Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Messenger RNA-Based Therapeutics and Vaccines: What’s beyond COVID-19?

“…Despite these challenges, impressive progress has been made in the research and development of mRNA therapeutics and vaccines. Most recently, Luis A. Rojas et al have reported the promising result of a Phase 1 clinical trial in which personalized uridine mRNA neoantigen vaccines induced substantial T cell activity in postsurgery patients with pancreatic ductal adenocarcinoma . The remarkable success of the mRNA vaccines for COVID-19, along with recent expansion of this technology into treatment of most lethal cancers, has validated the great promise of this new class of medications and significantly enhanced the chance to witness their extensive applications in the near future.…”

Features of functional and dysfunctional CD8+ T cells to guide HIV vaccine development

“…The key next step is determining the optimal vaccine modality to elicit highly functional and de novo CD8 + T cell responses, particularly in cure settings given concerns regarding the irreversible dysfunctional features of preexisting responses [21 ▪▪ ]. A number of recent studies using neoantigen epitope-based vaccines in novel formats, such as mRNA [89,90] and heterologous simian adenovirus/self-amplifying RNA immunization [91] provide reason for optimism. Inducing tissue-resident HIV-specific CD8 + T cell memory responses at relevant mucosal sites will also be another important part of future vaccine efforts [92].…”

The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities

“…Rojas and colleagues recently trialled the cevumeran neoantigen mRNA vaccine in combination with modified FOLFIRINOX and anti‐PD‐L1 antibody (atezolizumab) in resected PDAC patients [86]. In 50% of patients, a large neoantigen‐specific T‐cell population was observed [86]. The median recurrence‐free survival of those patients with vaccine‐expanded T‐cells (referred to as the responders) was significantly longer than in patients lacking those T‐cells (called the non‐responders) [86].…”

“…The authors suggested the vaccine may therefore be more effective in early-stage tumours [85]. Finally, personalised neoantigen mRNA vaccines are gradually being trialled in PDAC patients [86]. Rojas and colleagues recently trialled the cevumeran neoantigen mRNA vaccine in combination with modified FOLFIRINOX and anti-PD-L1 antibody (atezolizumab) in resected PDAC patients [86].…”

“…Finally, personalised neoantigen mRNA vaccines are gradually being trialled in PDAC patients [86]. Rojas and colleagues recently trialled the cevumeran neoantigen mRNA vaccine in combination with modified FOLFIRINOX and anti-PD-L1 antibody (atezolizumab) in resected PDAC patients [86]. In 50% of patients, a large neoantigen-specific T-cell population was observed [86].…”