An immunogenic personal neoantigen vaccine for patients with melanoma
Open accessAbstract
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
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mRNA-based cancer vaccines are typically given alone or with immune checkpoint inhibitors after resection, though they have also been used in neoadjuvant-adjuvant approaches.
“Cancer mRNA-based vaccines tend to be administered alone or in combination with ICIs, and after resection, although they have also been used in neoadjuvant–adjuvant treatment approaches136,138,139 (Fig. 3c,d).”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [138]
The Abstract (page unavailable) describes vaccination after surgical resection and reports that two patients later received anti-PD-1 therapy. But this was a long-peptide vaccine, not an mRNA vaccine; the paper does not establish typical practice for mRNA vaccines or describe a neoadjuvant–adjuvant approach. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHLA class I and class II molecules are centrally involved in CD8+ and CD4+ T cell immunity.
“As both classes of HLA molecule have previously been shown to have a central role in CD8+ and CD4+ T cell immunity43–49”
From Identification of bacteria-derived HLA-bound peptides in melanoma (2021) · cites this paper as [48]
Personalized neoantigen vaccines have been shown to modulate T cells in the tumor microenvironment and enhance responses to immune checkpoint therapy in both cold glioblastoma and hot melanoma.
“which have been shown to modulate T cells in the TME and enhance responses to ICT, including in both immunologically”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [135]
Vaccination approaches have produced encouraging preclinical and clinical results and can increase intratumoral T cell infiltration and anti-tumor immune responses.
“Vaccines have been used as an approach to enhance anti-tumor immune responses and have demonstrated encouraging results in preclinical and clinical studies, leading to an expansion of the intratumoral T cell infiltration and anti-tumor immune responses (Carreno et al., 2015; Ott et al., 2017).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Ott et al., 2017
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- Authors
- Ott, P. A., Hu, Z., Keskin, D. B., Shukla, S. A., Sun, J., Bozym, D. J., Zhang, W., Luoma, A., Giobbie-Hurder, A., Peter, L., Chen, C., Olive, O., Carter, T. A., Li, S., Lieb, D. J., Eisenhaure, T., Gjini, E., Stevens, J., Lane, W. J., Javeri, I., Nellaiappan, K., Salazar, A. M., Daley, H., Seaman, M., Buchbinder, E. I., Yoon, C. H., Harden, M., Lennon, N., Gabriel, S., Rodig, S. J., Barouch, D. H., Aster, J. C., Getz, G., Wucherpfennig, K., Neuberg, D., Ritz, J., Lander, E. S., Fritsch, E. F., Hacohen, N., & Wu, C. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Beth Israel Deaconess Medical Center (US)
- CuriRx (United States) (US)
- Harvard University (US)
- Corresponding author
- Wu, Catherine J.
- ORCID
- Ott, Patrick A.
- Keskin, Derin B.
- Shukla, Sachet A.
- Sun, Jing
- Bozym, David J.
- Zhang, Wandi
- Luoma, Adrienne
- Peter, Lauren
- Li, Shuqiang
- Lieb, David J.
- Eisenhaure, Thomas
- Gjini, Evisa
- Lane, William J.
- Nellaiappan, Kaliappanadar
- Daley, Heather
- Seaman, Michael
- Buchbinder, Elizabeth I.
- Yoon, Charles H.
- Harden, Maegan
- Lennon, Niall
- Gabriel, Stacey
- Rodig, Scott J.
- Barouch, Dan H.
- Aster, Jon C.
- Getz, Gad
- Wucherpfennig, Kai
- Neuberg, Donna
- Ritz, Jerome
- Lander, Eric S.
- Fritsch, Edward F.
- Hacohen, Nir
- Wu, Catherine J.
- Venue
- Nature
- Published
- 2017-07-05
- Volume
- 547
- Issue
- 7662
- Pages
- 217-221
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5577644
- OpenAlex
- W2728365508
- Cited by
- 2,936
- References
- 47
- Citations by year
- 2026: 277 · 2025: 299 · 2024: 307 · 2023: 312 · 2022: 316 · 2021: 381 · 2020: 369 · 2019: 309 · 2018: 283 · 2017: 79 · 2015: 1
- FWCI
- 130.08
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-03-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL103532)
- National Cancer Institute (T32CA207021, P50CA101942, R50CA211482, R01CA155010)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, personalized neoantigen vaccine, multipeptide vaccine, neoantigens, HLA-bound peptides, T cell response, CD4+ T cells, CD8+ T cells, tumor-infiltrating lymphocytes, tumor regression, immune checkpoint inhibitors, cancer immunotherapy, tumor mutational burden
- MeSH terms
- Machine Learning, Amino Acid Sequence, Histocompatibility Antigens Class II, Antigens, Neoplasm, Humans, Melanoma, Mutation, Neoplasm Recurrence, Local, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cancer Vaccines, Precision Medicine, High-Throughput Nucleotide Sequencing, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Patient Safety
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