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Direct Injection of Protamine-protected mRNA: Results of a Phase 1/2 Vaccination Trial in Metastatic Melanoma Patients
Abstract
In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.
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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 [39]
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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 [39]
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Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA
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“…designed for tumor vaccination (Steitz et al., 2006; Zhang et al., 2006; Amano et al., 2007; Mockey et al., 2007; Perche et al., 2011) and virus infection (Zarei et al., 2003; Yu et al., 2007; Petsch et al., 2012), even lead to some clinical progress (Weide et al., 2008, 2009; Rittig et al., 2011).”
BackgroundIn Vivo Messenger RNA Introduction into the Central Nervous System Using Polyplex Nanomicelle
Uchida, S., Itaka, K., Uchida, H., Hayakawa, K., Ogata, T., Ishii, T., Fukushima, S., Osada, K., & Kataoka, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056220 · Cited by 133
“there is only one phase 1 study clinical trial to treat metastatic melanoma by subcutaneous injection of naked or protaminestabilised mRNAs [9]; however, a more efficient system for in vivo mRNA administration would be strongly required to expand the application to many other clinical fields.”
BackgroundNanoplatforms for mRNA Therapeutics
Meng, C., Chen, Z., Li, G., Welte, T., & Shen, H. (2021) · Advanced Therapeutics · doi:10.1002/adtp.202000099 · Cited by 130
Moignic, A. L., Malard, V., Benvegnu, T. J., Lemiègre, L., Berchel, M., Jaffrès, P., Baillou, C., Guillot‐Delost, M., Macedo, R., Rochefort, J., et al. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.03.035 · Cited by 129
Biomedical applications of mRNA nanomedicine
Xiong, Q., Lee, G. Y., Ding, J., Li, W., & Shi, J. (2018) · Nano Research · doi:10.1007/s12274-018-2146-1 · Cited by 125
The nano delivery systems and applications of mRNA
Li, M., Li, Y., Li, S., Jia, L., Wang, H., Li, M., Deng, J., Zhu, A., Ma, L., Li, W., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113910 · Cited by 127
“Peptide-based delivery is a less explored system, as only protamine has been evaluated in clinical trials [69].”
Broos, K., Van der Jeught, K., Puttemans, J., Goyvaerts, C., Heirman, C., Dewitte, H., Verbeke, R., Lentacker, I., Thielemans, K., & Breckpot, K. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2016.38 · Cited by 121
mRNA therapeutics deliver a hopeful message
Zhong, Z., Cafferty, S. M., Combes, F., Huysmans, H., Temmerman, J. D., Gitsels, A., Vanrompay, D. C. G., Catani, J. P., & Sanders, N. N. (2018) · Nano Today · doi:10.1016/j.nantod.2018.10.005 · Cited by 124
Kallen, K., & Theß, A. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613508729 · Cited by 122
“com In the next trial, protamine-stabilized mRNAs coding for Melan-A, tyrosinase, gp100, Mage-A1, Mage-A3 and survivin were injected intradermally into 21 patients with metastatic melanoma with GM-CSF as adjuvant [Weide et al. 2009].”
MethodDendritic Cell Vaccines: A Shift from Conventional Approach to New Generations
Lee, K.-W., Yam, J. W. P., & Mao, X. (2023) · Cells · doi:10.3390/cells12172147 · Cited by 130
Tumor vaccination using messenger RNA: prospects of a future therapy
Kreiter, S., Diken, M., Selmi, A., Türeci, Ö., & Şahin, U. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.03.007 · Cited by 122
Advances in Therapeutic Cancer Vaccines
Wong, K. K. W., Li, A. W., Mooney, D. J., & Dranoff, G. (2016) · Advances in immunology · doi:10.1016/bs.ai.2015.12.001 · Cited by 115
From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape
Chakraborty, C., Sharma, A. R., Bhattacharya, M., & Lee, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.679344 · Cited by 114
Particle size and activation threshold: a new dimension of danger signaling
Rettig, L., Haen, S. P., Bittermann, A. G., von Boehmer, L., Fontecedro, A. C., Krämer, S. D., Knuth, A. K., & Pascolo, S. (2010) · Blood · doi:10.1182/blood-2009-11-247817 · Cited by 108
Self-citationEsprit, A., de Mey, W., Shahi, R. B., Thielemans, K., Franceschini, L., & Breckpot, K. (2020) · Vaccines · doi:10.3390/vaccines8040776 · Cited by 112
mRNA-Based Cancer Vaccines: A Therapeutic Strategy for the Treatment of Melanoma Patients
Bidram, M., Zhao, Y., Shebardina, N. G., Baldin, A. V., Bazhin, A. V., Ganjalikhany, M. R., Zamyatnin, A. A., & Ganjalıkhani-Hakemi, M. (2021) · Vaccines · doi:10.3390/vaccines9101060 · Cited by 111
The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments
Sasso, J. M., Ambrose, B. J. B., Tenchov, R., Datta, R. S., Basel, M. T., DeLong, R. K., & Zhou, Q. A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00024 · Cited by 108
Recent developments of RNA-based vaccines in cancer immunotherapy
Faghfuri, E., Pourfarzi, F., Faghfouri, A. H., Shadbad, M. A., Hajiasgharzadeh, K., & Baradaran, B. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1815704 · Cited by 100
“After administration, the level of immune-suppressive cells and vaccine-enhanced T-cell proliferation was improved in a subgroup of subjects with manifestations of complete clinical response [57].”
BackgroundLeal, 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].”
BackgroundMessenger RNA Delivery for Tissue Engineering and Regenerative Medicine Applications
Patel, S., Athirasala, A., Menezes, P. D. P., Ashwanikumar, N., Zou, T., Sahay, G., & Bertassoni, L. E. (2018) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0444 · Cited by 101
“Although both the reprogramming efficiency and mRNA delivery still need to be significantly improved for ultimate clinical use, the efforts expended on phase I/II clinical trials using naked, chemically modified, or protaminecomplexed mRNA show great promise for the use of mRNAguided reprogramming in future regenerati…”
BackgroundImmunotherapy in gastric cancer
Matsueda, S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i7.1657 · Cited by 98
The 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
“Moreover, one patient (out of seven) showed a complete objective response [119].”
BackgroundProtamine-Based Strategies for RNA Transfection
Jarzebska, N. T., Mellett, M., Frei, J., Kündig, T. M., & Pascolo, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060877 · Cited by 95
“Just after the evaluation of naked mRNA vaccine in melanoma patients [48], the Tuebingen-based research group explored Protamine-mRNA complexes in a Phase I/II vaccination trial in metastatic melanoma patients (NCT00204607) [42].”
BackgroundMethodSelf-citationThe advances of adjuvants in mRNA vaccines
Xie, C., Yao, R., & Xia, X. (2023) · npj Vaccines · doi:10.1038/s41541-023-00760-5 · Cited by 102
“A protamine-containing delivery platform for mRNA vaccine has been evaluated in clinical trials for treating melanoma, prostate cancer, and non-small-cell lung cancer 49 – 51 .”
MethodMoyo, N., Vogel, A. B., Buus, S., Erbar, S., Wee, E. G., Sahin, U., & Hanke, T. (2019) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.10.010 · Cited by 94
“Over the last decade, there have been great leaps toward solving these challenges through structural and chemical modifications to the RNA molecule itself, formulation into various nanoparticles or nanoemulsion, and use of polymers and conjugation.(40,41) These advances enhanced by the excellent safety features of mRN…”
Background
Metadata
- Authors
- Weide, B., Pascolo, S., Scheel, B., Derhovanessian, E., Pflugfelder, A., Eigentler, T. K., Pawelec, G., Hoerr, I., Rammensee, H.-G., & Garbe, C.
- Affiliations
- University of Tübingen (DE)
- CureVac (Germany) (DE)
- Corresponding author
- Weide, Benjamin
- Pflugfelder, Annette
- Eigentler, Thomas K.
- Garbe, Claus
- ORCID
- Venue
- Journal of Immunotherapy
- Published
- 2009-06
- Volume
- 32
- Issue
- 5
- Pages
- 498-507
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W1966322307
- Cited by
- 378
- References
- 28
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 29 · 2023: 45 · 2022: 45 · 2021: 40 · 2020: 22 · 2019: 14 · 2018: 19 · 2017: 16 · 2016: 14 · 2015: 16 · 2014: 17 · 2013: 12 · 2012: 13
- FWCI
- 6.18
- 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
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- mRNA vaccination, metastatic melanoma, tumor-associated antigens, Melan-A, tyrosinase, gp100, MAGE-1, MAGE-A3, survivin, keyhole limpet hemocyanin, GM-CSF, regulatory T cells, myeloid-derived suppressor cells, antitumor immunity, vaccine safety, complete response
- MeSH terms
- Adolescent, Adult, Aged, Antigens, Neoplasm, Bone Neoplasms, Feasibility Studies, Female, Hemocyanins, HLA-DR Antigens, Humans, Injections, Intradermal, Lung Neoplasms, Male, Melanoma, Middle Aged, Neoplasm Proteins, Neoplasm Staging, Protamines, Remission Induction, RNA, Messenger, CD4 Antigens, Granulocyte-Macrophage Colony-Stimulating Factor, Immunotherapy, Active, Cancer Vaccines, Myeloid Cells, CD11b Antigen, Cell Proliferation, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Melanoma-Specific Antigens
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