10c). This liver lesion disappeared on subsequent imaging (Fig. 4a), which suggests that autogene-cevumeran-expanded T cells may pos- sess the capacity to eradicate micrometastases. Discussion 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 treat - ment. 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 stud - ies of individualized mRNA neoantigen vaccines in PDAC. As multiple immunotherapies31 have emerged for immune-inflamed tumours, there remains a need for new immunotherapies for the major - ity of patients with non-inflamed tumours that are largely insensitive to current immunotherapies. Indeed, the prevailing thought has been that the low passenger mutation rate of such tumours renders them with insufficient neoantigens for vaccines. Here, we provided evidence that despite the low mutation rate of PDAC, a mRNA vac - cine can induce T cell activity against neoantigens in this cancer, a non-inflamed tumour with predominantly immune-excluded or desert phenotypes. Whether mRNA neoantigen vaccines can similarly activate T cells in other non-inflamed cancers should be more broadly tested. We 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 mice20, it is notable that non-responders were also mar - ginally enriched in patients with splenectomies (Extended Data Fig. 1b). Furthermore, that vaccines induced high-magnitude T cell responses in 50% of patients may highlight the need for biomarkers to select optimal patients and tumours for this treatment. Of note, although autogene cevumeran is designed to activate both neoantigen-specific CD4+ and CD8+ T cells and we find it activates high magnitude CD8+ T cells in PDAC, the primary and confirmatory immune response assays in this study do not distinguish CD8+ from CD4+ T cell responses. In fact, as these assays bias towards high-magnitude T cell responses, assays that detect lower magnitude responses may include both CD4+ T cell responses and pre-existing responses. In other tumours, we observed that a substantial proportion of vaccine neoantigens induce de novo b 06 12 18 24 30050100RFS from surgery (%)Responders (n = 8) Non-responders (n = 8) MonthsP = 0.003 Median RFS: 13.4 months Median RFS: not reached HR: 0.08 (0.01–0.4) At risk Responders Non-responders888675622 00 0Median follow-up: 18.0 months 06 12 18 24 30050100 Median RFS: not reached Median RFS: 11.0 months RFS from landmark time (%) Months Responders Non-responders8 77 55 12 00 00 0At riskResponders (n = 8) Non-responders (n = 7) P = 0.008 HR: 0.06 (0.008–0.4) Median follow-up: 18.0 months06 12 18 24050100OS (%) n = 19 19 18 15 94Median follow-up: 18.0 months Months At risk06 12 18 24 Months30 19 16 14 8 2030 0a 050100RFS (%) At risk Fig. 3 | mRNA vaccine response correlates with delayed PDAC recurrence. a, OS and RFS in n = 19 patients in the safety-evaluable cohort. b , RFS from surgery and from landmark time (date of the last vaccine priming dose) stratified by vaccine response in patients in the biomarker-evaluable cohort. n indicates individual patients. HR indicates hazard ratio with 95% CI. P values calculated using two-tailed log-rank test. Nature | Vol 618 | 1 June 2023 | 149responses that are below the ex vivo detectable threshold (manu - script in preparation), a level of response not assessed in this trial. Nevertheless, our results in PDAC imply that a high-magnitude T cell response may contribute to a favourable clinical outcome. Thus, strategies to ensure high-magnitude responses are being pursued, including further optimization of mRNA vaccine potency and exten - sion of the neoantigen discovery space to include genetic aberra - tions other than single nucleotide variations (SNVs) and insertions and deletions (indels) (for example, fusions)32. Notwithstanding, as vaccines expand polyclonal T cells, whether vaccine-induced clonal diversity contributes to durable control33,34 is another key query for future work. Our 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 survivors3. Thus, we speculate that a more clonal primary tumour may reflect the ability of the immune system to recognize a tumour and therefore respond to a vaccine. Moreover, the observation that neo - antigen quality2,3,30 correlates with immunogenic vaccine neoantigens provides further support for the concept that select neoantigens may possess higher immunogenic qualities that are possibly desirable for vaccines. However, in this trial, as responders and non-responders had comparable numbers of vaccine neoantigens drawn from a similar number of tumour mutations, we consider that an absence of a response in non-responders is unlikely due to a failure to include immunogenic neoantigens. Overall, these observations remain preliminary but support future investigation of whether tumour clonality and neo - antigen quality could serve as biomarkers of vaccine response.We 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 opti - mally functioning host immune system. In patients with advanced cancer, global impairments in host immunity and knowledge gaps on neoantigen heterogeneity between tumours may hamper neoan - tigen 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 NCT04486378) and in triple-negative breast cancer (ClinicalTrials. gov identifier NCT02316457 ). Notably, our study demonstrated that mRNA neoantigen vaccines can be individualized in 9 weeks and fully integrated into a standard clinical workflow even after complex onco - logic surgery. Given this trial was the index experience with individu-alized mRNA vaccination for PDAC, mFOLFIRINOX was administered >12 weeks35–37 after surgery. Furthermore, given its limited sample size, this trial enrolled only white individuals. Future studies must test individualized mRNA neoantigen vaccines in a diverse popula - tion of patients with PDAC, coupled with a faster time to adjuvant mFOLFIRINOX. Experience with individualized cancer vaccines16 that predated and accelerated mRNA-based SARS-CoV-2 pandemic vac - cines38 can now further hasten individualized cancer vaccine manu - facture times22,23 and enable more rapid adjuvant custom vaccination and chemotherapy. Overall, we reported preliminary evidence that adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, in combina - tion with atezolizumab and mFOLFIRINOX induces substantial T cell activity in patients with surgically resected PDAC that correlates with a 0.010.1110100 03 0 1020 Weeks after surgery40All blood T cells (%) Atezolizumab Autogene cevumeran mFOLFIRINOXSurgery Liver biopsy406080100 20 0 MRI All 15 vaccine-expanded T cell clones present n = 13,005 T cells Before surgery After vaccine priming 1 New suspicious liver lesion 100 /uni03BCmb 100 /uni03BCm DAPI CD8 CD3After vaccine priming 2 5010–3 Blood collections in bSuspicious liver lesion Vaccine-expanded T cells of all T cells (%) Weeks after surgery30 35 413 2 1 0Liver lesionBlood c Liver lesiongDNA controlTP53R175H (%)0.05 00.04 0.03 0.02 0.01 d Vaccine expanded UMAP1 UMAP1UMAP2CD4 CD8 IFNG 0.60.81.0 00.4 0.20.60.81.2 00.4 0.21.0GZMB PRF1 UMAP1 UMAP1 UMAP1 n =2 2CA 19-9 (U ml–1) CA 19-9 (U ml–1) ExpressionExpression Fig. 4 | Vaccine-expanded T cells can infiltrate a micrometastasis. Clinical and immunological snapshot of a disappearing intrahepatic lymphoid aggregate after vaccination in a patient who responded to the vaccine. a , Serial percentage of vaccine-expanded T cells in blood analysed using CloneTrack and serum CA19-9 (left), and abdominal MRI (right) before and after vaccination. b, Haematoxylin and eosin staining (left), multiplexed immunofluorescence (middle) and percentage of vaccine-expanded T cells measured using CloneTrack (right, grey bar) in a new liver lesion that developed after vaccination detected by MRI as in a . All 15 vaccine-expanded T cell clones ( a, red line) were present in liver lesion (right, grey bar). c , Percentage of mutant TP53 R175H reads by digital droplet PCR in the liver lesion. The bar indicates the median, the error bars are the s.e.m. d , Uniform manifold approximation and projection (UMAP) plots of single-cell phenotypes of all blood T cells (left) and vaccine-expanded clones (middle), with effector markers (right). n indicates the number of T cells detected in liver lesion ( b) or technical replicates ( c). Data represent analyses of a single patient. 150 | Nature | Vol 618 | 1 June 2023 Articledelayed recurrence. A follow-up global randomized trial (IMCODE 003, BNT122) is imminent. Online content Any methods, additional references, Nature Portfolio reporting summa - ries, source data, extended data, supplementary information, acknowl - edgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/s41586-023-06063-y . 1.