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.

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。