Discussion
colorectal cancer, PDACs, tumours, cancer, PDAC, tumour, margin-positive disease
COLORECTAL CANCER, RECURRENCE, TUMOURS, CANCER, ADVANCED CANCER, TUMOUR, MINIMAL RESIDUAL DISEASE
We demonstrated that adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, in combination with atezolizumab and mFOLFIRINOX, is safe, feasible and generates substantial neoantigen-specific T cells in 50% of unselected patients with resectable PDAC. Vaccine-expanded T cells were durable, persisting up to 2 years despite post-vaccination mFOLFIRINOX treatment. High-magnitude vaccine-induced T cell responses, the focus of our immune response analysis that included a new method to track vaccine-expanded clones, correlated with delayed PDAC recurrence. Despite the limited sample size, these early results warrant larger studies of individualized mRNA neoantigen vaccines in PDAC.As multiple immunotherapiesWe did not find evidence that the correlation of vaccine response to delayed recurrence is confounded by known prognostic variables, such as lymph node or margin-positive disease. Non-responders on average had slightly larger primary tumours than responders; however, larger primary tumour size did not correlate with shorter RFS. As the uridine mRNA–lipoplex vaccine technology is based on potent antigen delivery into lymphoid compartments and stimulates weak T cell responses in splenectomized miceOur study was not powered to detect differences in biomarkers of vaccine response. Despite this limitation, we observed that tumours in responders were more clonal—possibly representing tumours in immune-edited evolution as seen in immunogenic PDACs in long-term survivorsWe tested individualized mRNA cancer vaccines in the adjuvant setting motivated by observations that vaccines against pathogens have historically been most effective in preventive and not therapeutic settings, which likely reflects that vaccine efficacy requires an optimally functioning host immune system. In patients with advanced cancer, global impairments in host immunity and knowledge gaps on neoantigen heterogeneity between tumours may hamper neoantigen vaccination. Thus, we propose that vaccines should be tested in patients with minimal residual disease, as is currently ongoing in trials in high-risk colorectal cancer (ClinicalTrials.gov identifier Overall, we reported preliminary evidence that adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, in combination with atezolizumab and mFOLFIRINOX induces substantial T cell activity in patients with surgically resected PDAC that correlates with delayed recurrence. A follow-up global randomized trial (IMCODE 003, BNT122) is imminent.