Abstract PR-06: Personalized RNA neoantigen vaccines induce long-lived CD8+ T effector cells in pancreatic cancer
Authors: Guasp Pablo , Sethna Zachary , Reiche Charlotte , Milighetti Martina , Ceglia Nicholas , Patterson Erin , Pang Nan , Payne George , Akihiro Ohmoto , Rojas Luis A , Amisaki Masataka , Zebboudj Abderezak , Bruno Emmanuel , Zhang Linsey , Odgerel Zagaa , Cheng Charlotte , Derhovanessian Evelyna , Manning Luisa , Müller Felicitas , Rhee Ina , Yadav Mahesh , Gönen Mithat , Basturk Olca , Epstein Andre S , Momtaz Parisa , Park Wungki , Sugarman Ryan , Varghese Anna M , Won Elizabeth , Desai Avni , Wei Alice C , D'Angelica Michael I , Kingham Peter , Soares Kevin C , Jarnagin William R , Drevin Jeffrey , O'Reilly Eileen M , Mellman Ira , Sahin Ugur , Türeci Özlem , Greenbaum Benjamin D , Balachandran Vinod P 
Published: October 2024

Abstract
Background: A fundamental barrier for cancer vaccines is the challenge to generate long-lived functional T cells specific to tumor antigens. Here, in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations, we discover that mRNA vaccines against mutation-derived neoantigens may solve this challenge. We recently reported (Rojas et al., Nature 2023) 1.5-yr median follow-up data (phase-I, NCT04161755) of sequential adjuvant atezolizumab (αPD-L1), autogene cevumeran (individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles), and mFOLFIRINOX in 16 surgically resected PDAC patients. Autogene cevumeran induced high-magnitude neoantigen-specific T cells in 8 patients (responders). Responders had prolonged recurrence-free survival (RFS, not reached) versus non-responders (no vaccine-induced T cells, RFS 13.4 mo; HR=0.08; P=0.003). Here, we track if vaccine-induced T cells persist, function, and correlate with improved RFS at 3-yr median follow- up. Methods: In responders, we analyzed T cell clones before vaccination in tumors, tumor-draining lymphatic and adjacent tissues (24 samples, 212K clones), and sequentially up to 3 yr after vaccination in blood (q1-2 wk surgery to vaccination; q3 mo post-vaccination; 124 samples, 26 timepoints, 5M clones) with TCRVβ sequencing. We used our custom mathematical strategy (CloneTrack) to measure persistence and estimate lifespan of vaccine-induced clones. To assess long-term T cell function, we rechallenged peripheral T cells 1.8-2.6 yr post-vaccination (memory phase) with neopeptides in vitro. In 16 vaccinated patients, we analyzed RFS. Results: Autogene cevumeran induced 79 CD8+ T cell clones in the blood with an estimated median lifespan of 5.5 yr (range 1.3-70.2). Autogene cevumeran primed multiple CD8+ T cell clones per patient (median 8, range 2-28); 98% of clones were absent in pre- vaccination host tissues to suggest vaccines prime clones de novo. Of primed clones, 85% persisted into the memory phase at high frequencies (median 0.1% of all blood T cells). Despite post-vaccination chemotherapy, memory phase CD8+ T cells produced IFNγ, TNFα, and degranulated upon neoantigen rechallenge in 6 of 8 responders. At 3-yr median follow-up (range 2.3-3.8), responders continued to exhibit prolonged RFS (median RFS not reached) compared to non-responders (median RFS 13.4 mo; HR=0.14; 95% CI 0.03-0.6; P=0.007). Two responders recurred and evidenced fewer aggregate vaccine-induced T cells vs. responders who did not recur. Conclusion: In PDAC, autogene cevumeran induces polyfunctional CD8+ T effector cells of significant longevity, substantial magnitude, and durable function that correlate with delayed recurrence at sustained follow-up. mRNA may thus fulfill a pivotal requisite for effective cancer vaccines.
Citation Format: Pablo Guasp, Zachary Sethna, Charlotte Reiche, Martina Milighetti, Nicholas Ceglia, Erin Patterson, Nan Pang, George Payne, Ohmoto Akihiro, Luis A Rojas, Masataka Amisaki, Abderezak Zebboudj, Emmanuel Bruno, Linsey Zhang, Zagaa Odgerel, Charlotte Cheng, Evelyna Derhovanessian, Luisa Manning, Felicitas Müller, Ina Rhee, Mahesh Yadav, Mithat Gönen, Olca Basturk, Andre S Epstein, Parisa Momtaz, Wungki Park, Ryan Sugarman, Anna M Varghese, Elizabeth Won, Avni Desai, Alice C Wei, Michael I D'Angelica, Peter Kingham, Kevin C Soares, William R Jarnagin, Jeffrey Drevin, Eileen M O'Reilly, Ira Mellman, Ugur Sahin, Özlem Türeci, Benjamin D Greenbaum, Vinod P Balachandran. Personalized RNA neoantigen vaccines induce long-lived CD8T effector cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr PR-06.