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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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mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474
“This vaccine showed potent activity in preclinical studies 62 and is currently being tested in ongoing clinical trials in patients with prostate cancer (ClinicalTrials. gov identifiers: NCT00831467 and NCT01817738) and non-small-cell lung cancer (ClinicalTrials.gov identifiers: NCT00923312 and…”
Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., & Weissman, D. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.007 · Cited by 1,014
Karikó, K., Muramatsu, H., Ludwig, J., & Weissman, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr695 · Cited by 898
“For uses that require further purification, such as NMR (12), crystallography (13) and therapeutic applications (14), a number of techniques have been developed.”
MethodmRNA-based therapeutics: powerful and versatile tools to combat diseases
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01007-w · Cited by 852
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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