mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer
Open accessAbstract
BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.
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Additional emerging modalities for KRAS-targeted therapy include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression, neoantigen vaccines, and adoptive T-cell therapies targeting mutant KRAS-derived epitopes.
“Additional emerging modalities include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression [65,66], neoantigen vaccines [67,68], and adoptive T-cell therapies targeting mutant KRAS-derived epitopes [69,70].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [69]
Using a similar lipid nanoparticle formulation, mRNA vaccination has been shown to elicit specific T cell responses in patients with gastrointestinal cancer.
“Using a similar lipid nanoparticle formulation, mRNA vaccination has also been shown to elicit specific T cell responses in patients with gastrointestinal cancer (NCT03480152)212.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [212]
Several personalized cancer vaccines using lipid nanoparticle-mRNA formulations have entered clinical trials.
“Several personalized cancer vaccines using lipid nanoparticle–mRNA formulations have also entered clinical trials210–212.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [212]
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- Authors
- Cafri, G., Gartner, J. J., Zaks, T., Hopson, K., Levin, N., Paria, B. C., Parkhurst, M. R., Yossef, R., Lowery, F. J., Jafferji, M. S., Prickett, T. D., Goff, S. L., McGowan, C. T., Seitter, S., Shindorf, M. L., Parikh, A., Chatani, P. D., Robbins, P. F., & Rosenberg, S. A.
- Affiliations
- National Institutes of Health (US)
- Moderna Therapeutics (United States) (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2020-10-05
- Volume
- 130
- Issue
- 11
- Pages
- 5976-5988
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7598064
- OpenAlex
- W3091061098
- Cited by
- 427
- References
- 21
- Citations by year
- 2026: 50 · 2025: 78 · 2024: 84 · 2023: 96 · 2022: 77 · 2021: 42
- FWCI
- 18.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (20892)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- mRNA vaccines, neoantigens, T cell immunity, gastrointestinal cancer, metastatic cancer, tumor-infiltrating lymphocytes, KRAS G12D mutation, T cell receptor, driver mutations
- MeSH terms
- Antigens, Neoplasm, Female, Gastrointestinal Neoplasms, Humans, Immunity, Cellular, Male, RNA, Messenger, T-Lymphocytes, Proto-Oncogene Proteins p21(ras), Cancer Vaccines, Amino Acid Substitution, Mutation, Missense
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