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 and self-amplifying RNA packaged in VRPs.
“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]
Those studies showed RNA vaccines to be well tolerated and immunogenic.
“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]
Cites
Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004) · Nature Medicine · doi:10.1038/nm1093 · Cited by 5,151 · see citing works
Direct Gene Transfer into Mouse Muscle in Vivo
Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990) · Science · doi:10.1126/science.1690918 · Cited by 4,173 · see citing works
CD4+CD25+ suppressor T cells: more questions than answers
Shevach, E. M. (2002) · Nature reviews. Immunology · doi:10.1038/nri821 · Cited by 2,097 · see citing works
Caligiuri, M. A. (2008) · Blood · doi:10.1182/blood-2007-09-077438 · Cited by 1,910 · see citing works
Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.
Boczkowski, D., Nair, S. K., Snyder, D., & Gilboa, E. (1996) · The Journal of experimental medicine · doi:10.1084/jem.184.2.465 · Cited by 915 · see citing works
Increase of regulatory T cells in the peripheral blood of cancer patients.
Wolf, A. M., Wolf, D. G. F., Steurer, M., Gastl, G., Gunsilius, E., & Grubeck-Loebenstein, B. (2003) · PubMed · Cited by 655 · see citing works
Filipazzi, P., Valenti, R., Huber, V., Pilla, L., Canese, P., Iero, M., Castelli, C., Mariani, L., Parmiani, G., & Rivoltini, L. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.5829 · Cited by 646 · see citing works
(1995) · PubMed · Cited by 330 · see citing works
Results of the First Phase I/II Clinical Vaccination Trial With Direct Injection of mRNA
Weide, B., Carralot, J.-P., Reese, A., Scheel, B., Eigentler, T. K., Hoerr, I., Rammensee, H.-G., Garbe, C., & Pascolo, S. (2008) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31815ce501 · Cited by 261 · see citing works
Self-citationSteitz, J., Brück, J., Lenz, J., Knop, J., & Tüting, T. (2001) · PubMed · Cited by 214 · see citing works
Probst, J., Weide, B., Scheel, B., Pichler, B. J., Hoerr, I., Rammensee, H.-G., & Pascolo, S. (2007) · Gene Therapy · doi:10.1038/sj.gt.3302964 · Cited by 206 · see citing works
Self-citationNair, S. K., Morse, M. A., Boczkowski, D., Cumming, R. I., Vasović, L. V., Gilboa, E., & Lyerly, H. K. (2002) · Annals of Surgery · doi:10.1097/00000658-200204000-00013 · Cited by 205 · see citing works
Scheel, B., Teufel, R., Probst, J., Carralot, J., Geginat, J., Radsak, M. P., Jarrossay, D., Wagner, H., Jung, G., Rammensee, H., et al. (2005) · European Journal of Immunology · doi:10.1002/eji.200425656 · Cited by 198 · see citing works
Self-citationPolarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines
Carralot, J.-P., Probst, J., Hoerr, I., Scheel, B., Teufel, R., Jung, G., Rammensee, H.-G., & Pascolo, S. (2004) · Cellular and Molecular Life Sciences CMLS · doi:10.1007/s00018-004-4255-0 · Cited by 149 · see citing works
Self-citationImmunostimulating capacities of stabilized RNA molecules
Scheel, B., Braedel, S., Probst, J., Carralot, J., Wagner, H., Schild, H., Jung, G., Rammensee, H., & Pascolo, S. (2004) · European Journal of Immunology · doi:10.1002/eji.200324198 · Cited by 138 · see citing works
Self-citationRosenberg, S. A., Yang, J. C.-H., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Rogers-Freezer, L. J., et al. (2003) · Human Gene Therapy · doi:10.1089/104303403765255110 · Cited by 109 · see citing works
Myeloid suppressor cells regulate the adaptive immune response to cancer
Frey, A. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29906 · Cited by 93 · see citing works
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 · see citing works
Self-citationGranstein, R. D., Ding, W., & Ozawa, H. (2000) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2000.00929.x · Cited by 81 · see citing works
Scheibenbogen, C., Schadendorf, D., Bechrakis, N. E., Nagorsen, D., Hofmann, U., Servetopoulou, F., Letsch, A., Philipp, A., Foerster, M. H., Schmittel, A. H., et al. (2003) · International Journal of Cancer · doi:10.1002/ijc.10961 · Cited by 78 · see citing works
Jandus, C., Bioley, G., Speiser, D. E., & Romero, P. J. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0507-4 · Cited by 75 · see citing works
Nemunaitis, J. J., Meyers, T. P., Senzer, N. N., Cunningham, C. C., West, H., Vallières, E., Anthony, S. P., Vukelja, S. J., Berman, B. S., Tully, H., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.01.013 · Cited by 69 · see citing works
Human tumor-specific T lymphocytes: does function matter more than number?
Coulie, P. G., & Connerotte, T. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.03.002 · Cited by 50 · see citing works
Carralot, J., Weide, B., Schoor, O., Probst, J., Scheel, B., Teufel, R., Hoerr, I., Garbe, C., Rammensee, H., & Pascolo, S. (2005) · Genetic Vaccines and Therapy · doi:10.1186/1479-0556-3-6 · Cited by 37 · see citing works
Self-citationTeufel, R., Carralot, J.-P., Scheel, B., Probst, J., Walter, S., Jung, G., Hoerr, I., Rammensee, H.-G., & Pascolo, S. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5067-6 · Cited by 22 · see citing works
Self-citationHoerr, I. (2000) · doi:10.1002/1521-4141(200001)30:1
Self-citation
Flagged first, then by citations
2 of the 28 references couldn’t be matched to a known paper.
Cited by
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mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667 · see citing works
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 · see citing works
“Discovery that nucleoside-modified RNA is non-immunogenic 75 • First human cancer immunotherapy using direct injection of mRNA 16 • F irst adoptive immunotherapy with CAR mRNA 237 , 238 • Protein replacement preclinical study: nucleoside-modified mRNA corrects disease 25 • Development of TALEN mRNA…”
mRNA vaccines for infectious diseases: principles, delivery and clinical translation
Chaudhary, N., Weissman, D., & Whitehead, K. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00283-5 · Cited by 1,555 · see citing works
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 · see citing works
The clinical progress of mRNA vaccines and immunotherapies
Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R., & Anderson, D. G. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01294-2 · Cited by 823 · see citing works
mRNA-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 801 · see citing works
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
Oberli, M. A., Reichmuth, A. M., Dorkin, J. R., Mitchell, M. J., Fenton, O. S., Jaklenec, A., Anderson, D. G., Langer, R., & Blankschtein, D. (2017) · Nano Letters · doi:10.1021/acs.nanolett.6b03329 · Cited by 719 · see citing works
Nonviral delivery of self-amplifying RNA vaccines
Geall, A. J., Verma, A., Otten, G. R., Shaw, C. A., Hekele, A., Banerjee, K., Cu, Y., Beard, C. W., Brito, L. A., Krucker, T., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209367109 · Cited by 675 · see citing works
Bahl, K., Senn, J. J., Yuzhakov, O., Bulychev, A., Brito, L. A., Hassett, K. J., Laska, M. E., Smith, M., Almarsson, Ö., Thompson, J., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.03.035 · Cited by 642 · see citing works
“Although first identified in the early 1990s, mRNA vaccines were not advanced into the clinic until recently due to concerns around stability and production.(42,43) The mRNA vaccines are produced by a well-controlled, enzymatic, and well-characterized scalable process that is agnostic to the antigen being produced.”
BackgroundmRNA vaccine delivery using lipid nanoparticles
Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R., & Blankschtein, D. (2016) · Therapeutic Delivery · doi:10.4155/tde-2016-0006 · Cited by 624 · see citing works
Developing mRNA-vaccine technologies
Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K.-J. (2012) · RNA Biology · doi:10.4161/rna.22269 · Cited by 622 · see citing works
“43,141,142 A further clinical trial with patients with renal cell carcinoma stage IV included the administration of GM-CSF as adjuvant 24 h after vaccination with six antigens, 143 an approach that will be discussed in more detail in the next section.”
Guo, C., Manjili, M. H., Subjeck, J. R., Sarkar, D., Fisher, P. B., & Wang, X. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00007-1 · Cited by 598 · see citing works
“RNA-based cancer vaccines have only been clinically tested in phase I/II trials with patients with melanoma (Weide et al., 2008; Weide et al., 2009) or RCC (Oshiumi et al.”
BackgroundWang, H.-X., Li, M., Lee, C. M., Chakraborty, S., Kim, H.-W., Bao, G., & Leong, K. W. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00799 · Cited by 560 · see citing works
mRNA vaccines manufacturing: challenges and bottlenecks
Rosa, S. S., Prazeres, D. M. F., Azevedo, A. M., & Marques, M. P. C. (2021) · Vaccine · doi:10.1016/j.vaccine.2021.03.038 · Cited by 545 · see citing works
Alberer, M., Gnad-Vogt, U., Hong, H. S., Mehr, K. T., Backert, L., Finak, G., Gottardo, R., Bica, M. A., Garofano, A., Koch, S. D., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31665-3 · Cited by 530 · see citing works
Self-citationThess, A., Grund, S., Mui, B. L., Hope, M. J., Baumhof, P., Fotin-Mleczek, M., & Schlake, T. (2015) · Molecular Therapy · doi:10.1038/mt.2015.103 · Cited by 513 · see citing works
Delany, I., Rappuoli, R., & Gregorio, E. D. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201403876 · Cited by 426 · see citing works
“To date, several exploratory trials in cancer patients with mRNA vaccines have resulted in the induction of anti-tumor immunity, demonstrating proof of concept in humans (Weide et al , 2008, 2009; Rittig et al , 2011).”
mRNA vaccine: a potential therapeutic strategy
Wang, Y., Zhang, Z., Luo, J., Han, X., Wei, Y., & Wei, X. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01311-z · Cited by 422 · see citing works
The challenge and prospect of mRNA therapeutics landscape
Weng, Y., Li, C., Yang, T., Hu, B., Zhang, M., Guo, S., Xiao, H., Liang, X.-J., & Huang, Y. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107534 · Cited by 417 · see citing works
Chahal, J. S., Khan, O. F., Cooper, C. L., McPartlan, J. S., Tsosie, J. K., Tilley, L. D., Sidik, S. M., Lourido, S., Langer, R., Bavari, S., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600299113 · Cited by 414 · see citing works
RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges
Yu, A., Choi, Y. H., & Tu, M. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019554 · Cited by 405 · see citing works
“…modalities has great potential in vaccination, protein replacement therapy, and antibody therapy for the treatment of a wide variety of human diseases, including infections, cancers, and genetic disorders (Sahin et al., 2014; Weissman and Kariko, 2015; Pardi et al., 2018; Kowalski et al., 2019).”
BackgroundMaterials for non-viral intracellular delivery of messenger RNA therapeutics
Kauffman, K. J., Webber, M. J., & Anderson, D. G. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.12.032 · Cited by 400 · see citing works
mRNA therapeutics in cancer immunotherapy
Beck, J. D., Reidenbach, D., Salomon, N., Sahin, U., Türeci, Ö., Vormehr, M., & Kranz, L. M. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01348-0 · Cited by 385 · see citing works
mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection
Xu, S., Yang, K., Li, R., & Zhang, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186582 · Cited by 368 · see citing works
Three decades of messenger RNA vaccine development
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2019) · Nano Today · doi:10.1016/j.nantod.2019.100766 · Cited by 342 · see citing works
A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines
Brito, L. A., Chan, M., Shaw, C. A., Hekele, A., Carsillo, T., Schaefer, M., Archer, J., Seubert, A., Otten, G. R., Beard, C. W., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.133 · Cited by 338 · see citing works
Kreiter, S., Selmi, A., Diken, M., Koslowski, M., Britten, C. M., Huber, C., Türeci, Ö., & Sahin, U. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0699 · Cited by 309 · see citing works
An Update on Self-Amplifying mRNA Vaccine Development
Blakney, A. K., Ip, S., & Geall, A. J. (2021) · Vaccines · doi:10.3390/vaccines9020097 · Cited by 288 · see citing works
Kübler, H., Scheel, B., Gnad-Vogt, U., Miller, K., Schultze-Seemann, W., vom Dorp, F., Parmiani, G., Hampel, C., Wedel, S., Trojan, L., et al. (2015) · Journal for Immunotherapy of Cancer · doi:10.1186/s40425-015-0068-y · Cited by 287 · see citing works
“The observed injection site erythema, injection site reactions and influenza-like symptoms were mild to moderate and have been observed in previous clinical trials with cancer vaccines [5], including mRNA vaccines [10, 32, 33].”
BackgroundResultSelf-citationMcKinlay, C. J., Vargas, J. R., Blake, T. R., Hardy, J. W., Kanada, M., Contag, C. H., Wender, P. A., & Waymouth, R. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614193114 · Cited by 288 · see citing works
Su, X., Fricke, J., Kavanagh, D. G., & Irvine, D. J. (2011) · Molecular Pharmaceutics · doi:10.1021/mp100390w · Cited by 287 · see citing works
Karikó, K., Muramatsu, H., Keller, J. M., & Weissman, D. (2012) · Molecular Therapy · doi:10.1038/mt.2012.7 · Cited by 282 · see citing works
RNA therapy: rich history, various applications and unlimited future prospects
Kim, Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00757-5 · Cited by 266 · see citing works
An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo
Li, B., Luo, X., Deng, B., Wang, J., McComb, D. W., Shi, Y., Gaensler, K. M. L., Tan, X., Dunn, A. L., Kerlin, B. A., et al. (2015) · Nano Letters · doi:10.1021/acs.nanolett.5b03528 · Cited by 261 · see citing works
Emerging mRNA technologies: delivery strategies and biomedical applications
Xiao, Y., Tang, Z., Huang, X., Chen, W., Zhou, J., Liu, H., Liu, C., Kong, N., & Tao, W. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00617g · Cited by 255 · see citing works
mRNA vaccines in disease prevention and treatment
Zhang, G., Tang, T., Chen, Y., Huang, X., & Liang, T. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01579-1 · Cited by 253 · see citing works
Cancer mRNA vaccines: clinical advances and future opportunities
Sayour, E. J., Boczkowski, D., Mitchell, D. A., & Nair, S. K. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00902-1 · Cited by 251 · see citing works
“One of the first RNA vaccine trials testing a non-cellular delivery method involved an intra-dermally administered protamine-complexed mRNA encoding the tumour-associated antigens Melan A, tyrosinase, gp100, MAGEA1, MAGEA3 and survivin in patients with metastatic melanoma 85 .”
Immunologic Basis of Vaccine Vectors
Liu, M. A. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.004 · Cited by 237 · see citing works
Mechanism of action of mRNA-based vaccines
Iavarone, C., O’hagan, D. T., Yu, D., Delahaye, N. F., & Ulmer, J. B. (2017) · Expert Review of Vaccines · doi:10.1080/14760584.2017.1355245 · Cited by 234 · see citing works
mRNA as gene therapeutic: How to control protein expression
Tavernier, G., Andries, O., Demeester, J., Sanders, N. N., De Smedt, S. C., & Rejman, J. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.10.020 · Cited by 232 · see citing works
Di, J., Du, Z., Wu, K., Jin, S., Wang, X., Li, T., & Xu, Y. (2022) · Pharmaceutical Research · doi:10.1007/s11095-022-03166-5 · Cited by 229 · see citing works
Kuhn, A. N., Diken, M., Kreiter, S., Selmi, A., Kowalska, J., Jemielity, J., Darzynkiewicz, E., Huber, C., Türeci, Ö., & Sahin, U. (2010) · Gene Therapy · doi:10.1038/gt.2010.52 · Cited by 226 · see citing works
“9 In summary, our data reveal 5 0 mRNA cap analogs as a further structural feature to modify the stability and translational efficiency of in vitro transcribed RNA for pharmaceutical applications.”
BackgroundWeissman, D. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.973859 · Cited by 228 · see citing works
“Clinical trials using uncomplexed (naked) or protamine-complexed mRNA in vaccines with delivery either by the intradermal route [33–37] or with direct injection into lymph nodes [38–40] are currently ongoing.”
MethodIonizable lipid nanoparticles encapsulating barcoded mRNA for accelerated in vivo delivery screening
Guimarães, P. P. G., Zhang, R., Spektor, R., Tan, M., Chung, A., Billingsley, M. M., El-Mayta, R. D., Riley, R., Wang, L., Wilson, J. M., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.10.028 · Cited by 219 · see citing works
RNA-Based Vaccines in Cancer Immunotherapy
McNamara, M. A., Nair, S. K., & Holl, E. K. (2015) · Journal of Immunology Research · doi:10.1155/2015/794528 · Cited by 223 · see citing works
“Both of these accomplishments represent examples of “naked” RNA vaccines, meaning the mRNA is injected directly, formulated only in buffer and without a carrier.”
BackgroundCancer Vaccines: Toward the Next Breakthrough in Cancer Immunotherapy
Igarashi, Y., & Sasada, T. (2020) · Journal of Immunology Research · doi:10.1155/2020/5825401 · Cited by 223 · see citing works
Formulation and Delivery Technologies for mRNA Vaccines
Zeng, C., Zhang, C., Walker, P. G., & Dong, Y. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_217 · Cited by 221 · see citing works
Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications
Shi, Y., Shi, M., Wáng, Y., & You, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02002-z · Cited by 231 · see citing works
Current status of granulocyte–macrophage colony-stimulating factor in the immunotherapy of melanoma
Kaufman, H. L., Ruby, C. E., Hughes, T. M., & Slingluff, C. L. (2014) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-2-11 · Cited by 211 · see citing works
“These include an oncolytic vaccinia virus encoding GM-CSF [91], autologous dendritic cells and allogeneic whole tumor cells encoding GM-CSF [92-94], adjuvant GM-CSF following vaccination with peptide or RNA encoding melanoma peptides [95,96] and autologous dendritic cell or whole tumor cell vaccines [97], and GM-CSF D…”
MethodSebastian, M., Schröder, A., Scheel, B., Hong, H. S., Muth, A., von Boehmer, L., Zippelius, A., Mayer, F., Reck, M., Atanackovic, D., et al. (2019) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-019-02315-x · Cited by 209 · see citing works
Self-citationLipid-based mRNA vaccine delivery systems
Midoux, P., & Pichon, C. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.986104 · Cited by 209 · see citing works
“For example, mRNAs coding Melan-A, tyrosinase, gp100, melanoma-associated antigen (MAGEA1), MAGE-A3, survivin and GM-CSF as adjuvant were injected for metastatic melanoma [11,12] and the tumor-associated antigens mucin 1, carcinoembryonic antigen, human epidermal growth factor receptor 2, telomerase, survivin and MAGE…”
MethodIn Vitro Transcription of Long RNA Containing Modified Nucleosides
Pardi, N., Muramatsu, H., Weissman, D., & Karikó, K. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-260-5_2 · Cited by 204 · see citing works
Wang, Y., Zhang, L., Xu, Z., Miao, L., & Huang, L. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2017.11.009 · Cited by 206 · see citing works
“As was often observed in the clinical studies of mRNA vaccine, adjuvant such as GM-CSF was administered with mRNA antigen to boost the immune response.(4,7) Although single-stranded RNA with several structure features could activate various RNA sensors, such as Tolllike receptor, RIG-I, and PKR,(15,16,36) to potentiat…”
Cancer Vaccines, Adjuvants, and Delivery Systems
Paston, S. J., Brentville, V. A., Symonds, P., & Durrant, L. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.627932 · Cited by 200 · see citing works
Diken, M., Kreiter, S., Selmi, A., Britten, C. M., Huber, C. G., Türeci, Ö., & Şahin, U. (2011) · Gene Therapy · doi:10.1038/gt.2011.17 · Cited by 192 · see citing works
Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination
Persano, S., Guevara, M. L., Li, Z., Mai, J., Ferrari, M., Pompa, P. P., & Shen, H. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.02.019 · Cited by 187 · see citing works
Polymer‐Based mRNA Delivery Strategies for Advanced Therapies
Yang, W., Mixich, L., Boonstra, E., & Cabral, H. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202202688 · Cited by 190 · see citing works
RNA: The new revolution in nucleic acid vaccines
Geall, A. J., Mandl, C. W., & Ulmer, J. B. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.05.001 · Cited by 187 · see citing works
Ulmer, J. B., Mason, P. W., Geall, A. J., & Mandl, C. W. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.04.060 · Cited by 183 · see citing works
Clinical and immunological effects of mRNA vaccines in malignant diseases
Heine, A., Juranek, S., & Brossart, P. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01339-1 · Cited by 185 · see citing works
“In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe NCT00204607 [170] Heine et al.”
BackgroundHPLC purification of in vitro transcribed long RNA
Weissman, D., Pardi, N., Muramatsu, H., & Karikó, K. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-260-5_3 · Cited by 180 · see citing works
Altieri, D. C. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.03.005 · Cited by 178 · see citing works
Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines
Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A., & Geall, A. J. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.901308 · Cited by 177 · see citing works
“There was one clinical response (1/7) [35]”
BackgroundDelivery Strategies for mRNA Vaccines
Ramachandran, S., Satapathy, S. R., & Dutta, T. (2022) · Pharmaceutical Medicine · doi:10.1007/s40290-021-00417-5 · Cited by 182 · see citing works
“Although it stabilizes the mRNA, the intracellular delivery of the complex is questionable, and mRNA complexed with protamine are translated poorly in clinical trials [46].”
BackgroundBiomaterials for mRNA delivery
Islam, M. A., Reesor, E. K. G., Xu, Y., Zope, H. R., Zetter, B. R., & Shi, J. (2015) · Biomaterials Science · doi:10.1039/c5bm00198f · Cited by 176 · see citing works
Mechanism of Action of Immunotherapy
Disis, M. L. (2014) · Seminars in Oncology · doi:10.1053/j.seminoncol.2014.09.004 · Cited by 176 · see citing works
Nanoscale platforms for messenger RNA delivery
Li, B., Zhang, X., & Dong, Y. (2019) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1530 · Cited by 170 · see citing works
“In 2009, Weide et al. (2009) reported the results from a phase 1/2 clinical trial in metastatic melanoma patients using a direction injection of protamine/ mRNA encoding tumor-associated antigens (Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin).”
BackgroundmRNA cancer vaccines: Advances, trends and challenges
He, Q., Gao, H., Tan, D., Zhang, H., & Wang, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.011 · Cited by 167 · see citing works
“In 2009, Weide et al. 45 conducted a phase 1/2 clinical study on a protamine (RNActive (cid:2) )-protected mRNA cancer vaccine, adopting GM-CSFas an adjuvant that encoded 6 TAAs (Melan-A, tyrosinase, gp100, MAGE-A1, MAGE-A3, and survivin).”
Strategies for Cancer Vaccine Development
Vergati, M., Intrivici, C., Huen, N., Schlom, J., & Tsang, K. Y. (2010) · BioMed Research International · doi:10.1155/2010/596432 · Cited by 155 · see citing works
“Clinical trials have been performed employing mRNAtransfected DCs or injecting mRNA directly into patients with prostate cancer [18, 89, 95], RCC [96], ovarian cancer [97], lung cancer, breast cancer [90], pediatric brain cancer [98], neuroblastoma [99], and melanoma [100, 101].”
BackgroundAntigen-specific vaccines for cancer treatment
Tagliamonte, M., Petrizzo, A., Tornesello, M. L., Buonaguro, L., & Buonaguro, L. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/21645515.2014.973317 · Cited by 152 · see citing works
mRNA vaccine in cancer therapy: Current advance and future outlook
Li, Y., Wang, M., Peng, X., Yang, Y., Chen, Q., Liu, J., She, Q., Tan, J., Lou, C., Liao, Z., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1384 · Cited by 152 · see citing works
Lazăr, D. C., Avram, M. F., Romosan, I., Cornianu, M., Tăban, S. M., & Goldiș, A. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i32.3583 · Cited by 144 · see citing works
da Silva, J. R., Rodrigues, K. B., Pelegrin, G. F., Sales, N. S., Muramatsu, H., Silva, M. D. O., Porchia, B. F. M. M., Moreno, A. C. R., Aps, L. R. M. M., Venceslau-Carvalho, A. A., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abn3464 · Cited by 148 · see citing works
mRNA in the Context of Protein Replacement Therapy
Vavilis, T., Stamoula, Ε., Ainatzoglou, A., Sachinidis, A., Lamprinou, M., Dardalas, I., & Vizirianakis, I. S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010166 · Cited by 143 · see citing works
Challenges and advances towards the rational design of mRNA vaccines
Pollard, C., Koker, S. D., Saelens, X., Vanham, G. L., & Grooten, J. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.09.002 · Cited by 134 · see citing works
Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA
Zhao, M., Li, M., Zhang, Z., Gong, T., & Sun, X. (2016) · Drug Delivery · doi:10.3109/10717544.2015.1038856 · Cited by 132 · see citing works
“…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 131 · see citing works
“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 · see citing works
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 127 · see citing works
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 · see citing works
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 124 · see citing works
“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 · see citing works
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 120 · see citing works
Kallen, K., & Theß, A. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613508729 · Cited by 120 · see citing works
“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 124 · see citing works
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 120 · see citing works
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 113 · see citing works
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 111 · see citing works
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 · see citing works
Self-citationEsprit, A., de Mey, W., Shahi, R. B., Thielemans, K., Franceschini, L., & Breckpot, K. (2020) · Vaccines · doi:10.3390/vaccines8040776 · Cited by 105 · see citing works
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 106 · see citing works
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 104 · see citing works
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 99 · see citing works
“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 100 · see citing works
“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 99 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 98 · see citing works
“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 · see citing works
“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
- 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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