Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Nat Med. 2021 Mar;27(3):515-525. doi: 10.1038/s41591-020-01206-4. Epub 2021 Jan 21.
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.
个体化新抗原疫苗被认为是一种有效的方法，可以诱导、放大和多样化抗肿瘤 T 细胞反应。为了确定这种疫苗的长期效果，我们评估了 8 名接受手术切除 IIIB/C 期或 IVM1a/b 期黑色素瘤的患者的临床结果和循环免疫反应，这些患者在接受针对每个患者多达 20 个个体化新抗原的长肽疫苗 NeoVax 治疗后中位数时间接近 4 年（NCT01970358）。所有患者均存活，6 名患者无疾病活动证据。我们观察到接种疫苗后长期存在新抗原特异性 T 细胞反应，体外检测到具有记忆表型的新抗原特异性 T 细胞。我们还发现新抗原特异性 T 细胞克隆随时间推移而多样化，出现多个 T 细胞受体克隆型，具有不同的功能亲和力。此外，我们在接种疫苗后和表位扩展后检测到新抗原特异性 T 细胞克隆浸润肿瘤的证据，提示疫苗诱导的肿瘤细胞杀伤作用具有针对性。因此，个体化新抗原肽疫苗可诱导 T 细胞反应持续多年，并拓宽黑色素瘤患者的肿瘤特异性细胞毒性谱。
