RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer.
Sethna Zachary, Guasp Pablo, Reiche Charlotte, Milighetti Martina, Ceglia Nicholas, Patterson Erin, Lihm Jayon, Payne George, Lyudovyk Olga, Rojas Luis A, Pang Nan, Ohmoto Akihiro, Amisaki Masataka, Zebboudj Abderezak, Odgerel Zagaa, Bruno Emmanuel M, Zhang Siqi Linsey, Cheng Charlotte, Elhanati Yuval, Derhovanessian Evelyna, Manning Luisa, Müller Felicitas, Rhee Ina, Yadav Mahesh, Merghoub Taha, Wolchok Jedd D, Basturk Olca, Gönen Mithat, 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, Soares Kevin C, Jarnagin William R, Drebin Jeffrey, O'Reilly Eileen M, Mellman Ira, Sahin Ugur, Türeci Özlem, Greenbaum Benjamin D, Balachandran Vinod P
Nature · 2025 · PMID 39972124 · 인용 278
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.