 RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancerZachary Sethna,
Pablo Guasp,
Charlotte Reiche,
Martina Milighetti,
Nicholas Ceglia,
Erin Patterson,
Jayon Lihm,
George Payne,
Olga Lyudovyk,
Luis A. Rojas,
Nan Pang,
Akihiro Ohmoto,
Masataka Amisaki,
Abderezak Zebboudj,
Zagaa Odgerel,
Emmanuel M. Bruno,
Siqi Linsey Zhang,
Charlotte Cheng,
Yuval Elhanati,
Evelyna Derhovanessian,
Luisa Manning,
Felicitas Müller,
Ina Rhee,
Mahesh Yadav,
Taha Merghoub,
Jedd D. Wolchok,
Olca Basturk,
Mithat Gönen,
Andrew S. Epstein,
Parisa Momtaz,
Wungki Park,
Ryan Sugarman,
Anna M. Varghese,
Elizabeth Won,
Avni Desai,
Alice C. Wei,
Michael I. D’Angelica,
T. Peter Kingham,
Kevin C. Soares,
William R. Jarnagin,
Jeffrey Drebin,
Eileen M. O’Reilly,
Ira Mellman,
Ugur Sahin,
Özlem Türeci,
Benjamin D. Greenbaum and
Vinod P. Balachandran ()
Nature, 2025, vol. 639, issue 8056, 1042-1051 Abstract: Abstract 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. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:639:y:2025:i:8056:d:10.1038_s41586-024-08508-4 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-024-08508-4 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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