TY  - JOUR
AU  - Lutz, Johannes
AU  - Feist, Randi K
AU  - Sonntag, Tim
AU  - Peguero-Sánchez, Esteban
AU  - Wolter, Katharina
AU  - Bick, Ronja
AU  - Bauer, Jens
AU  - Walz, Juliane
AU  - Heidenreich, Regina
TI  - Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma.
JO  - Cancer immunology immunotherapy
VL  - 74
IS  - 11
SN  - 0340-7004
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2025-02051
SP  - 329
PY  - 2025
AB  - Glioblastoma (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).
KW  - Glioblastoma: immunology
KW  - Glioblastoma: therapy
KW  - Glioblastoma: genetics
KW  - Animals
KW  - Humans
KW  - Mice
KW  - Immunotherapy: methods
KW  - RNA, Messenger: immunology
KW  - RNA, Messenger: genetics
KW  - Brain Neoplasms: immunology
KW  - Brain Neoplasms: therapy
KW  - Antigens, Neoplasm: immunology
KW  - Antigens, Neoplasm: genetics
KW  - Cell Line, Tumor
KW  - Nanoparticles
KW  - Epitopes, T-Lymphocyte: immunology
KW  - Epitopes, T-Lymphocyte: genetics
KW  - Female
KW  - Mice, Inbred C57BL
KW  - Cancer Vaccines: immunology
KW  - Cancer vaccine (Other)
KW  - Glioblastoma (Other)
KW  - Immunotherapy (Other)
KW  - mRNA-based immunotherapeutic (Other)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Antigens, Neoplasm (NLM Chemicals)
KW  - Epitopes, T-Lymphocyte (NLM Chemicals)
KW  - Cancer Vaccines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41051649
DO  - DOI:10.1007/s00262-025-04178-x
UR  - https://inrepo02.dkfz.de/record/305099
ER  -