Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
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DOI：
10.1038/s41586-023-06063-y
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发表时间：
2023-06
期刊：
影响因子：
64.8
通讯作者：
Balachandran, Vinod P.
中科院分区：
文献类型：
--
作者：
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;Mueller, Felicitas;Rhee, Ina;Yadav, Mahesh;Dobrin, Anton;Sadelain, Michel;Luksza, Marta;Cohen, Noah;Tang, Laura;Basturk, Olca;Goenen, 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.;D'Angelica, Michael I.;Kingham, T. Peter;Mellman, Ira;Merghoub, Taha;Wolchok, Jedd D.;Sahin, Ugur;Tuereci, Oezlem;Greenbaum, Benjamin D.;Jarnagin, William R.;Drebin, Jeffrey;O'Reilly, Eileen M.;Balachandran, Vinod P.
胰腺导管腺癌（PDAC）在88%的患者中是致命的，但含有适用于疫苗的突变衍生的T细胞新抗原。在一项关于自体免疫佐剂的I期试验中，我们从手术切除的PDAC肿瘤中真实的时间合成了mRNA新抗原疫苗，自体免疫佐剂是一种基于尿苷mRNA-lipoplex纳米颗粒的个体化新抗原疫苗。手术后，我们依次给予atezolizumab（一种抗PD-L1免疫疗法）、自体cevuminescent（每例患者最多20种新抗原）和改良版的四药化疗方案（mFOLFIRINOX，包括亚叶酸、氟尿嘧啶、伊立替康和奥沙利铂）。研究终点包括通过高阈值试验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。我们用atezolizumab和自体cevumulizumab治疗了16例患者，然后用mFOLFIRINOX治疗了15例患者。在基准时间的3天内给予自体cevuminescent，在16名患者中的8名患者中是可耐受的，并且从头诱导了高量级的新抗原特异性T细胞，其中一半靶向一种以上的疫苗新抗原。使用一种新的数学策略来跟踪T细胞克隆（CloneTrack）和功能测定，我们发现疫苗扩增的T细胞占所有血液T细胞的10%，用疫苗加强剂重新扩增，并包括长寿命的多功能新抗原特异性效应CD 8 + T细胞。在18个月的中位随访中，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，疫苗扩增T细胞的患者（应答者）的中位无复发生存期（未达到）更长。患者免疫适应性的差异并没有混淆这种相关性，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疫苗具有相同的免疫力。因此，辅助atezolizumab、自体基因cevumuli和mFOLFIRINOX诱导大量T细胞活性，这可能与延迟PDAC复发相关。在胰腺导管癌患者中进行的辅助个性化mRNA新抗原疫苗（autogene cevuminescent）的I期临床试验表明，该疫苗可诱导T细胞活性，这可能与疾病的延迟复发相关。
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. A phase I clinical trial of an adjuvant personalized mRNA neoantigen vaccine, autogene cevumeran, in patients with pancreatic ductal carcinoma demonstrates that the vaccine can induce T cell activity that may correlate with delayed recurrence of disease.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
20.3
作者：
Holtkamp, Silke;Kreiter, Sebastian;Sahin, Ugur
通讯作者：
Sahin, Ugur
影响因子：
20.3
作者：
Gallardo, HF;Tan, C;Sadelain, M
通讯作者：
Sadelain, M
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS