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