小柯机器人

美国纪念斯隆-凯特琳癌症中心Vinod P. Balachandran等研究人员合作发现，个性化的RNA新抗原疫苗能刺激胰腺癌的T细胞。相关论文于2023年5月10日在线发表于国际学术期刊《自然》。

在一项佐剂自体宿主的I期试验中，一种基于尿苷mRNA-脂质体纳米颗粒的个体化新抗原疫苗，研究人员从手术切除的胰腺导管腺癌（PDAC）肿瘤中实时合成了mRNA新抗原疫苗。手术后，研究人员依次施用阿替利珠单抗（一种抗PD-L1的免疫疗法）、自体cevumeran（每个病人最多20个新抗原）和改良版的四药化疗方案（mFOLFIRINOX，包括叶酸、氟尿嘧啶、伊立替康和奥沙利铂）。终点包括通过高阈值检测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。

研究人员用阿替利珠单抗和自体cevumeran治疗16名患者，然后用mFOLFIRINOX治疗15名患者。自体cevumeran在基准时间的3天内给药，是可以容忍的，并在16名患者中的8名患者中诱导出新的高量级新抗原特异性T细胞，其中一半的患者针对一种以上的疫苗新抗原。使用一种新的数学策略来追踪T细胞克隆（CloneTrack）和功能检测，研究人员发现疫苗扩增的T细胞占所有血液T细胞的10%，在疫苗增强剂的作用下重新扩增，包括长寿的多功能新抗原特异性效应CD8⁺T细胞。

在18个月的中位随访中，有疫苗扩增T细胞的患者（应答者）与没有疫苗扩增T细胞的患者（无应答者；13.4个月，P=0.003）相比，具有更长的中位无复发生存期（未达到）。患者免疫能力的差异并没有混淆这种相关性，因为应答者和非应答者对同时进行的非相关的针对SARS-CoV-2的mRNA疫苗具有同等的免疫力。因此，辅助性的阿替利珠单抗、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。

据悉，PDAC在88%的患者中是致命的，但却蕴藏着突变衍生的T细胞新抗原，适合用于疫苗。

附：英文原文

Title: Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Author: Rojas, Luis A., Sethna, Zachary, Soares, Kevin C., Olcese, Cristina, Pang, Nan, Patterson, Erin, Lihm, Jayon, Ceglia, Nicholas, Guasp, Pablo, Chu, Alexander, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Ruan, Jennifer, Amisaki, Masataka, Zebboudj, Abderezak, Odgerel, Zagaa, Payne, George, Derhovanessian, Evelyna, Mller, Felicitas, Rhee, Ina, Yadav, Mahesh, Dobrin, Anton, Sadelain, Michel, uksza, Marta, Cohen, Noah, Tang, Laura, Basturk, Olca, Gnen, Mithat, Katz, Seth, Do, Richard Kinh, Epstein, Andrew S., Momtaz, Parisa, Park, Wungki, Sugarman, Ryan, Varghese, Anna M., Won, Elizabeth, Desai, Avni, Wei, Alice C., DAngelica, Michael I., Kingham, T. Peter, Mellman, Ira, Merghoub, Taha, Wolchok, Jedd D., Sahin, Ugur, Treci, zlem, Greenbaum, Benjamin D., Jarnagin, William R., Drebin, Jeffrey, OReilly, Eileen M., Balachandran, Vinod P.

Issue&Volume: 2023-05-10

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived Tcell neoantigens that are suitable for vaccines 2,3. Here in a phaseI 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 Tcells 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 3days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific Tcells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track Tcell clones (CloneTrack) and functional assays, we found that vaccine-expanded Tcells comprised up to 10% of all blood Tcells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ Tcells. At 18-month median follow-up, patients with vaccine-expanded Tcells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4months, 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 Tcell activity that may correlate with delayed PDAC recurrence.

DOI: 10.1038/s41586-023-06063-y

Source: https://www.nature.com/articles/s41586-023-06063-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html