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Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
Nature Medicine ( IF 58.7 ) Pub Date : 2021-01-21 , DOI: 10.1038/s41591-020-01206-4
Zhuting Hu 1 , Donna E Leet 1, 2 , Rosa L Allesøe 3 , Giacomo Oliveira 1 , Shuqiang Li 4, 5 , Adrienne M Luoma 6 , Jinyan Liu 7 , Juliet Forman 1, 4, 5 , Teddy Huang 5 , J Bryan Iorgulescu 1, 2, 8 , Rebecca Holden 9 , Siranush Sarkizova 4 , Satyen H Gohil 1, 4, 10 , Robert A Redd 11 , Jing Sun 1 , Liudmila Elagina 4 , Anita Giobbie-Hurder 11 , Wandi Zhang 1 , Lauren Peter 7 , Zoe Ciantra 12 , Scott Rodig 8, 12 , Oriol Olive 1 , Keerthi Shetty 1 , Jason Pyrdol 6 , Mohamed Uduman 11, 12 , Patrick C Lee 1, 2 , Pavan Bachireddy 1, 2, 4, 13 , Elizabeth I Buchbinder 1, 2, 13 , Charles H Yoon 2, 14 , Donna Neuberg 11 , Bradley L Pentelute 4, 9, 15 , Nir Hacohen 2, 4, 16 , Kenneth J Livak 1, 5 , Sachet A Shukla 1, 4, 5 , Lars Rønn Olsen 17, 18 , Dan H Barouch 2, 7, 19 , Kai W Wucherpfennig 2, 6 , Edward F Fritsch 1, 4 , Derin B Keskin 1, 4, 5 , Catherine J Wu 1, 2, 4, 13 , Patrick A Ott 1, 2, 4, 13
Affiliation  

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient (NCT01970358). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.



中文翻译:


个人新抗原疫苗可诱导黑色素瘤患者持续记忆 T 细胞反应和表位扩散



个人新抗原疫苗被认为是诱导、放大和多样化抗肿瘤 T 细胞反应的有效方法。为了确定这种疫苗的长期效果,我们评估了 8 名手术切除 IIIB/C 期或 IVM1a/b 期黑色素瘤患者的临床结果和循环免疫反应,这些患者接受 NeoVax 治疗后平均近 4 年。针对每位患者多达 20 个个人新抗原的长肽疫苗 (NCT01970358)。所有患者均存活,其中六名患者没有活动性疾病的证据。我们观察到疫苗接种后新抗原特异性 T 细胞反应的长期持续性,离体检测新抗原特异性 T 细胞表现出记忆表型。我们还发现,随着时间的推移,新抗原特异性 T 细胞克隆出现多样化,多种 T 细胞受体克隆型的出现表现出不同的功能亲和力。此外,我们检测到疫苗接种和表位扩散后新抗原特异性 T 细胞克隆浸润肿瘤的证据,表明疫苗可诱导肿瘤细胞杀伤。因此,个人新抗原肽疫苗可诱导持续多年的 T 细胞反应,并扩大黑色素瘤患者的肿瘤特异性细胞毒性范围。

更新日期:2021-01-21
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