Actively personalized vaccination trial for newly diagnosed glioblastoma
Actively personalized vaccination trial for newly diagnosed glioblastoma
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DOI：
10.1038/s41586-018-0810-y
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发表时间：
2019-01-10
期刊：
影响因子：
64.8
通讯作者：
Wick, Wolfgang
中科院分区：
文献类型：
--
作者：
Hilf, Norbert;Kuttruff-Coqui, Sabrina;Wick, Wolfgang
胶质母细胞瘤患者目前没有充分受益于使用检查点抑制剂(1，2)的癌症治疗的最新突破。为了使使用检查点抑制剂的治疗取得成功，高突变负荷和对新表位的反应被认为是必不可少的(3)。在胶质母细胞瘤中有有限的免疫细胞在肿瘤内的渗透(4)，这些肿瘤只有30-50个非同义突变(5)。开发完整的肿瘤抗原--即未突变抗原和新表位--可能会提供更有效的免疫疗法，特别是对于突变负荷较低的肿瘤。这里，在胶质瘤主动个性化疫苗联盟(GAPVAC)的第一阶段试验GAPVAC-101中，我们将这两种肿瘤抗原的高度个性化疫苗集成到标准护理中，以最佳地利用新诊断的胶质母细胞瘤患者有限的靶向空间。15例人类白细胞抗原(HL A)-A*02：01或HL A*A*24：02阳性的胶质母细胞瘤患者接受了从预制的未突变抗原库中提取的疫苗(APVAC1)治疗，然后用优先靶向新表位的APVAC2治疗。个人化是基于对单个肿瘤的转录本和免疫肽的突变和分析。以多聚核苷-多核糖核酸-多L赖氨酸羧甲基纤维素和粒-巨噬细胞集落刺激因子为佐剂的疫苗具有良好的安全性和较强的免疫原性。未突变的APVAC1抗原可诱导中枢记忆CD8(+)T细胞的持续应答。APVAC2主要诱导针对预测的新表位的辅助性T细胞1型的CD4(+)T细胞反应。
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors(1,2). For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential(3). There is limited intratumoural infiltration of immune cells(4) in glioblastoma and these tumours contain only 30-50 non-synonymous mutations(5). Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A* 24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8(+) T cells. APVAC2 induced predominantly CD4(+) T cell responses of T helper 1 type against predicted neoepitopes.