An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma
Abstract
Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours 1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
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Clinical trials of mRNA-based immunotherapeutics encoding unmutated full-length TAAs in checkpoint inhibitor-treated melanoma and individualised mRNA-based immunotherapeutics encoding patient-specific mutated tumour neoantigens in pancreatic and lung cancer have shown encouraging results.
“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 [18]
Previous studies have demonstrated that the use of BNT111 alone or in combination with PD-1 antibody can activate tumor antigen-specific CD4+ and CD8+ T cells and elicit durable immune responses.
“Previous studies have demonstrated that the use of BNT111 alone or in combination with PD-1 antibody can activate tumor antigen-specific CD4+ and CD8+ T cells and elicit durable immune responses.345,350–352”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [345]
FixVac, developed based on the RNA-LPX formulation, is a systemic mRNA vaccine encoding four non-mutated antigens of melanoma.
“For example, FixVac, which was developed based on the RNA-LPX formulation, is a systemic mRNA vaccine encoding four non-mutated antigens of melanoma200.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [200]
After the eighth immunization with FixVac, more than 75% of patients generated immune responses against at least one tumour-associated antigen, and CD8+ T cells played a major role in high-magnitude T cell responses.
“After the eighth immunization, more than 75% of patients generated immune responses against at least one tumour-associated antigen, and CD8+ T cells played a major role in high-magnitude T cell responses200.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [200]
A combination of FixVac/anti-programmed cell death protein 1 antibody augmented the antitumour effect of FixVac, resulting in a >35% tumour regression rate in immune checkpoint inhibitor-experienced patients.
“Moreover, a combination of FixVac/anti-programmed cell death protein 1 (PD1) antibody augmented the antitumour effect of FixVac, resulting in a >35% tumour regression rate in immune checkpoint inhibitor-experienced patients200.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [200]
Interim analysis from the phase I trial of FixVac showed that the metabolic activity of the spleen increased post the sixth immunization, indicating targeted delivery of FixVac and activation of resident immune cells.
“The interim analysis from the phase I trial (NCT02410733) showed that the metabolic activity of the spleen increased post the sixth immunization, indicating targeted delivery of FixVac and activation of resident immune cells200.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [200]
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- Authors
- Sahin, U., Oehm, P., Derhovanessian, E., Jabulowsky, R. A., Vormehr, M., Gold, M., Maurus, D., Schwarck-Kokarakis, D., Kuhn, A. N., Omokoko, T., Kranz, L. M., Diken, M., Kreiter, S., Haas, H., Attig, S., Rae, R., Cuk, K., Kemmer-Brück, A., Breitkreuz, A., Tolliver, C., Caspar, J., Quinkhardt, J., Hebich, L., Stein, M., Hohberger, A., Vogler, I., Liebig, I., Renken, S., Sikorski, J., Leierer, M., Müller, V., Mitzel-Rink, H., Miederer, M., Huber, C., Grabbe, S., Utikal, J., Pinter, A., Kaufmann, R., Hassel, J. C., Loquai, C., & Türeci, Ö.
- Affiliations
- BioNTech (Germany) (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- German Cancer Research Center (DE)
- University Hospital Frankfurt (DE)
- ORCID
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 585
- Issue
- 7823
- Pages
- 107-112
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3046115489
- Cited by
- 1,052
- References
- 36
- Citations by year
- 2026: 140 · 2025: 204 · 2024: 191 · 2023: 190 · 2022: 174 · 2021: 131 · 2020: 21
- FWCI
- 44.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- RNA vaccines, melanoma, anti-PD-1 therapy, immune checkpoint inhibitors, tumor-associated antigens, cancer immunotherapy, CD4+ T cells, CD8+ T cells, cytotoxic T lymphocyte response
- MeSH terms
- Antigens, Neoplasm, Antineoplastic Agents, Combined Modality Therapy, Humans, Melanoma, Neoplasm Staging, RNA, Neoplasm, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Vaccination, Cancer Vaccines, Programmed Cell Death 1 Receptor
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