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Results of the First Phase I/II Clinical Vaccination Trial With Direct Injection of mRNA
Abstract
Vaccination against tumor antigens has been shown to be a safe and efficacious prophylactic and therapeutic antitumor treatment in many animal models. Clinical studies in humans indicate that specific immunotherapy can also result in clinical benefits. The active pharmaceutical ingredient in such vaccines can be DNA, RNA, protein, or peptide and can be administered naked, encapsulated, or after delivery in vitro into cells that are then adoptively transferred. One of the easiest, most versatile and theoretically safest technologies relies on the direct injection of naked messenger RNA (mRNA) that code for tumor antigens. We and others have shown in mice that intradermal application of naked mRNA results in protein expression and the development of an immune response. We used this protocol to vaccinate 15 melanoma patients. For each patient a growing metastasis was removed, total RNA was extracted, reverse-transcribed, amplified, and cloned. Libraries of cDNA were transcribed to produce unlimited amounts of copy mRNA. Autologous preparations were applied intradermally in combination with granulocyte macrophage colony-stimulating factor as adjuvant. We demonstrate here that such treatment is feasible and safe (phase 1 criteria). Furthermore, an increase in antitumor humoral immune response was seen in some patients. However, a demonstration of clinical effectiveness of direct injection of copy mRNA for antitumor immunotherapy was not shown in this study and must be evaluated in subsequent trials.
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“Those studies showed RNA vaccines to be well tolerated and immunogenic.”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [38]
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“Various RNA vaccines have been evaluated in human clinical trials, including naked and formulated non-amplifying mRNA (37-39) and self-amplifying RNA packaged in VRPs (25).”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [38]
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“Contrary to these data, we have previously shown induction of strong and balanced immune responses following intradermal immunization with our mRNA vaccine [8,11] and the pre-clinical data was also reflected in the results of clinical trials [12,13,28].”
BackgroundResultLeal, L., Guardo, A. C., Morón‐López, S., Salgado, M., Mothe, B., Heirman, C., Pannus, P., Vanham, G., van den Ham, H., Gruters, R. A., et al. (2018) · AIDS · doi:10.1097/qad.0000000000002026 · Cited by 102
“of iHIVARNA (Groups 4 and 5) in HIV-1 ultrasensitive plasma R and induced boostable functional antibodies [17] and direct administration of mRNA has entered clinical testing in cancer [15,16,18,19].”
BackgroundIntradermal Electroporation of Naked Replicon RNA Elicits Strong Immune Responses
Johansson, D. X., Ljungberg, K., Kakoulidou, M., & Liljeström, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029732 · Cited by 98
“Vaccination of cancer patients in two Phase I Clinical trials also demonstrated safety as well as increased cellular or humoral immunity in some patients, respectively [8,9].”
BackgroundImmunotherapy in gastric cancer
Matsueda, S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i7.1657 · Cited by 98
RNA therapeutics in the clinic
Curreri, A. M., Sankholkar, D., Mitragotri, S., & Zhao, Z. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10374 · Cited by 100
“Melanoma was the indication for the very first mRNA trial in 2008.(95) Other cancer types included in these trials are glioblastoma, breast cancer, ovarian cancer, prostate”
BackgroundThe ReNAissanCe of mRNA-based cancer therapy
Van Lint, S., Renmans, D., Broos, K., Dewitte, H., Lentacker, I., Heirman, C., Breckpot, K., & Thielemans, K. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.957685 · Cited by 95
“However, no clinical responses were observed, despite an increased humoral responses in some patients [118].”
BackgroundPersonalized pancreatic cancer therapy: from the perspective of mRNA vaccine
Huang, X., Zhang, G., Tang, T., Gao, X., & Liang, T. (2022) · Military Medical Research · doi:10.1186/s40779-022-00416-w · Cited by 98
“The first clinical study of mRNA vaccine was conducted in 2008 in melanoma patients [114].”
BackgroundSystemic activation of antigen-presenting cells via RNA-loaded nanoparticles
Sayour, E. J., De Leon, G., Pham, C., Grippin, A., Kemeny, H., Chua, J., Huang, J., Sampson, J. H., Sanchez-Perez, L., Flores, C., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2016.1256527 · Cited by 93
“genic material for induction of antitumor immunity, “naked” RNA is inherently unstable.(20) Clinically available nanolipo-”
BackgroundFrameworks for transformational breakthroughs in RNA-based medicines
Androsavich, J. R. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00943-2 · Cited by 100
Plasmid DNA- and messenger RNA-based anti-cancer vaccination
Weide, B., Garbe, C., Rammensee, H., & Pascolo, S. (2007) · Immunology Letters · doi:10.1016/j.imlet.2007.09.012 · Cited by 90
Self-citationSelmi, A., Vascotto, F., Kautz‐Neu, K., Türeci, Ö., Şahin, U., von Stebut, E., Diken, M., & Kreiter, S. (2016) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-016-1869-7 · Cited by 90
Nucleic Acid Drugs—Current Status, Issues, and Expectations for Exosomes
Yamada, Y. (2021) · Cancers · doi:10.3390/cancers13195002 · Cited by 92
“An attempt to clinically deliver naked mRNA without using any DDS has been made for cancer vaccines [60,84].”
BackgroundGolombek, S., Pilz, M., Steinle, H., Kochba, E., Levin, Y., Lunter, D., Schlensak, C., Wendel, H. P., & Avci-Adali, M. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.03.005 · Cited by 88
Synthetic Messenger RNA-Based Vaccines: From Scorn to Hype
Pascolo, S. (2021) · Viruses · doi:10.3390/v13020270 · Cited by 87
“This first study was a personalized vaccine, where mRNA was extracted from tumor biopsies, reverse transcribed in cDNA libraries, transcribed into ivt mRNA [18], formulated, and injected in the very same patient from whom the biopsy originated [12].”
MethodSelf-citationScreening of mRNA Chemical Modification to Maximize Protein Expression with Reduced Immunogenicity
Uchida, S., Kataoka, K., & Itaka, K. (2015) · Pharmaceutics · doi:10.3390/pharmaceutics7030137 · Cited by 90
“To date, this has limited the application of mRNA mainly to vaccine therapy [14–16].”
Maiyo, F., & Singh, M. (2019) · Pharmaceuticals · doi:10.3390/ph12040164 · Cited by 84
“Safe and efficient delivery of a nucleic acid to a target site of action remains a major obstacle to successful gene therapy, halting many clinical trials [13].”
BackgroundLorenzi, J. C. C., Trombone, A. P. F., Rocha, C. D., de Almeida, L. P., Lousada, R. L., Malardo, T., Fontoura, I. C., Rossetti, R. A. M., Gembre, A. F., Silva, A. M., et al. (2010) · BMC Biotechnology · doi:10.1186/1472-6750-10-77 · Cited by 84
“Pascolo and others showed the feasibility and safety of this protocol in humans [43].”
BackgroundDevelopment of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles
Rodríguez‐Gascón, A., del Pozo‐Rodríguez, A., & Solinís, M. Á. (2014) · International Journal of Nanomedicine · doi:10.2147/ijn.s39810 · Cited by 79
FLT3 Ligand Enhances the Cancer Therapeutic Potency of Naked RNA Vaccines
Kreiter, S., Diken, M., Selmi, A., Diekmann, J., Attig, S., Hüsemann, Y., Koslowski, M., Huber, C., Türeci, Ö., & Sahin, U. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0291 · Cited by 75
mRNA therapeutics: New vaccination and beyond
Wei, H. Y., Zheng, L., & Wang, Z. (2023) · Fundamental Research · doi:10.1016/j.fmre.2023.02.022 · Cited by 77
“In 2008, patient-derived autologous mRNA was first applied as a vaccine to treat patients bearing melanoma [29] .”
BackgroundElectroporation-enhanced delivery of nucleic acid vaccines
Broderick, K. E., & Humeau, L. M. P. F. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.990890 · Cited by 74
“Several clinical trials delivering mRNA vaccines to melanoma patients without EP [88,89] and patients with stage IV renal cell cancer [90] have resulted in the induction of antitumor immunity, demonstrating proof of concept clinical efficacy.”
BackgroundA personalized view on cancer immunotherapy
Wayteck, L., Breckpot, K., Demeester, J., Smedt, S. C. D., & Raemdonck, K. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.09.016 · Cited by 82
“feasible, safe and elicits potent T cell responses with therapeutic efficacy [92–95].”
BackgroundReview on Up-to-Date Status of Candidate Vaccines for COVID-19 Disease
Belete, T. M. (2021) · Infection and Drug Resistance · doi:10.2147/idr.s288877 · Cited by 74
“It is also generally safe and provided complete protection in a mouse challenge model.(48) Moderna has collaborated with Catalent since June 25, 2020 to perform large-scale, commercial fill-finish manufacturing of Moderna’s mRNA-1273 COVID-19 vaccine at Catalent’s biologics facility in Indiana, US.”
BackgroundmRNA – A game changer in regenerative medicine, cell-based therapy and reprogramming strategies
Chabanovska, O., Galow, A.-M., David, R., & Lemcke, H. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114002 · Cited by 81
“vaccine to medicate metastatic melanoma patients [26,27].”
BackgroundVallazza, B., Petri, S., Poleganov, M. A., Eberle, F., Kuhn, A. N., & Şahin, U. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1288 · Cited by 74
Dendrimer-Coated Gold Nanoparticles for Efficient Folate-Targeted mRNA Delivery In Vitro
Mbatha, L. S., Maiyo, F., Daniels, A. N., & Singh, M. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060900 · Cited by 71
“The feasibility and non-toxicity of naked mRNA and mRNA complexed with protamine were demonstrated in human patients via intradermal injections, resulting in promising immunological responses [7,8].”
BackgroundmRNA-based therapeutics–Advances and perspectives
Sergeeva, O. V., Koteliansky, V., & Zatsepin, T. S. (2016) · Biochemistry (Moscow) · doi:10.1134/s0006297916070075 · Cited by 74
Lint, S. V., Heirman, C., Thielemans, K., & Breckpot, K. (2013) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.22661 · Cited by 59
Metadata
- Authors
- Weide, B., Carralot, J.-P., Reese, A., Scheel, B., Eigentler, T. K., Hoerr, I., Rammensee, H.-G., Garbe, C., & Pascolo, S.
- Affiliations
- University of Tübingen (DE)
- CureVac (Germany) (DE)
- Corresponding author
- Weide, Benjamin
- Reese, Anne
- Eigentler, Thomas Kurt
- Garbe, Claus
- Venue
- Journal of Immunotherapy
- Published
- 2008-02
- Volume
- 31
- Issue
- 2
- Pages
- 180-188
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W2066847748
- Cited by
- 261
- References
- 15
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 17 · 2023: 26 · 2022: 22 · 2021: 30 · 2020: 13 · 2019: 12 · 2018: 8 · 2017: 11 · 2016: 16 · 2015: 13 · 2014: 12 · 2013: 14 · 2012: 13
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Immunotherapy (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- mRNA vaccination, cancer immunotherapy, melanoma, tumor antigens, intradermal injection, GM-CSF, adjuvants, humoral immune response, feasibility and safety
- MeSH terms
- Adult, Aged, Antibody Formation, Antigens, Neoplasm, Female, Humans, Immunity, Cellular, Injections, Intradermal, Interferon-gamma, Male, Melanoma, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, RNA, Messenger, Monitoring, Immunologic, CD4-Positive T-Lymphocytes, Granulocyte-Macrophage Colony-Stimulating Factor, Treatment Outcome, CD8-Positive T-Lymphocytes, Cancer Vaccines, Cell Line, Tumor
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