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

• 成果类型: Article
• 署名作者: 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; Mueller, Felicitas; Rhee, Ina; Yadav, Mahesh; Merghoub, Taha; Wolchok, Jedd D.; Basturk, Olca; Goenen, 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; Tuereci, Oezlem; Greenbaum, Benjamin D.; Balachandran, Vinod P.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; BioNTech SE; Roche Holding; Genentech; Roche Holding USA; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3633
• DOI: 10.1038/s41586-024-08508-4
• 发表日期: 2025-03-27
• 关键词: adjuvant chemotherapy; sensitive detection; open-label; memory; gemcitabine; residency; immunity; phase-3

摘要

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.