Zachary Sethna; Pablo Guasp; Charlotte Reiche; Martina Milighetti; Nicholas Ceglia; Erin Patterson; Jayon Lihm; George C. Payne; Olga Lyudovyk; Luis A. Rojas; Nan Pang; Akihiro Ohmoto; Masataka Amisaki; Abderezak Zebboudj; Zagaa Odgerel; Emmanuel M. Bruno; Siqi Linsey Zhang; C. K. Cheng; Yuval Elhanati; Evelyna Derhovanessian; Luisa Manning; Felicitas Müller; Ina Rhee; Mahesh Yadav; Taha Merghoub; Jedd D. Wolchok; Olca Baştürk; Mithat Gönen; Andrew S. Epstein; Parisa Momtaz; Wungki Park; Ryan Sugarman; Anna M. Varghese; Elizabeth Won; Avni M. Desai; Alice C. Wei; Michael I. D’Angelica; T. Peter Kingham; Kevin C. Soares; William R. Jarnagin; Jeffrey A. Drebin; Eileen M. O’Reilly; Ira Mellman; Uğur Şahin; Özlem Türeci; Benjamin D. Greenbaum; Vinod P. Balachandran · 2025 · Nature
Paper
A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA–lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA–lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA–lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination. In a phase 1 trial, patients with pancreatic ductal adenocarcinoma who were treated with surgery and bespoke neoantigen mRNA vaccines combined with anti-PD-L1 and chemotherapy exhibited marked long-lived persistence of neoantigen-specific CD8+ T cell clones, which correlated with prolonged recurrence-free survival at a 3.2-year follow-up.
Analysis
A phase 1 trial in pancreatic ductal adenocarcinoma (PDAC) patients demonstrated that individualized neoantigen mRNA vaccines, combined with atezolizumab and modified FOLFIRINOX, induced long-lived CD8+ T cells that correlated with prolonged recurrence-free survival.
Discovery
Vladimir Zyrin; Evgeniy Mozheiko; Ivan Valiev; Alexey Lazarev; Tigran Gevorkyan; Matvey Murashko; Konstantin Okonechnikov
Ashling Cannon
Dinghai Zheng; Justin Hong; Jun Wang; Adrien Villain; Mickaël Costallat; Fernando Ulloa Montoya; Vikram Agarwal
Petar Brlek; Jan Kolić; Luka Bulić; Vedrana Škaro; Dragan Primorac
Almohanad A. Alkayyal
Crodel CC; Gork L; Göpel W; Linke P; Sinn K; Miethke J; Hochhaus A; Hilgendorf I
Source record