫苗相关的客观反应。其中一名患者晚期复发是由于缺乏β2微球蛋白的黑色素瘤细胞的生长是一种获得性耐药机制。第三名患者在接种疫苗和PD-1阻断治疗的同时出现完全反应。我们的研究表明，个体突变可以被利用，从而为癌症患者开辟了一条个性化免疫治疗的道路。
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-neoepitope approach to mobilize immunity against a spectrum of cancer mutations(1,2). 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 beta 2-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.