Personalized Neoantigen Vaccination Strategies in Cancer Immunotherapy

Personalized neoantigen vaccination harnesses tumour‐specific mutations to elicit targeted immune responses. Advances in next‐generation sequencing and computational pipelines enable rapid identification of individual mutanomes and selection of high‐affinity peptides that bind to major histocompatibility complex (MHC) molecules. Vaccine platforms have evolved from peptide and dendritic cell formulations to nucleic acid formats, including mRNA and DNA plasmids, as well as viral vectors. These approaches seek to prime and expand neoantigen‐specific CD4+ and CD8+ T cells while minimising off‐target effects. Clinical trials in solid tumours such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma have demonstrated the feasibility of real‐time vaccine synthesis, acceptable safety profiles and induction of durable T cell clones. Combination regimens incorporating checkpoint inhibitors or chemotherapeutic backbones have further augmented efficacy by overcoming local immunosuppression. Persisting challenges include accurate epitope prediction, efficient delivery to antigen‐presenting cells, management of tumour heterogeneity and optimisation of immunomonitoring. Despite these hurdles, personalised neoantigen vaccines represent a promising frontier in precision immunotherapy, offering the prospect of tailored, potent antitumour immunity with broad applicability across cancer types.

Research from Nature Portfolio

In a phase I trial of metastatic pancreatic ductal adenocarcinoma, an individualized uridine mRNA‐lipoplex vaccine targeting up to 20 patient‐specific neoantigens was administered adjunctively to anti‐PD-L1 therapy and chemotherapy. Vaccine production was achieved within days of tumour resection, and de novo expansion of high‐magnitude neoantigen-specific T cell clones was observed in half of the cohort, correlating with prolonged recurrence-free intervals. A mathematical tracking method revealed long-lived, polyfunctional CD8+ T cells that re-expanded upon boosting.

In hepatocellular carcinoma, a DNA plasmid vaccine encoding up to 40 neoantigens delivered alongside interleukin-12 and pembrolizumab achieved a 30.6% objective response rate without dose-limiting toxicities. Neoantigen-specific CD4+ and CD8+ effector T cells were confirmed by cellular profiling and T cell receptor sequencing, demonstrating intratumoural clonal expansion and functional cytotoxicity. Clinical responses were positively associated with vaccine antigen load, supporting a dose‐dependent mechanism of action.

Personalized Neoantigen Vaccination Strategies in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in personalized neoantigen vaccination strategies in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Neoantigen: A novel peptide derived from tumour‐specific mutations that is recognised as non-self by the immune system.

Major histocompatibility complex (MHC): A set of cell surface molecules responsible for presenting antigenic peptides to T cells.

mRNA vaccine: A vaccine modality employing messenger RNA to encode target antigens, which are expressed by host cells to stimulate immunity.

Checkpoint inhibitor: An antibody that blocks inhibitory pathways in T cells, such as PD-1 or CTLA-4, to enhance antitumour responses.

Dendritic cell vaccine: An immunotherapy in which patient-derived dendritic cells are loaded with antigens ex vivo and reinfused to prime T cell responses.

Tumour microenvironment: The cellular milieu surrounding a tumour, including immune cells, stromal elements and signalling molecules that influence therapy response.

References

1. Neoantigens: promising targets for cancer therapy. Signal Transduction and Targeted Therapy (2023).
2. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature (2023).
3. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nature Medicine (2024).
4. The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells. Molecular Cancer (2023).
5. Clinical development of mRNA therapies against solid tumors. Journal of Hematology & Oncology (2023).
6. Therapeutic cancer vaccines: advancements, challenges and prospects. Signal Transduction and Targeted Therapy (2023).
7. Computational Prediction and Validation of Tumor-Associated Neoantigens. Frontiers in Immunology (2020).