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T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study
Published version of a preprint
Abstract
mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non–small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021
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“Clinical trials of mRNA-based immunotherapeutics encoding unmutated full-length TAAs in checkpoint inhibitor-treated melanoma [18] and individualised mRNA-based immunotherapeutics encoding patient-specific mutated tumour neoantigens in pancreatic and lung cancer [19, 20] have shown encouraging results.”
From Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma (2025) · cites this paper as [19]
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Metadata
- Authors
- Gainor, J. F., Patel, M. R., Weber, J. S., Gutierrez, M., Bauman, J. E., Clarke, J. M., Julian, R., Scott, A. J., Geiger, J. L., Kirtane, K., Robert-Tissot, C., Coder, B., Tasneem, M., Sun, J., Zheng, W., Gerbereux, L., Laino, A., Porichis, F., Pollard, J. R., Hou, P., Sehgal, V., Chen, X., Morrissey, M., Daghestani, H. N., Feldman, I., Srinivasan, L., Frederick, J. P., Brown, M., Aanur, P., Meehan, R., & Burris, H. A.
- Affiliations
- Massachusetts General Hospital (US)
- Sarah Cannon (US)
- NYU Langone Health (US)
- Hackensack University Medical Center (US)
- George Washington University (US)
- Duke University (US)
- University of Arizona Cancer Center (US)
- Banner - University Medical Center Tucson (US)
- Cleveland Clinic (US)
- Moffitt Cancer Center (US)
- 11Moderna, Inc., Cambridge, Massachusetts.
- Moderna Therapeutics (United States) (US)
- HiFiBiO Therapeutics (United States) (US)
- ORCID
- Gainor, Justin F.
- Patel, Manish R.
- Weber, Jeffrey S.
- Gutierrez, Martin
- Bauman, Julie E.
- Clarke, Jeffrey M.
- Julian, Ricklie
- Scott, Aaron J.
- Geiger, Jessica L.
- Kirtane, Kedar
- Robert-Tissot, Celine
- Coder, Brandon
- Tasneem, Moomal
- Sun, Jing
- Zheng, Wei
- Gerbereux, Lauren
- Laino, Andressa
- Porichis, Filippos
- Pollard, Jack Russella
- Hou, Peijie
- Sehgal, Vasudha
- Chen, Xing
- Morrissey, Manju
- Daghestani, Hikmat N.
- Feldman, Igor
- Srinivasan, Lakshmi
- Frederick, Joshua P.
- Brown, Michelle
- Aanur, Praveen
- Meehan, Robert
- Burris, Howard A.
- Venue
- Cancer Discovery
- Published
- 2024-08-08
- Volume
- 14
- Issue
- 11
- Pages
- 2209-2223
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W4401422221
- Cited by
- 124
- References
- 45
- Citations by year
- 2026: 58 · 2025: 63 · 2024: 3
- FWCI
- 20.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- neoantigens, T cell response, pembrolizumab, non-small cell lung cancer, cutaneous melanoma, mRNA vaccines, immunogenicity, CD8+ T cells, CD4+ T cells, adjuvant therapy
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Melanoma, Middle Aged, Skin Neoplasms, T-Lymphocytes, Precision Medicine, Antibodies, Monoclonal, Humanized
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