新抗原可以通过个性化新肽疫苗作为 T 细胞介导的抗肿瘤免疫的靶标。我们的临床研究 NCT03715985 的中期数据表明，以脂质体佐剂 CAF09b 配制的个性化肽新抗原疫苗 EVX-01 是安全的，并且能够在转移性黑色素瘤患者中引发 EVX-01 特异性 T 细胞反应。在这里，我们展示了该研究剂量递增部分的结果，评估了 EVX-01 除抗 PD-1 治疗外的可行性、安全性、有效性和免疫原性。接受抗 PD-1 治疗的转移性黑色素瘤患者分三组进行治疗，疫苗剂量增加（两倍和四倍）。肿瘤源性新抗原由人工智能平台PIONEER筛选并用于个性化治疗性癌症肽疫苗EVX-01。疫苗每隔2周注射一次，总共注射3次腹腔注射和3次肌肉注射。该研究的主要终点是安全性和耐受性。其他终点包括免疫学反应、生存率和客观反应率。与之前报告的基础剂量水平相比，EVX-01 与抗 PD-1 药物联合使用的剂量递增期间，没有观察到新的疫苗相关严重不良事件根据当地指南。两名患者在第三剂量水平（四倍剂量）时出现 3 级毒性，很可能与派姆单抗有关。总体而言，12 名患者中有 8 名出现客观临床缓解（6 名部分缓解 (PR) 和 2 名 CR），最高剂量水平的所有 4 名患者均获得 CR（1 名 CR，3 名 PR）。 EVX-01 在所有接受治疗的患者中诱导肽特异性 CD4 和/或 CD8 T 细胞反应，其中 CD4 T 细胞是主要反应。通过 IFN-γ ELISpot 测定测量的免疫反应强度与个体肽剂量相关。检测到 PIONEER 质量评分与诱导 T 细胞免疫原性之间存在显着相关性，而更好的 CR 与免疫原性 EVX-01 肽的数量和 PIONEER 质量评分相关。除了抗 PD- 疫苗外，还使用 ​​EVX-01-CAF09b 进行免疫1 疗法被证明是安全且耐受性良好的，并且在所有剂量水平下都能引发疫苗新抗原特异性 CD4 和 CD8 T 细胞反应。此外，67% 的患者观察到客观肿瘤反应。结果鼓励进一步评估 EVX-01 与抗 PD-1 疗法联合使用的抗肿瘤功效。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。由英国医学杂志出版。

Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy.Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates.Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score.Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.