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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02894-y

摘要内容如下：

程序性细胞死亡蛋白1（PD-1）抑制剂作为单一疗法治疗肝细胞癌（HCC）的疗效一般。个性化治疗性癌症疫苗（PTCV）可以通过诱导肿瘤特异性免疫来增强对PD-1抑制剂的反应。我们展示了一项单臂、开放标签、1/2期研究的结果，该研究将编码多达40种新抗原的DNA质粒pTCV（gNOS-PV02）与质粒编码的白细胞介素-12和pembrolizumab联合应用于既往接受过多酪氨酸激酶抑制剂治疗的晚期HCC患者。安全性和免疫原性作为主要终点进行评估，治疗有效性和可行性作为次要终点进行评估。最常见的治疗相关不良事件是注射部位反应，在36例患者中有15例（41.6%）观察到。未观察到剂量限制性毒性或治疗相关的≥3级事件。根据实体瘤1.1的疗效评价标准，客观缓解率（改良意向治疗）为30.6%（11/36），其中8.3%（3/36）的患者达到完全缓解。临床反应与疫苗中编码的新抗原数量有关。通过酶联免疫吸附斑点试验，22例可评价患者中有19例（86.4%）证实了新抗原特异性T细胞应答。多参数细胞谱显示活性、增殖性和溶细胞性疫苗特异性CD4+和CD8+效应T细胞。T细胞受体β链（TCRβ）批量测序结果显示疫苗富集的T细胞克隆扩增和肿瘤浸润。单细胞分析显示治疗后细胞毒性T细胞表型的T细胞克隆扩增。疫苗接种后肿瘤中扩增的T细胞克隆的TCR互补决定区克隆证实了对疫苗编码的新抗原的反应性。我们的结果支持PTCV基于诱导抗肿瘤T细胞的作用机制，并表明PTCV联合pembrolizumab在晚期HCC中具有临床活性。ClinicalTrials.gov标识符：NCT04251117。

英文原文如下：

Abstracts

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. T cell receptor β-chain (TCRβ) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .

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