Purpose: Personalized vaccines targeting multiple neoantigens (nAgs) are a promising strategy for eliciting a diversified antitumor T cell response to overcome tumor heterogeneity. NOUS-PEV is a vector based personalized vaccine, expressing 60 nAgs and consists of priming with a non-human Great Ape Adenoviral vector (GAd20) followed by boosts with Modified Vaccinia Ankara (MVA). Here, we report data of a phase Ib trial of NOUS-PEV in combination with pembrolizumab in treatment naïve metastatic melanoma patients (NCT04990479). Experimental Design: The feasibility of this approach was demonstrated by producing, releasing and administering to six patients 11 out of 12 vaccines within 8 weeks from biopsy collection to GAd20 administration. Results: The regimen was safe, with no treatment-related serious adverse events observed and mild vaccine-related reactions. Vaccine immunogenicity was demonstrated in all evaluable patients receiving the prime/boost regimen, with detection of robust neoantigen specific immune responses to multiple neoantigens comprising both CD4 and CD8 T cells. Expansion and diversification of vaccine-induced TCR clonotypes was observed in the post-treatment biopsies of patients with clinical response providing evidence of tumor infiltration by vaccine-induced neoantigen-specific T cell. Conclusions: These findings indicate the ability of NOUS-PEV to amplify and broaden the repertoire of tumor reactive T cells to empower a diverse, potent and durable antitumor immune response. Finally, a gene signature indicative for reduced presence of activated T cells together with very poor expression of the antigen processing machinery (APM) genes has been identified in pre-treatment biopsies as a potential biomarker of resistance to the treatment.

中文翻译：

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基于病毒载体的个性化疫苗接种的 I 期试验引发了强大的新抗原特异性抗肿瘤 T 细胞反应

目的：针对多种新抗原 (nAg) 的个性化疫苗是引发多样化抗肿瘤 T 细胞反应以克服肿瘤异质性的一种有前途的策略。 NOUS-PEV 是一种基于载体的个性化疫苗，表达 60 个 nAg，包括用非人类类人猿腺病毒载体 (GAd20) 引发，然后用改良安卡拉牛痘 (MVA) 加强。在这里，我们报告了 NOUS-PEV 联合派姆单抗治疗初治转移性黑色素瘤患者的 Ib 期试验数据 (NCT04990479)。实验设计：通过在从活检收集到 GAd20 施用的 8 周内生产、释放并向 6 名患者施用 12 种疫苗中的 11 种，证明了这种方法的可行性。结果：该方案是安全的，没有观察到与治疗相关的严重不良事件和轻微的疫苗相关反应。疫苗的免疫原性在接受初免/加强方案的所有可评估患者中得到证实，并检测到对包含 CD4 和 CD8 T 细胞的多种新抗原的强烈新抗原特异性免疫反应。在具有临床反应的患者的治疗后活检中观察到疫苗诱导的 TCR 克隆型的扩展和多样化，这提供了疫苗诱导的新抗原特异性 T 细胞肿瘤浸润的证据。结论：这些发现表明 NOUS-PEV 能够放大和拓宽肿瘤反应性 T 细胞的功能，从而增强多样化、有效且持久的抗肿瘤免疫反应。最后，在治疗前活组织检查中，已将表明活化 T 细胞存在减少以及抗原加工机制 (APM) 基因表达非常差的基因特征确定为治疗耐药的潜在生物标志物。