In 2019, Verbeke etal.58 showed that the invivo antitumor effects of Galsomes mRNA alone were modest, and this treatment could increase the number of cytotoxic T lymphocyte (CTL), invariant NKT (iNKT), NK and M1 tumor-associated macrophages (TAMs) in the immune microenvironment; these authors also found that negative regulation of the PD-1/PD-L1 pathway by the treatment might limit its antitumor effects. Krishna S., Anderson K.S. official website and that any information you provide is encrypted Kwak M., Leick K.M., Melssen M.M., Slingluff C.L., Jr. This review analyzes the advances in mRNA cancer vaccines from various perspectives, including the selection and expression of antigens/targets, the . HLA-A loci (HLA-A alleles: A0101, A0201, A0301, A1101 and A2402) account for 60% of HLA I alleles, and HLA-B loci (HLA-B alleles: B0702, B0801, B2705, B3501 and B5701) account for more than 35% of those alleles 183. Bookshelf Based on these results, BNT111 has received FDA fast track designation for clinical translation to treat advanced melanoma ({"type":"clinical-trial","attrs":{"text":"NCT04526899","term_id":"NCT04526899"}}NCT04526899). Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. Mai Y., Guo J., Zhao Y., Ma S., Hou Y., Yang J. Intranasal delivery of cationic liposomeprotamine complex mRNA vaccine elicits effective anti-tumor immunity. An overview of delivery systems adopted for mRNA cancer vaccines in the preclinical setting. the contents by NLM or the National Institutes of Health. Schnee M., Vogel A.B., Voss D., Petsch B., Baumhof P., Kramps T., et al. Bialkowski etal.90 showed that the TME of TC-1 tumors can be significantly different depending on the site of tumor inoculation (i.e., subcutaneous, in the lungs and in the genital tract), which directly affected the antitumor effects of the E7-TriMix mRNA vaccine. In contrast to mRNA, DNA must enter the nucleus to be translated into the corresponding antigens, which has a potential risk caused by insertional mutations and is likely less safe than mRNA. doi: 10.1016/B978-0-12-407190-2.00007-1. Moyer T.J., Zmolek A.C., Irvine D.J. Pardi N., Hogan M.J., Porter F.W., Weissman D. mRNA vaccinesa new era in vaccinology. See this image and copyright information in PMC. Erasmus J.H., Khandhar A.P., O'Connor M.A., Walls A.C., Hemann E.A., Murapa P., et al. Inclusion in an NLM database does not imply endorsement of, or agreement with, Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Kozak M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. Moss B. Furuichi Y., Miura K. A blocked structure at the 5 terminus of mRNA from cytoplasmic polyhedrosis virus. Targeted mRNA therapy for ornithine transcarbamylase deficiency. Bijker M.S., van den Eeden S.J., Franken K.L., Melief C.J., Offringa R., van der Burg S.H. Adjuvant LPS treatment further improved the level of CD8+ T cells and the antitumor activity of the cells induced by LNP mRNAs77. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. Chakraborty C, Sharma AR, Bhattacharya M, Lee SS. New strategies for therapeutic cancer vaccines. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Lin Y.X., Wang Y., Ding J., Jiang A., Wang J., Yu M., et al. Before The invivo antitumor effects of mRNA-CART combined with CpG were significantly stronger than those of mRNA-CART and the combination of naked mRNA and CpG, which were also stronger than those of the combination of mRNA-CART and TLR7 ligand or CD80/86 mRNA54. Human dendritic cell maturation and activation by a heat-killed recombinant yeast (. The TME is composed of immune cells, mesenchymal cells and various cytokines and tissue factors, which play an important role in tumorigenesis and immune escape187,188. Patients exhibit good tolerance to messenger ribonucleic acid (mRNA) vaccines, and the choice of encoded molecules is flexible and diverse. Finally, we look forward to the successful clinical translation of mRNA cancer vaccines. Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. mRNA vaccines a new era in vaccinology - Nature CpG, as the adjuvant contained in the VLVP, can improve the effects of the vaccine and prevent PD-1 expression in T cells103. Editorial: mRNA Vaccines and Immunotherapy in Oncology: A New Era for Personalized Medicine. Intranodal administration of mRNA encoding nucleoprotein provides cross-strain immunity against influenza in mice. and transmitted securely. As a potent recall antigen, Td can promote DC migration and improve antitumor effects through the CCL3106. In 2011, Fotin-Mleczek etal.72 conducted a preclinical study on protamine-complexed mRNA cancer vaccines encoding ovalbumin (OVA)/PSMA/STEAP and showed that the two-component mRNA cancer vaccine could induce self-adjuvant action via TLR7, balanced adaptive immune responses and sustained antitumor effects ({"type":"clinical-trial","attrs":{"text":"NCT00831467","term_id":"NCT00831467"}}NCT00831467, {"type":"clinical-trial","attrs":{"text":"NCT00923312","term_id":"NCT00923312"}}NCT00923312). In 2015, Kreiter etal.48 analyzed the mutant peptides in murine tumor cells (e.g., the melanoma cell line B16F10, colon cancer cell line CT26 and breast cancer cell line 4T1) via exome sequencing and an MHC-II epitope predictive binding algorithm and prepared RNA vaccines encoding those mutant peptides to evaluate their antitumor effects in a preclinical setting. This partnership could mean access to precision cancer treatment for up to 10 000 patients in the UK by 2030 and includes plans for new facilities and staff to support the initiative. The 5 cap and 3 poly(A) can be added during IVT or added enzymatically after initial IVT117. Karik K., Buckstein M., Ni H., Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Holtkamp S., Kreiter S., Selmi A., Simon P., Koslowski M., Huber C., et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. Tombcz I., Weissman D., Pardi N. Vaccination with messenger RNA: a promising alternative to DNA vaccination. Effective antitumor responses require the synergistic action of multiple immune cells rather than the action of a single cell. Vaccination with a recombinant, Remondo C., Cereda V., Mostbck S., Sabzevari H., Franzusoff A., Schlom J., et al. Abbreviations: GBM, glioblastoma; HNC, head and neck cancer; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small-cell lung cancer; OC, ovarian cancer; PC, prostate cancer; PCV, personalized cellular vaccine; TNBC, triple-negative breast cancer. In 2013 and 2016, Wilgenhof etal.95 showed that DCs coelectroporated with TriMix and mRNA encoding one of four melanoma-associated antigens (either MAGE-A3, MAGE-C2, tyrosinase or gp100) linked to an HLA II targeting signal (DC-LAMP) (named TriMixDC-MEL) were well tolerated in pretreated advanced melanoma patients and caused a complete response and a partial response in two patients ({"type":"clinical-trial","attrs":{"text":"NCT01066390","term_id":"NCT01066390"}}NCT0106639095). C1 or C1 mRNA can promote BMDC activation through the TLR4-dependent nuclear factor B signaling pathway, and the invivo antitumor effects of C1-OVA mRNA were TLR4-dependent61. Br J Haematol. Neoantigens in cancer immunotherapy. mRNA therapies and mRNA vaccines in cancer - BioMed Central The sequence of an antigenic peptide is well defined and easily controlled. An experimental vaccine for pancreatic cancer showed . Herpesvirus has a wide host range; can infect nerve cells, peripheral blood monocytes and DCs; and has a short replication cycle, a large capacity and relatively good safety160, 161, 162. Wansley E.K., Chakraborty M., Hance K.W., Bernstein M.B., Boehm A.L., Guo Z., et al. Heiser A., Coleman D., Dannull J., Yancey D., Maurice M.A., Lallas C.D., et al. Mai etal.62 showed that intranasal delivery of a LPC loaded with cytokeratin 19-encoding mRNA could induce APC maturation and strong cellular immune responses and decrease the growth of tumors in mice. Next-Generation Vaccines: Nanovaccines in the Fight against SARS-CoV-2 Virus and beyond SARS-CoV-2. Regulation of poly(A) tail and translation during the somatic cell cycle. Joe P.T., Christopoulou I., van Hoecke L., Schepens B., Ysenbaert T., Heirman C., et al. Schlake T., Thess A., Fotin-Mleczek M., Kallen K.J. Synthesis and properties of mRNAs containing the novel anti-reverse cap analogs 7-methyl(3-. UK-BioNTech partnership for mRNA cancer vaccines - The Lancet Careers. Results of tests in mice, reported June 20 in the Proceedings of the National Academy of Sciences, show that the degradable, polymer-based nanoparticle carrying an mRNA-based vaccine, when injected into the bloodstream of mice, was able to travel to the spleen and activate certain cancer-fighting immune cells in a targeted way.. mRNA-based cancer therapeutics | Nature Reviews Cancer To obtain more accurate evaluation information, humanized animal models can be established. -, Papachristofilou A, Hipp MM, Klinkhardt U, Fruh M, Sebastian M, Weiss C, et al. Hollingsworth R.E., Jansen K. Turning the corner on therapeutic cancer vaccines. Durable anticancer immunity from intratumoral administration of IL-23, IL-36. After a person gets the vaccine, the mRNA enters cells in the body and tells them to make copies of the COVID-19 virus's "spike" protein (the protein that normally helps the virus infect human cells). Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. Moderna/Merck cancer vaccine shows promise in trials Intralymphatic immunotherapy and vaccination in mice. In 2019, Miao etal.57 established a high-throughput technique for ionizable lipidoid construction, which enabled synthesis of thousands of lipid formulations in one day, and used DCs (e.g., HeLa cells, BMDCs or bone marrow-derived macrophages) to evaluate the transfection efficiency of the LNPs with high throughput. High-throughput techniques for screening and identifying these vectors have also been considered30. Howitt B.E., Shukla S.A., Sholl L.M., Ritterhouse L.L., Watkins J.C., Rodig S., et al. Zhang N.N., Li X.F., Deng Y.Q., Zhao H., Huang Y.J., Yang G., et al. mRNA vaccines have many shared characteristics. In 2018, Liu etal.51 conducted a preclinical evaluation of LCP NPs loaded with MUC1 mRNA in combination with an anti-CTLA-4 antibody to treat TNBC and showed that LCP-mRNA NPs as a monotherapy or part of a combined treatment (LCP-mRNA NPs+anti-CTLA-4) could significantly inhibit tumor growth, and the inhibitory effect of the combined treatment was significantly stronger than that of LCP-mRNA NP monotherapy51. Hilf N., Kuttruff-Coqui S., Frenzel K., Bukur V., Stevanovi S., Gouttefangeas C., et al. Developing mRNA-vaccine technologies. Systemic delivery of factor IX messenger RNA for protein replacement therapy. Overly strong inflammatory reactions can also cause toxic side effects. Islam M.A., Xu Y., Tao W., Ubellacker J.M., Lim M., Aum D., et al. Do ASS used humanized mice, which were established via intravenous injection of CD34+ hematopoietic stem cells from human peripheral blood mononuclear cells (HLA-A2 type) into immunodeficient NOD/Shi-scid IL-2Rnull mice or C57BL/6 mice, to establish invivo tumor models (e.g., human brain tumor stem cell 5 and murine GL261) and showed that the median survival of the humanized mouse model treated by DCs transfected with modified human CD133 mRNA was more than 60 days and that of the homologous mouse tumor model treated by DCs transfected with modified mouse CD133 mRNA was 38 days79. BN111 is an mRNA cancer vaccine candidate encoding a fixed combination of 4 TAAs (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE) that are prevalent in melanoma and delivered as an RNA-lipoplex formulation (Lipo-MERIT). De Beuckelaer A., Grooten J., De Koker S. Type I interferons modulate CD8, Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S., et al. Mitchell D.A., Batich K.A., Gunn M.D., Huang M.N., Sanchez-Perez L., Nair S.K., et al. Oberli M.A., Reichmuth A.M., Dorkin J.R., Mitchell M.J., Fenton O.S., Jaklenec A., et al. An intranodal naked RNA-based multiple neoepitope vaccine induced effective antigen-specific T cell immune responses ({"type":"clinical-trial","attrs":{"text":"NCT02035956","term_id":"NCT02035956"}}NCT0203595649). In 2020, Son etal.60 showed that Mann-capsules, prepared using polysaccharide-coated silica nanoparticles, could activate bone marrow-derived dendritic cells (BMDCs) via Dectin-2 or TLR-4 and that the ability of Mann-capsules to promote BMDC differentiation and maturation was significantly stronger than that of PEI or Lipofectamine; moreover, PEI and Lipofectamine were highly toxic. No potential conflict of interest exists. Peptide antigens often contain only one epitope, while full-length antigens encoded by mRNAs contain multiple epitopes, which can induce T cells to target those epitopes and produce stronger antitumor effects. mRNA therapies and mRNA vaccines in cancer More than 30 years ago Jon A. Wolff demonstrated the idea of nucleic acid-encoded drugs by direct injecting in vitro transcribed mRNA in mice. Intratumoral administration is mainly used for mRNA vaccines encoding immunocostimulatory molecules (e.g., TriMix, CV8102, mRNA-2752, mRNA-2416, BNT131 and MEDI1191) as immunoadjuvant therapy and also permits a small vaccine volume and involves complicated procedures.
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