Synapse - RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer

RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer Journal Article

Authors:	Sethna, Z.; Guasp, P.; Reiche, C.; Milighetti, M.; Ceglia, N.; Patterson, E.; Lihm, J.; Payne, G.; Lyudovyk, O.; Rojas, L. A.; Pang, N.; Ohmoto, A.; Amisaki, M.; Zebboudj, A.; Odgerel, Z.; Bruno, E. M.; Zhang, S. L.; Cheng, C.; Elhanati, Y.; Derhovanessian, E.; Manning, L.; Müller, F.; Rhee, I.; Yadav, M.; Merghoub, T.; Wolchok, J. D.; Basturk, O.; Gönen, M.; Epstein, A. S.; Momtaz, P.; Park, W.; Sugarman, R.; Varghese, A. M.; Won, E.; Desai, A.; Wei, A. C.; D’Angelica, M. I.; Kingham, T. P.; Soares, K. C.; Jarnagin, W. R.; Drebin, J.; O’Reilly, E. M.; Mellman, I.; Sahin, U.; Türeci, Ö; Greenbaum, B. D.; Balachandran, V. P.
Article Title:	RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer
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. © The Author(s) 2025.
Keywords:	controlled study; human tissue; disease-free survival; unclassified drug; gene mutation; human cell; clinical trial; fluorouracil; solid tumor; disease free survival; pancreas cancer; neoadjuvant therapy; pancreatic neoplasms; flow cytometry; follow up; follow-up studies; antineoplastic agent; polymerase chain reaction; cd3 antigen; cd8+ t lymphocyte; cd8-positive t-lymphocytes; quality control; phenotype; gene; gene expression; antineoplastic combined chemotherapy protocols; carcinoma, pancreatic ductal; gene frequency; transcription factor; cytotoxicity; tumor antigen; time factors; irinotecan; monoclonal antibody; rna; immunology; chemistry; immune response; amino acid sequence; antigens, neoplasm; gamma interferon; cancer vaccine; cancer vaccines; messenger rna; folinic acid; immunogenicity; pancreas tumor; cancer immunization; retrovirus vector; nanoparticles; nanoparticle; cytokine production; effector cell; upregulation; phase 1 clinical trial; cell clone; tumor; oxaliplatin; enzyme linked immunospot assay; half life time; ex vivo study; good clinical practice; leucovorin; clone cells; therapy; vaccine; peripheral blood mononuclear cell; lifespan; tumor necrosis factor; phylogeny; recurrence free survival; memory t lymphocyte; cell; phase 1 clinical trial (topic); single cell analysis; pancreatic ductal carcinoma; time factor; cd56 antigen; mathematical phenomena; density gradient centrifugation; antibodies, monoclonal, humanized; rna vaccine; cancer; humans; human; male; female; article; lipoplex; folfirinox; whole exome sequencing; gene set enrichment analysis; atezolizumab; ec50; receptor type tyrosine protein phosphatase c; draining lymph node; mrna vaccines; autogene cevumeran; folfirinox drug; klf2 gene; znf683 gene
Journal Title:	Nature
Volume:	639
Issue:	8056
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2025-05-27
Start Page:	1042
End Page:	1051
Language:	English
DOI:	10.1038/s41586-024-08508-4
PUBMED:	39972124
PROVIDER:	scopus
PMCID:	PMC11946889
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218079236&doi=10.1038%2fs41586-024-08508-4&partnerID=40&md5=9fa9976fe513d71e8575c36d487b2eaa
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Vinod Balachandran -- Source: Scopus