22P - Pre-clinical development of CVGBM: A therapeutic mRNA-based multiepitope vaccine for glioblastoma

Background

Clinical trials in glioblastomas (GBM) applying peptide vaccinations which target tumor-associated antigens (TAAs) over-presented on HLA class I/II molecules have shown promising results. To harness the immunogenic potential of messenger ribonucleic acid (mRNA) vaccines, we developed a mRNA-based multiepitope vaccine for GBM, CVGBM. CVGBM comprises a mRNA sequence with unmodified nucleotides, encapsulated in lipid nanoparticles (LNPs). It encodes a fusion protein containing eight TAA-derived epitopes that have previously shown immunogenicity as peptide vaccine. Presentation on HLA-A*02:01 (HLA class I) or on various HLA class II molecules enables the induction of CD8⁺ and CD4⁺ T cell responses, respectively.

Methods

We evaluated the presentation of CVGBM-encoded peptides by immunopeptidomic analysis using two human cell lines (HEK293T; THP-1) endogenously expressing HLA-A*02:01. The immunogenicity of CVGBM vaccine candidates was assessed in naïve C57BL/6 x BALB/c F1 (CB6F1) mice. These mice were vaccinated intramuscularly three times in a weekly interval. To confirm functionality of the multiepitope vaccine design we analyzed the anti-tumoral efficacy of a murine surrogate mRNA in a syngeneic B16.F10 tumor model.

Results

Immunopeptidomics analysis of CVGBM mRNA-transfected cells confirmed the presentation of HLA-A*02:01-presented peptides encoded by CVGBM. Importantly, no additional peptides originating from other regions of the fusion protein were detected. Upon vaccination of naïve CB6F1 mice with CVGBM robust CD8⁺ and CD4⁺ T cell responses were observed demonstrating the accurate translation and processing of the CVGBM-encoded fusion protein. To assess the anti-tumor efficacy of the multiepitope vaccine design, we evaluated a murine surrogate vaccine encoding ten epitopes derived from the murine B16.F10 tumor model. When administered to B16.F10 tumor-bearing mice the mRNA vaccine elicited anti-tumoral immune responses significantly extending the survival time.

Conclusions

These data supported the initiation of a phase I clinical trial (CV-GBLM-001; NCT05938387) evaluating CVGBM in HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated glioblastoma (CNS WHO Grade 4).

Clinical trial identification

CV-GBLM-001; NCT05938387.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

CureVac SE, Tübingen, Germany.

Disclosure

R.I. Mülfarth, J. Lutz, R.K. Feist, K. Wolter, J. Krüger, M. Barends Cabello, R. Heidenreich: Financial Interests, Full or part-time Employment: CureVac SE. All other authors have declared no conflicts of interest.