Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature. 2023 Jun;618(7963):144-150. doi: 10.1038/s41586-023-06063-y. Epub 2023 May 10.
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
胰腺导管腺癌 (PDAC) 在 88%的患者中是致命的，但它具有适合疫苗的突变衍生 T 细胞新抗原。在这里，我们进行了一项辅助自体 cevumeran 的 I 期试验，这是一种基于尿苷 mRNA-脂质体纳米颗粒的个体化新抗原疫苗，我们实时从手术切除的 PDAC 肿瘤中合成 mRNA 新抗原疫苗。手术后，我们依次给予阿替利珠单抗（一种抗 PD-L1 免疫疗法）、自体 cevumeran（每个患者最多 20 个新抗原）和改良的四药化疗方案（mFOLFIRINOX，包括亚叶酸、氟尿嘧啶、伊立替康和奥沙利铂）。终点包括高阈值测定法检测到的疫苗诱导的新抗原特异性 T 细胞、18 个月无复发生存率和肿瘤学可行性。我们用阿替利珠单抗和自体 cevumeran 治疗了 16 例患者，然后用 mFOLFIRINOX 治疗了 15 例患者。自体 cevumeran 在基准时间内 3 天内给药，可耐受，并在 16 例患者中的 8 例中诱导出全新高幅度的新抗原特异性 T 细胞，其中一半针对超过一个疫苗新抗原。使用一种跟踪 T 细胞克隆的新数学策略（CloneTrack）和功能测定法，我们发现疫苗扩增的 T 细胞占所有血液 T 细胞的 10%，用疫苗增强剂再次扩增，包括具有长期多功能性的新抗原特异性效应 CD8 T 细胞。在 18 个月的中位随访中，具有疫苗扩增 T 细胞（应答者）的患者无复发生存中位数（未达到）明显长于无疫苗扩增 T 细胞的患者（无应答者；13.4 个月，P=0.003）。患者的免疫适应性差异并未混淆这种相关性，因为应答者和无应答者对同时进行的针对 SARS-CoV-2 的无关 mRNA 疫苗产生了等效的免疫反应。因此，辅助阿替利珠单抗、自体 cevumeran 和 mFOLFIRINOX 诱导了大量的 T 细胞活性，这可能与 PDAC 复发的延迟有关。
Zotero 插件
