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000305099 1001_ $$00000-0001-7452-0023$$aLutz, Johannes$$b0
000305099 245__ $$aPreclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma.
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000305099 520__ $$aGlioblastoma (GBM), an aggressive brain tumour associated with poor prognosis and high recurrence rate, has limited clinical treatment options. However, novel immunotherapeutics targeting over-presented epitopes of tumour-associated antigens (TAAs) represent a promising solution. Here we describe the preclinical development of CVGBM, an mRNA-based immunotherapeutic candidate for GBM consisting of a nucleotide-unmodified mRNA encapsulated in lipid nanoparticles (LNP). CVGBM mRNA encodes a fusion protein comprising eight TAA-derived epitopes that have previously induced T-cell responses in patients with GBM as peptide-based immunotherapeutics: five restricted to class I human leukocyte antigen (HLA) allele A*02:01 and three restricted to various class II HLA-DR alleles. Translation and processing of the mRNA-encoded fusion protein and presentation of derived epitopes on HLA molecules were confirmed in human cell lines after lipofection with CVGBM mRNA. Immunopeptidomics confirmed the presentation of four of the six HLA-A*02:01-restricted epitopes; however, HLA class II-bound epitopes were not detected. Administration of CVGBM to mice demonstrated functionality of the immunotherapeutic in vivo by inducing CD8+ and CD4+ T-cell responses. As CVGBM requires an intact immune system for its mode of action, it could not be tested in xenograft models. Instead, anti-tumoural efficacy was demonstrated for a surrogate mRNA-based immunotherapeutic, which has a similar mRNA and protein design as CVGBM but encodes a fusion protein comprising epitopes of the murine B16.F10 melanoma cell line. Administration of the surrogate immunotherapeutic prolonged median survival time of B16.F10 tumour-bearing mice relative to controls. Based on these results, a Phase I clinical trial with CVGBM was started in HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated GBM (NCT05938387).
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000305099 650_7 $$2Other$$aCancer vaccine
000305099 650_7 $$2Other$$aGlioblastoma
000305099 650_7 $$2Other$$aImmunotherapy
000305099 650_7 $$2Other$$amRNA-based immunotherapeutic
000305099 650_7 $$2NLM Chemicals$$aRNA, Messenger
000305099 650_7 $$2NLM Chemicals$$aAntigens, Neoplasm
000305099 650_7 $$2NLM Chemicals$$aEpitopes, T-Lymphocyte
000305099 650_7 $$2NLM Chemicals$$aCancer Vaccines
000305099 650_2 $$2MeSH$$aGlioblastoma: immunology
000305099 650_2 $$2MeSH$$aGlioblastoma: therapy
000305099 650_2 $$2MeSH$$aGlioblastoma: genetics
000305099 650_2 $$2MeSH$$aAnimals
000305099 650_2 $$2MeSH$$aHumans
000305099 650_2 $$2MeSH$$aMice
000305099 650_2 $$2MeSH$$aImmunotherapy: methods
000305099 650_2 $$2MeSH$$aRNA, Messenger: immunology
000305099 650_2 $$2MeSH$$aRNA, Messenger: genetics
000305099 650_2 $$2MeSH$$aBrain Neoplasms: immunology
000305099 650_2 $$2MeSH$$aBrain Neoplasms: therapy
000305099 650_2 $$2MeSH$$aAntigens, Neoplasm: immunology
000305099 650_2 $$2MeSH$$aAntigens, Neoplasm: genetics
000305099 650_2 $$2MeSH$$aCell Line, Tumor
000305099 650_2 $$2MeSH$$aNanoparticles
000305099 650_2 $$2MeSH$$aEpitopes, T-Lymphocyte: immunology
000305099 650_2 $$2MeSH$$aEpitopes, T-Lymphocyte: genetics
000305099 650_2 $$2MeSH$$aFemale
000305099 650_2 $$2MeSH$$aMice, Inbred C57BL
000305099 650_2 $$2MeSH$$aCancer Vaccines: immunology
000305099 7001_ $$00000-0001-5201-8366$$aFeist, Randi K$$b1
000305099 7001_ $$00000-0001-8487-6963$$aSonntag, Tim$$b2
000305099 7001_ $$00000-0002-8317-5572$$aPeguero-Sánchez, Esteban$$b3
000305099 7001_ $$aWolter, Katharina$$b4
000305099 7001_ $$00000-0001-7618-887X$$aBick, Ronja$$b5
000305099 7001_ $$0P:(DE-He78)f01eee7fbf54dc1fe47b67c4eff9fdec$$aBauer, Jens$$b6$$udkfz
000305099 7001_ $$0P:(DE-He78)aa8b428f7b1df6694113a5a7d3c4832a$$aWalz, Juliane$$b7$$udkfz
000305099 7001_ $$00000-0002-8607-9412$$aHeidenreich, Regina$$b8
000305099 773__ $$0PERI:(DE-600)1458489-X$$a10.1007/s00262-025-04178-x$$gVol. 74, no. 11, p. 329$$n11$$p329$$tCancer immunology immunotherapy$$v74$$x0340-7004$$y2025
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