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Messenger RNA-based Vaccines With Dual Activity Induce Balanced TLR-7 Dependent Adaptive Immune Responses and Provide Antitumor Activity
Abstract
Direct vaccination with messenger RNA (mRNA) molecules encoding tumor-associated antigens is a novel and promising approach in cancer immunotherapy. The main advantage of using mRNA for vaccination is that the same molecule not only provides an antigen source for adaptive immunity, but can simultaneously bind to pattern recognition receptors, thus stimulating innate immunity. However, achieving both features remains challenging, as the complexation of mRNA required for immune-stimulating activity may inhibit its translatability. In this study, we present a new and more effective vaccine design: a two-component mRNA-based tumor vaccine that supports both: antigen expression and immune stimulation, mediated by Toll like receptor 7 (TLR7). The two-component mRNA vaccines, containing free and protamine-complexed mRNA, induce balanced adaptive immune responses providing humoral as well as T cell mediated immunity. This balanced immune response is based on the induction of antigen-specific CD4(+) T helper cells and cytotoxic CD8(+) T cells. Once activated, these CD4(+) and CD8(+) T cells secrete a wide set of cytokines, which drive a TH1 response. Immunization with the two-component vaccines induces sustained memory responses, mediated by antigen-specific memory T cells. Moreover, treatment of mice with the two-component mRNA vaccine mediates a strong antitumor response against OVA-expressing tumor cells, not only in a prophylactic but also in a therapeutic setting. In conclusion,…
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In the citing paper
“The schedule was designed to prevent the typical post-expansion T-cell retraction phase and maintain high frequencies of antigen-specific T cells.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [34]
In the citing paper
“Both CVnCoV and CV2CoV are based on RNActive technology4–7 and consist of non-chemically modified sequence-engineered mRNA without pseudouridine6–12.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [6]
In the citing paper
“Hence, mRNA vaccines have been formulated with synthetic delivery vehicles such as liposomes (16) and cationic polymers (17) to increase potency.”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [17]
In the citing paper
“Several studies have demonstrated the utility of mRNA as the basis of vaccines in cancer immunotherapy as well as to promote prophylactic protection from infectious diseases (Hoerr et al, 2000; Fotin‐Mleczek et al, 2011; Petsch et al, 2012; Kubler et al, 2015; Kranz et al, 2016).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Fotin‐Mleczek et al, 2011
In the citing paper
“In addition, it has been previously demonstrated that mRNA represents a potent vaccine technology (Kreiter et al, 2010; Fotin‐Mleczek et al, 2011).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Fotin‐Mleczek et al, 2011
In the citing paper
“Benefits are the induction of balanced and enduring immunity as demonstrated for anti-tumor and prophylactic vaccination [14–16], simple supply, and storage at elevated temperature, as reviewed elsewhere [17,18].”
In the citing paper
“Studies have shown that adenylate-uridylate-rich elements are involved in mRNA degradation. Degradation rate and translation life cycle can be adjusted by replacing adenylate-uridylate-rich sequences found in the 3′ UTR.137–139”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [138]
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Gao, Y., Yang, L., Li, Z., Peng, X., & Li, H. (2024) · Biomarker Research · doi:10.1186/s40364-024-00644-3 · Cited by 34
“F u r t h e r m o r e , t h e p r o t a m i n e - m R N A c o m p l e x e s d e m o n s t r a t e a d j u v a n t p r o p e r t i e s , s t i m u l a t i n g T L R 7 / 8 t o t r i gg e r r o b u s t i nn a t e i mm u n e r e s p o n s e s [ 90 ] .”
BackgroundZhang, L., ZHANG, T.-T., Wang, L., Shao, S., Chen, Z., & Zhang, Z. (2014) · Gene Therapy · doi:10.1038/gt.2014.50 · Cited by 31
At the bench: Engineering the next generation of cancer vaccines
Shae, D., Baljon, J. J., Wehbe, M., Becker, K. W., Sheehy, T. L., & Wilson, J. T. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.5bt0119-016r · Cited by 32
Novel Vectors and Administrations for mRNA Delivery
Bai, C., Wang, C., & Lu, Y. (2023) · Small · doi:10.1002/smll.202303713 · Cited by 32
mRNA-Based Vaccines and Mode of Action
Gergen, J., & Petsch, B. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_230 · Cited by 36
Roßmann, L., Bagola, K., Stephen, T., Gerards, A.-L., Walber, B., Ullrich, A., Schülke, S., Kamp, C., Spreitzer, I., Hasan, M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2103651118 · Cited by 31
In Vitro Transcribed mRNA Vaccines with Programmable Stimulation of Innate Immunity
Loomis, K. H., Lindsay, K. E., Zurla, C., Bhosle, S. M., Vanover, D. A., Blanchard, E. L., Kirschman, J. L., Bellamkonda, R. V., & Santangelo, P. J. (2018) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.8b00443 · Cited by 32
Nanotechnology‐based CRISPR/Cas9 delivery system for genome editing in cancer treatment
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Rahman, M. M., Zhou, N., & Huang, J. (2021) · Vaccines · doi:10.3390/vaccines9030244 · Cited by 32
“OVA (GgOVA), control vaccine (Ecβ-gal sh), PSMA (HsPSMA), and STEAP vaccine (HsSTEAP) Rat (C57BL/6, BALB/c) Showed antitumor by activating adaptive and innate immune systems, stimulation of toll-like receptor 7 (TLR-7), ability to inhibit established tumors, induction of two component mRNA vaccine [64]”
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The notorious R.N.A. in the spotlight - drug or target for the treatment of disease
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Single-nucleotide resolution of RNAs up to 59 nucleotides by high-performance liquid chromatography
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Advancing personalized medicine in brain cancer: exploring the role of mRNA vaccines
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“In a mouse tumor model, the two-component mRNA vaccine demonstrates robust antitumor activity against OVA-expressing tumor cells, serving as both preventive and therapeutic intervention [50].”
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“Application of mRNA has so far proven its effectiveness for vaccination against infectious diseases and tumors in animal models [13, 14] and also in clinical studies with Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 797421, 12 pages http://dx.”
BackgroundThe European Regulatory Environment of RNA-Based Vaccines
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Self-citationResearch progress and challenges to coronavirus vaccine development
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“Data has shown the potential therapeutic benefit in TLR7-based cancer immunotherapy (39,40).”
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Metadata
- Authors
- Fotin-Mleczek, M., Duchardt, K. M., Lorenz, C., Pfeiffer, R., Ojkić-Zrna, S., Probst, J., & Kallen, K.-J.
- Affiliations
- CureVac (Germany) (DE)
- Venue
- Journal of Immunotherapy
- Published
- 2011-01
- Volume
- 34
- Issue
- 1
- Pages
- 1-15
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W2014992495
- Cited by
- 335
- References
- 0
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 26 · 2023: 32 · 2022: 34 · 2021: 26 · 2020: 28 · 2019: 18 · 2018: 24 · 2017: 22 · 2016: 19 · 2015: 18 · 2014: 23 · 2013: 19 · 2012: 11
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Immunotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- mRNA vaccines, TLR7, tumor-associated antigens, cancer immunotherapy, antitumor immunity, CD4+ T helper cells, CD8+ cytotoxic T lymphocytes, Th1 response, memory T cells, innate immune activation, self-adjuvanting vaccine
- MeSH terms
- Animals, Antigens, Neoplasm, B-Lymphocytes, Humans, Immunity, Cellular, Immunologic Memory, Immunotherapy, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Protamines, RNA, Messenger, Vaccines, Synthetic, CD4-Positive T-Lymphocytes, Cytokines, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, Adaptive Immunity, Immunity, Humoral
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