Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma
Open accessAbstract
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).
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Written from the paper’s full text.
TL;DR
CVGBM is an unmodified mRNA-LNP immunotherapeutic encoding eight GBM tumour-associated antigen-derived epitopes, designed for HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated glioblastoma. Preclinical studies confirmed translation, HLA class I presentation of four of six HLA-A*02:01-restricted epitopes, in vivo CD8+ and CD4+ T-cell induction, and anti-tumour efficacy of a murine surrogate, supporting a Phase I trial (NCT05938387).
Key findings
- CVGBM mRNA encodes eight TAA-derived epitopes: five HLA-A*02:01-restricted class I epitopes and three HLA-DR-restricted class II epitopes, plus an HLA-A*02:01-restricted HBV reporter epitope, concatenated into a fusion protein with CTLA-4 domains and an E5 degron.
- Using TCGA gene expression data from 155 patients with GBM, simulation showed a median of 96% of patients express at least three of the four targeted TAAs.
- Immunopeptidomics in CVGBM mRNA-transfected HEK293T and THP-1 cells confirmed presentation of four of the six HLA-A*02:01-restricted epitopes; no CVGBM-derived HLA class II epitopes were detected.
- In CB6F1 mice, CVGBM induced CD8+ and CD4+ T-cell responses against two and four of the nine segments, respectively. A murine B16 surrogate immunotherapeutic prolonged median survival of B16.F10 tumour-bearing mice to 31.5 days versus 23.5 days for control mRNA-LNP and 22.4 days for untreated mice.
Methods
- Preclinical design: CVGBM and reporter/surrogate mRNAs were generated using unmodified nucleotides and LNP delivery; fusion protein variants with different localisation domains were tested in murine BMDCs and human cell lines.
- Data/sample: TAA expression was simulated from TCGA data from 155 patients with GBM; immunopeptidomics used HEK293T and THP-1 cells; in vivo immunogenicity used CB6F1 mice (n = 8 per group) and C57BL/6 mice (n = 5 per group); B16.F10 efficacy used C57BL/6 mice (n = 10 treated, n = 6 untreated).
- Main analyses: flow cytometry for reporter epitope presentation and T-cell responses, LC–MS/MS immunopeptidomics for HLA ligands, and tumour growth/survival analysis with log-rank testing.
Limitations
- The paper states that CVGBM anti-tumour efficacy could not be tested in human GBM xenograft models because CVGBM requires an intact immune system; instead, efficacy was shown with a murine B16.F10 surrogate immunotherapeutic sharing similar mRNA and protein design.
- The paper states that no CVGBM-derived HLA class II epitopes were detected by immunopeptidomics, likely due to low HLA class II expression on THP-1 cells or fewer recovered HLA class II than class I epitopes, despite CD4+ T-cell responses in mice.
- The paper notes a potential risk that CTLA-4 domains in the fusion protein could induce unwanted on-target, off-tumour CTLA-4-specific T-cell responses, although no CTLA-4-derived epitope presentation was detected; evident from the text, the approach is HLA-restricted and the reported human immunogenicity/efficacy data remain preclinical, with Phase I results only mentioned as interim.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
36 of 46 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The epitopes encoded by CVGBM have previously induced T-cell responses in patients with GBM when given as peptide-based immunotherapeutics in the GAPVAC-101 or IMA950 studies.
“The epitopes encoded by CVGBM have previously induced T-cell responses in the GAPVAC-101 or IMA950 studies in patients with GBM when given as peptide-based immunotherapeutics in combination with adjuvants [14, 15].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] Hilf N, Kuttruff-Coqui S, Frenzel K et al (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–245. https://doi.org/10.1038/s41586-018-0810-y source
- cites [15] Migliorini D, Dutoit V, Allard M et al (2019) Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol 21:923–933. https://doi.org/10.1093/neuonc/noz040 source
The Introduction identifies IMA950 as a peptide vaccine, and Safety Data reports tumor-peptide-specific CD8 T-cell responses in 62.5% of the GBM-only cohort. The paper does not identify CVGBM or establish that the epitopes it encodes are the IMA950 epitopes, so it supports the IMA950 response finding but not that overlap. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
The NLGN4X epitope encoded by CVGBM is over-presented on GBM tumours compared with healthy brain tissue.
“NLGN4X is less over-expressed in GBM; however, the encoded epitope is over-presented on GBM tumours compared with healthy brain tissue [28].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Dutoit V, Herold-Mende C, Hilf N et al (2012) Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135:1042–1054. https://doi.org/10.1093/brain/aws042 source
The Selection and characterization section identifies NLGN4X 131–139 among the selected peptides and reports that all ten were either detected only on tumour cells or over-presented on GBM compared with normal tissues, including normal brain. Our copy does not identify CVGBM as encoding the epitope, so it does not support that part of the claim. Page numbers were not provided for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
The current standard of care for GBM includes surgical resection and post-surgery radiotherapy with or without temozolomide chemotherapy.
“The current standard of care for GBM includes surgical resection and post-surgery radiotherapy with or without temozolomide (TMZ) chemotherapy [4, 5].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [4] Wen PY, Weller M, Lee EQ et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol 22:1073–1113. https://doi.org/10.1093/neuonc/noaa106 source
- cites [5] Weller M, van den Bent M, Preusser M et al (2021) EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 18:170–186. https://doi.org/10.1038/s41571-020-00447-z source
The Recommendations (page unavailable) support resection when feasible, followed by radiotherapy with temozolomide, for fit patients under 70 with IDH-wild-type glioblastoma. The claim omits important alternatives: the guidelines allow biopsy instead of resection and recommend temozolomide alone, without radiotherapy, for some elderly patients. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Checkpoint inhibitors against CTLA-4 and PD-1/PD-L1 have shown only very limited benefits in patients with GBM.
“Immunotherapies such as checkpoint inhibitors against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1)/PD ligand 1 (PD-L1) have represented a major advancement in the treatment of several types of solid tumour; however, these treatments have shown only very limited benefits in patients with GBM [7–9].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Habashy KJ, Mansour R, Moussalem C, Sawaya R, Massaad MJ (2022) Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them. Br J Cancer 127:976–987. https://doi.org/10.1038/s41416-022-01864-w source
- cites [8] Desbaillets N, Hottinger AF (2021) Immunotherapy in glioblastoma: a clinical perspective. Cancers (Basel) 13:3721. https://doi.org/10.3390/cancers13153721 source
- cites [9] Long GV, Shklovskaya E, Satgunaseelan L et al (2025) Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma. Nat Med. https://doi.org/10.1038/s41591-025-03512-1 source
- Premisecitation
GBM immunoresistance may also be acquired in response to therapy, through changes in checkpoint expression, epigenetic changes, and loss of tumour antigen expression.
“GBM immunoresistance may also be acquired in response to therapy, through changes in checkpoint expression, epigenetic changes, and loss of tumour antigen expression [10].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Wang EJ, Chen JS, Jain S, Morshed RA, Haddad AF, Gill S, Beniwal AS, Aghi MK (2021) Immunotherapy resistance in glioblastoma. Front Genet 12:750675. https://doi.org/10.3389/fgene.2021.750675 source
- Study design and conductcitation
98% of all detected peptides in the immunopeptidomics assay have been previously experimentally validated and are reported in the Immune Epitope Database.
“The specificity of the assay was corroborated by the finding that 98% of all detected peptides have been previously experimentally validated and are reported in the Immune Epitope Database [31] (Supplementary data).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [31] Vita R, Blazeska N, Marrama D et al (2025) The Immune Epitope Database (IEDB): 2024 update. Nucleic Acids Res 53:D436–D443. https://doi.org/10.1093/nar/gkae1092 source
The Introduction (page not provided) says the IEDB curates published experimental data on immune epitopes, including peptides. It does not report results from the citing paper’s immunopeptidomics assay or establish that 98% of its detected peptides were previously validated and listed in the IEDB. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
For HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated GBM following standard of care, there is currently no efficacious treatment option available.
“For this patient population, there is currently no efficacious treatment option available [4].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Wen PY, Weller M, Lee EQ et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol 22:1073–1113. https://doi.org/10.1093/neuonc/noaa106 source
The Predictive Biomarkers section says temozolomide has little or no benefit in MGMT-unmethylated glioblastoma. The Recurrent Glioblastoma section says there is no clear standard-of-care salvage therapy and that listed options have not prolonged survival in randomized trials. Neither passage establishes that no efficacious treatment exists specifically for HLA-A*02:01-positive, surgically resected patients following standard care. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
The eight CVGBM-encoded epitopes have induced immune responses in previous clinical trials as peptide-based immunotherapeutics.
“CVGBM encodes eight epitopes that are frequently presented on the surface of GBM tumour samples and have induced immune responses in previous clinical trials as peptide-based immunotherapeutics [14, 15].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] Hilf N, Kuttruff-Coqui S, Frenzel K et al (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–245. https://doi.org/10.1038/s41586-018-0810-y source
- cites [15] Migliorini D, Dutoit V, Allard M et al (2019) Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol 21:923–933. https://doi.org/10.1093/neuonc/noz040 source
The Introduction (page unavailable) describes IMA950 as containing nine CD8 T-cell epitopes derived from eight proteins, not eight epitopes. The Safety Data and Discussion (pages unavailable) report vaccine-induced responses to tumor peptides, but do not establish that all eight epitopes described in the claim induced responses. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
CVGBM encodes eight epitopes that are frequently presented on the surface of GBM tumour samples.
“CVGBM encodes eight epitopes that are frequently presented on the surface of GBM tumour samples and have induced immune responses in previous clinical trials as peptide-based immunotherapeutics [14, 15].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] Hilf N, Kuttruff-Coqui S, Frenzel K et al (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–245. https://doi.org/10.1038/s41586-018-0810-y source
- cites [15] Migliorini D, Dutoit V, Allard M et al (2019) Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol 21:923–933. https://doi.org/10.1093/neuonc/noz040 source
The Introduction (page unavailable) says that peptides formulated in IMA950 were eluted from GBM tumour surfaces and presented on GBM samples in vivo. But it describes nine CD8 T-cell epitopes from eight proteins, not eight epitopes, and does not identify CVGBM or establish which epitopes it encodes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
HLA-A*02:01 is the most frequent MHC class I allele in the Caucasian population, with up to 50% of individuals bearing this allele.
“To maximise the eligible patient population, the epitopes selected for CVGBM were either restricted to HLA-A*02:01 (BCAN, PTPRZ1, NLGNX4) as the most frequent MHC class I allele in the Caucasian population (up to 50% of individuals bearing this allele according to the allele frequency net database [39]), or to various HLA-DR alleles (BIRC5).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [39] Gonzalez-Galarza Faviel F, McCabe A, Santos Eduardo JMd et al (2019) Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res 48:D783–D788. https://doi.org/10.1093/nar/gkz1029 source
The Database content section says AFND lets users browse HLA allele and genotype frequencies, but it gives no frequency or ranking for HLA-A*02:01. Searches for HLA-A*02:01, Caucasian or European populations, and 50% found no passage in our copy establishing that it is the most frequent MHC class I allele in that population or that up to 50% of individuals carry it. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Premisecitation
CTLA-4 has also been detected in natural killer cells, B cells, dendritic cells and myeloid cells.
“CTLA-4 has also been detected in natural killer cells, B cells, dendritic cells and myeloid cells [44].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] Roy D, Gilmour C, Patnaik S, Wang LL (2023) Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors. Front Immunol 14:1264327. https://doi.org/10.3389/fimmu.2023.1264327 source
- Premisecitation
Peptide-based immunotherapeutics often tend to induce primarily CD4+ T-cell responses.
“In contrast, peptide-based immunotherapeutics often tend to induce primarily CD4+ T-cell responses [36].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [36] Kreiter S, Vormehr M, van de Roemer N et al (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–696. https://doi.org/10.1038/nature14426 source
The Abstract reports that synthetic 27-mer neo-epitope peptides induced CD4+ responses to 16 of 17 responsive epitopes in vaccinated mice. This supports the pattern in that specific setting, but not the broader claim that peptide-based immunotherapeutics generally tend to induce primarily CD4+ responses; the paper also found predominantly CD4+ responses with RNA vaccination. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
LNP-formulated mRNAs with unmodified nucleotides primarily induce CD8+ T-cell responses.
“They primarily induce CD8+ T-cell responses [22], which can exceed those induced by LNP-formulated mRNAs with modified nucleotides [34, 35], as well as CD4+ T-cell responses.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Lutz J, Lazzaro S, Habbeddine M et al (2017) Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2:29. https://doi.org/10.1038/s41541-017-0032-6 source
The Results section on mice reports antigen-specific CD8+ T-cell responses after vaccination with LNP-formulated unmodified mRNA, but also reports CD4+ responses; it does not establish that CD8+ responses predominate. In the Results section on non-human primates, CD4+ responses appeared at both rabies-vaccine doses while CD8+ responses appeared only at the higher dose, and influenza-specific CD8+ responses were absent (pages not provided). (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Cytoreductive therapy significantly impairs the immune system.
“Since cytoreductive therapy significantly impairs the immune system [37], the potential to induce strong CD8+ T-cell responses is particularly relevant for an antigen-based immunotherapeutic for GBM, where chemotherapy and radiotherapy remain the standard of care, and induced T cells must cross the blood–brain barrier to invade the immunologically “cold” tumour.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [37] Velardi E, Tsai JJ, van den Brink MRM (2021) T cell regeneration after immunological injury. Nat Rev Immunol 21:277–291. https://doi.org/10.1038/s41577-020-00457-z source
- Premisecitation
LNP-formulated mRNAs with unmodified nucleotides are a potent modality to deliver antigens for presentation on HLA class I and II molecules due to their intrinsic immunostimulatory capacities.
“Due to their intrinsic immunostimulatory capacities, LNP-formulated mRNAs with unmodified nucleotides are a potent modality to deliver antigens for presentation on HLA class I and II molecules.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Lutz J, Lazzaro S, Habbeddine M et al (2017) Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2:29. https://doi.org/10.1038/s41541-017-0032-6 source
The Results report that unmodified, LNP-formulated mRNA produced antigen-specific CD4+ and CD8+ T-cell responses in mice, while the Discussion reports strong antigen expression and innate immune activation. These findings support its vaccine potency, but the paper does not directly demonstrate antigen presentation on HLA class I and II molecules. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
The epitopes are derived from four TAAs that are either over-expressed (BCAN, BIRC5, PTPRZ1) or over-presented (NLGNX4) in a large proportion of GBM tumours compared with most healthy tissues.
“The epitopes are derived from four TAAs that are either over-expressed (BCAN, BIRC5, PTPRZ1 [Supplementary Fig. 1b]) or where the epitope is over-presented (NLGNX4) in a large proportion of GBM tumours compared with most healthy tissues [28].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Dutoit V, Herold-Mende C, Hilf N et al (2012) Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135:1042–1054. https://doi.org/10.1093/brain/aws042 source
The Selection and characterization section reports higher antigen expression and peptide presentation in GBM than in healthy tissues, and Table 1 identifies peptides derived from BCAN, PTPRZ1 and NLGN4X. It does not list a BIRC5-derived peptide, so it does not support that part of the four-antigen claim. The source spells the fourth antigen NLGN4X, rather than NLGNX4. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
CD8+ T-cell responses induced by LNP-formulated mRNAs with unmodified nucleotides can exceed those induced by LNP-formulated mRNAs with modified nucleotides.
“They primarily induce CD8+ T-cell responses [22], which can exceed those induced by LNP-formulated mRNAs with modified nucleotides [34, 35], as well as CD4+ T-cell responses.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [34] Oberli MA, Reichmuth AM, Dorkin JR, Mitchell MJ, Fenton OS, Jaklenec A, Anderson DG, Langer R, Blankschtein D (2017) Lipid nanoparticle assisted mrna delivery for potent cancer immunotherapy. Nano Lett 17:1326–1335. https://doi.org/10.1021/acs.nanolett.6b03329 source
- cites [35] Sittplangkoon C, Alameh MG, Weissman D, Lin PJC, Tam YK, Prompetchara E, Palaga T (2022) mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model. Front Immunol 13:983000. https://doi.org/10.3389/fimmu.2022.983000 source
- Premisecitation
CTLA-4 is an immune checkpoint receptor expressed on Foxp3+ regulatory T cells and conventional T cells.
“Physiologically, CTLA-4 is an immune checkpoint receptor expressed on Foxp3+ regulatory T cells and conventional T cells.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] Roy D, Gilmour C, Patnaik S, Wang LL (2023) Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors. Front Immunol 14:1264327. https://doi.org/10.3389/fimmu.2023.1264327 source
- Premisecitation
Interim results from the initial dose escalation part of the Phase I trial demonstrated that CVGBM was well tolerated with an acceptable safety profile.
“Interim results from the initial dose escalation part of the study demonstrated that CVGBM was well tolerated with an acceptable safety profile and TAA-specific T-cell responses were induced in the majority of patients [47].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [47] de Freitas Chama LL, Romer Roche P, Tabatabai G et al (2025) Preliminary immunogenicity results from the dose escalation phase of a first-in-human study of the mRNA-based cancer vaccine CVGBM in patients with newly diagnosed MGMT-unmethylated glioblastoma. J Immunother Cancer 13:A3. https://doi.org/10.1136/jitc-2025-ITOC11.5 source
- Premisecitation
Interim results from the initial dose escalation part of the Phase I trial demonstrated that TAA-specific T-cell responses were induced in the majority of patients.
“Interim results from the initial dose escalation part of the study demonstrated that CVGBM was well tolerated with an acceptable safety profile and TAA-specific T-cell responses were induced in the majority of patients [47].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [47] de Freitas Chama LL, Romer Roche P, Tabatabai G et al (2025) Preliminary immunogenicity results from the dose escalation phase of a first-in-human study of the mRNA-based cancer vaccine CVGBM in patients with newly diagnosed MGMT-unmethylated glioblastoma. J Immunother Cancer 13:A3. https://doi.org/10.1136/jitc-2025-ITOC11.5 source
- Findingown data
Anti-tumoural efficacy was demonstrated for a surrogate mRNA-based immunotherapeutic with similar mRNA and protein design as CVGBM but encoding epitopes of the murine B16.F10 melanoma cell line.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-tumour efficacy of the surrogate B16 immunotherapeutic predicts anti-tumour efficacy of CVGBM in GBM.
- Findingown data
Administration of the surrogate immunotherapeutic prolonged median survival time of B16.F10 tumour-bearing mice relative to controls.
“Administration of the surrogate immunotherapeutic prolonged median survival time of B16.F10 tumour-bearing mice relative to controls.”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-tumour efficacy of the surrogate B16 immunotherapeutic predicts anti-tumour efficacy of CVGBM in GBM.
- Findingown data
Four of the six HLA-A*02:01-restricted epitopes encoded by CVGBM were presented by HLA class I molecules in immunopeptidomics of CVGBM mRNA-transfected HEK293T and THP-1 cells.
“Four of the six HLA-A*02:01-restricted epitopes encoded by CVGBM were presented by HLA class I molecules (Fig. 4, Supplementary Table 3, Supplementary data).”
Quote in the paperSubstantial claim - Findingown data
CVGBM mRNA encodes a fusion protein comprising eight TAA-derived epitopes.
“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.”
Quote in the paperSubstantial claim - Findingcitation
Simulation using TCGA gene expression data showed that a median of 96% of patients with GBM express at least three of the four TAAs targeted by CVGBM in their tumour.
“Simulation results using gene expression data of GBM tumours from The Cancer Genome Atlas database [24] showed that a median of 96% patients express at least three of the four TAAs in their tumour (Fig. 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] National Cancer Institute Center for Cancer Genomics (2024) The Cancer Genome Atlas Program (TCGA). https://www.cancer.gov/ccg/research/genome-sequencing/tcga. Accessed Oct 2024
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
NLGN4X is less over-expressed in GBM than other TAAs.
“NLGN4X is less over-expressed in GBM; however, the encoded epitope is over-presented on GBM tumours compared with healthy brain tissue [28].”
Quote in the paperNot a substantial claim - Findingown data
HLA class II-bound CVGBM-derived epitopes were not detected by immunopeptidomics.
“Immunopeptidomics confirmed the presentation of four of the six HLA-A*02:01-restricted epitopes; however, HLA class II-bound epitopes were not detected.”
Quote in the paperSubstantial claim - Findingnone given
CVGBM is an mRNA-based immunotherapeutic candidate for GBM consisting of a nucleotide-unmodified mRNA encapsulated in lipid nanoparticles (LNP).
“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).”
Quote in the paperSubstantial claim - Findingown data
Translation and processing of the CVGBM mRNA-encoded fusion protein and presentation of derived epitopes on HLA molecules were confirmed in human cell lines after lipofection with CVGBM mRNA.
“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.”
Quote in the paperSubstantial claim - Findingown data
Flow cytometry showed similar staining of SIINFEKL/MHC class I complexes on the surface of BMDCs 9 h after transfection with mRNAs encoding the five different GBMr proteins.
“Flow cytometry results demonstrated similar staining of SIINFEKL/MHC class I complexes on the surface of BMDCs 9 h after transfection with mRNAs encoding the five different GBMr proteins (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Immunopeptidomics confirmed presentation of four of the six HLA-A*02:01-restricted epitopes encoded by CVGBM by HLA class I molecules.
“Immunopeptidomics confirmed the presentation of four of the six HLA-A*02:01-restricted epitopes; however, HLA class II-bound epitopes were not detected.”
Quote in the paperSubstantial claim - Findingown data
Three of the TAAs targeted by CVGBM (BCAN, PTPRZ1, BIRC5) are highly over-expressed in GBM tumours compared with healthy tissue (except testis).
“Three of the TAAs (BCAN, PTPRZ1, BIRC5) are highly over-expressed in GBM tumours compared with healthy tissue (except testis) (Supplementary Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
By 17 h post-transfection, presentation of Eα decreased to background levels for all variants, except for GBMr-CTLA-4-E5.
“By 17 h post-transfection, presentation of Eα decreased to background levels for all variants, except for GBMr-CTLA-4-E5 (Supplementary Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Eα/MHC class II complexes were only detected above background levels in BMDCs transfected with mRNAs encoding GBMr-CTLA-4-E5 and GBMr-LAMP1, and to a lesser extent GBMr-CTLA-4.
“In contrast, Eα/MHC class II complexes on these cells were only detected above background levels in BMDCs transfected with mRNAs encoding GBMr-CTLA-4-E5 and GBMr-LAMP1, and to a lesser extend GBMr-CTLA-4 (Fig. 2b).”
Quote in the paperSubstantial claim - Findingreasoning
All segments in the CVGBM core fusion protein are separated by G4S linkers to reduce presentation of junctional epitopes.
“All segments are separated by G4S linkers to reduce presentation of junctional epitopes.”
Quote in the paperSubstantial claim - Findingown data
There was no correlation between the frequency of cells presenting the Eα epitope and the frequency of cells with detectable GBMr fusion protein.
“Steady-state protein amounts were assessed by HA staining, showing no correlation between the frequency of cells presenting the Eα epitope and the frequency of cells with detectable GBMr fusion protein (Fig. 2b and c).”
Quote in the paperSubstantial claim - Findingown data
Four of the six HLA-A*02:01-restricted epitopes were presented on human cells transfected with the final CVGBM mRNA.
“Immunopeptidomic analysis of two human cell lines transfected with the final CVGBM mRNA confirmed translation and processing of the CVGBM fusion protein and presentation of four of the six HLA-A*02:01-restricted epitopes on human cells”
Quote in the paperSubstantial claim - Findingown data
In a comparison in murine cells, the protein design containing the CTLA-4 domains and the E5 degron demonstrated the best presentation of the reporter epitopes on MHC class I and II molecules.
“In this comparison in murine cells, the protein design containing the CTLA-4 domains and the E5 degron demonstrated the best presentation of the reporter epitopes on MHC class I and II molecules.”
Quote in the paperSubstantial claim - Findingown data
In CB6F1 mice, CVGBM induced CD8+ T-cell responses against two of the nine antigen segments.
“Results confirmed the functionality of the multi-epitope CVGBM in vivo by inducing CD8+ and CD4+ T-cell responses against two and four of the nine segments, respectively (Fig. 5).”
Quote in the paperSubstantial claim - Findingreasoning
No CVGBM-derived HLA class II epitopes were detected in the immunopeptidomic analysis.
“however, no CVGBM-derived HLA class II epitopes were detected”
Quote in the paperNot a substantial claim - Findingown data
CD4+ T-cell responses were detected in mice treated with CVGBM.
“Of note, CD4+ T-cell responses were detected in mice treated with CVGBM, demonstrating the ability for MHC class II presentation.”
Quote in the paperSubstantial claim - Findingown data
Treatment of naïve C57BL/6 mice with the B16 immunotherapeutic induced T-cell responses against six of the eleven encoded segments.
“Treatment of naïve C57BL/6 mice with the B16 immunotherapeutic induced T-cell responses against six of the eleven encoded segments.”
Quote in the paperSubstantial claim - Findingown data
In CB6F1 mice, CVGBM induced CD4+ T-cell responses against four of the nine antigen segments.
“Results confirmed the functionality of the multi-epitope CVGBM in vivo by inducing CD8+ and CD4+ T-cell responses against two and four of the nine segments, respectively (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data
Immunopeptidomic analysis of two human cell lines transfected with the final CVGBM mRNA confirmed translation and processing of the CVGBM fusion protein.
“Immunopeptidomic analysis of two human cell lines transfected with the final CVGBM mRNA confirmed translation and processing of the CVGBM fusion protein and presentation of four of the six HLA-A*02:01-restricted epitopes on human cells”
Quote in the paperSubstantial claim - Findingown data
The B16 immunotherapeutic induced CD8+ T-cell responses against five segments in naïve C57BL/6 mice.
“CD8+ T-cell responses were observed against five segments and a CD4+ T-cell response against the T-helper epitope PADRE (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
All CVGBM-derived epitopes were detected only in cells transfected with CVGBM mRNA, not in control mRNA-transfected cells.
“All CVGBM-derived epitopes were only detected in cells transfected with CVGBM mRNA.”
Quote in the paperSubstantial claim - Findingown data
The B16 immunotherapeutic induced a CD4+ T-cell response against the T-helper epitope PADRE in naïve C57BL/6 mice.
“CD8+ T-cell responses were observed against five segments and a CD4+ T-cell response against the T-helper epitope PADRE (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
No additional epitopes derived from other parts of the CVGBM fusion protein, such as the epitope junctions, were detected.
“No additional epitopes derived from other parts of the fusion protein, such as the epitope junctions, were detected.”
Quote in the paperNot a substantial claim - Findingown data
No CVGBM-derived HLA class II epitopes could be detected in THP-1 cells by anti-HLA class II pull-down.
“Therefore, an additional pull-down by anti-HLA class II antibodies was performed for the THP-1 cells; however, no CVGBM-derived HLA class II epitopes could be detected (Supplementary Table 2).”
Quote in the paperNot a substantial claim - Findingown data
The B16 immunotherapeutic increased median survival time of B16.F10 tumour-bearing C57BL/6 mice to 31.5 days compared with 23.5 days for control mRNA-LNP treated and 22.4 days for untreated mice.
“The immune response also translated into an anti-tumour effect and increased the median survival time of B16.F10 tumour-bearing C57BL/6 mice to 31.5 days following treatment with the B16 immunotherapeutic compared with 23.5 days and 22.4 days for control mRNA-LNP treated and untreated mice, respectively (Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
The B16 immunotherapeutic induced CD8+ and CD4+ T-cell responses in naïve mice from different parts of the fusion protein, including the N-terminal first (Pmel) and C-terminal last segment (PADRE).
“This B16 immunotherapeutic induced CD8+ and CD4+ T-cell responses in naïve mice from different parts of the fusion protein, including the N-terminal first (Pmel) and C-terminal last segment (PADRE).”
Quote in the paperSubstantial claim - Findingown data
The surrogate B16 immunotherapeutic exhibited anti-tumoural efficacy in B16.F10 tumour-bearing mice.
“Consistently, our surrogate immunotherapeutic exhibited anti-tumoural efficacy in B16.F10 tumour-bearing mice, thus supporting the functionality of CVGBM mRNA and protein design.”
Quote in the paperSubstantial claim - Findingown data
The immunopeptidomic analysis of the two human cell lines transfected with CVGBM mRNA did not detect any presentation of CTLA-4-derived epitopes on HLA molecules.
“However, the immunopeptidomic analysis of the two human cell lines transfected with CVGBM mRNA did not detect any presentation of CTLA-4-derived epitopes on HLA molecules.”
Quote in the paperSubstantial claim - Interpretationreasoning
Evidence of robust and durable efficacy of antigen-based immunotherapeutics in patients with GBM is limited despite the apparently prolonged overall survival in the GAPVAC-101 trial compared with historical controls.
“While these studies demonstrated that antigen-based immunotherapeutics can elicit T-cell responses in patients with GBM, evidence of robust and durable efficacy is limited despite the apparently prolonged overall survival in the GAPVAC-101 trial compared with historical controls.”
Quote in the paperSubstantial claim - Interpretationreasoning
A Phase I clinical trial with CVGBM was started in HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated GBM (NCT05938387).
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-tumour efficacy of the surrogate B16 immunotherapeutic predicts anti-tumour efficacy of CVGBM in GBM.
- Rests on an assumption: Epitope processing and presentation observed in human cell lines reflects that in GBM patients.
- Interpretationown data
Based on the BMDC data, the clinical candidate CVGBM was designed containing the core fusion protein, the CTLA-4 domains, and the E5 degron.
“Based on these data, the clinical candidate CVGBM was designed containing the core fusion protein, the CTLA-4 domains, and the E5 degron (Supplementary Fig. 2c).”
Quote in the paperSubstantial claim - Interpretationreasoning
The TAA-derived epitope approach limits the therapy to patients carrying the HLA alleles to which the epitopes are restricted.
“However, this approach limits the therapy to patients carrying the HLA alleles to which the epitopes are restricted.”
Quote in the paperSubstantial claim - Interpretationreasoning
A high percentage of eligible GBM patients will have tumours presenting CVGBM-encoded epitopes of multiple TAAs.
“As a result of the frequent overexpression of the selected TAAs and the restriction to HLA-A*02:01-positive patients, a high percentage of eligible GBM patients will have tumours presenting CVGBM-encoded epitopes of multiple TAAs, which might increase efficacy of the immunotherapeutic and reduce the risk of immune evasion by antigen loss.”
Quote in the paperSubstantial claim - Interpretationreasoning
There is a risk that the CTLA-4 domains in the CVGBM fusion protein could induce unwanted on-target, off-tumour CTLA-4-specific T-cell responses.
“Consequently, there is a risk that the CTLA-4 domains in the CVGBM fusion protein could induce unwanted on-target, off-tumour CTLA-4-specific T-cell responses.”
Quote in the paperNot a substantial claim - Interpretationcitation
The use of TAA-derived epitopes allows development of an off-the-shelf product for a tumour indication with low mutational burden such as GBM.
“The use of TAA-derived epitopes has the advantage of allowing development of an off-the-shelf product for a tumour indication with low mutational burden such as GBM, where patients’ tumours express only few tumour-specific antigens [38].”
Quote in the paperSubstantial claim - Interpretationown data
The B16 immunotherapeutic results demonstrate the anti-tumoural potential of the protein and mRNA designs used for CVGBM.
“These results demonstrate the anti-tumoural potential of the protein and mRNA designs used for CVGBM.”
Quote in the paperSubstantial claim- Rests on an assumption: The syngeneic B16.F10 melanoma model is a valid surrogate for assessing the anti-tumoural potential of the mRNA and protein designs used for CVGBM.
- Interpretationown data
The detection of CD4+ T-cell responses in mice treated with CVGBM demonstrates the ability for MHC class II presentation.
“Of note, CD4+ T-cell responses were detected in mice treated with CVGBM, demonstrating the ability for MHC class II presentation.”
Quote in the paperSubstantial claim - Interpretationown data
The anti-tumoural efficacy of the B16 surrogate supports the functionality of the CVGBM mRNA and protein design.
“Consistently, our surrogate immunotherapeutic exhibited anti-tumoural efficacy in B16.F10 tumour-bearing mice, thus supporting the functionality of CVGBM mRNA and protein design.”
Quote in the paperSubstantial claim- Rests on an assumption: The syngeneic B16.F10 melanoma model is a valid surrogate for assessing the anti-tumoural potential of the mRNA and protein designs used for CVGBM.
- May combine two claims. 22
- Classified as probably not a substantial claim. 4
May combine two claims.
PremisecitationTumour cell heterogeneity and an immunosuppressive microenvironment contribute to primary GBM immunoresistance, which dampens anti-tumour responses by macrophages and T cells.
“Tumour cell heterogeneity and an immunosuppressive microenvironment contribute to primary GBM immunoresistance, which dampens anti-tumour responses by macrophages and T cells [7, 10].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [7] Habashy KJ, Mansour R, Moussalem C, Sawaya R, Massaad MJ (2022) Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them. Br J Cancer 127:976–987. https://doi.org/10.1038/s41416-022-01864-w source
- cites [10] Wang EJ, Chen JS, Jain S, Morshed RA, Haddad AF, Gill S, Beniwal AS, Aghi MK (2021) Immunotherapy resistance in glioblastoma. Front Genet 12:750675. https://doi.org/10.3389/fgene.2021.750675 source
May combine two claims.
PremisecitationClinical trials of mRNA-based immunotherapeutics encoding unmutated full-length TAAs in checkpoint inhibitor-treated melanoma and individualised mRNA-based immunotherapeutics encoding patient-specific mutated tumour neoantigens in pancreatic and lung cancer have shown encouraging results.
“Clinical trials of mRNA-based immunotherapeutics encoding unmutated full-length TAAs in checkpoint inhibitor-treated melanoma [18] and individualised mRNA-based immunotherapeutics encoding patient-specific mutated tumour neoantigens in pancreatic and lung cancer [19, 20] have shown encouraging results.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [18] Sahin U, Oehm P, Derhovanessian E et al (2020) An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585:107–112. https://doi.org/10.1038/s41586-020-2537-9 source
- cites [19] Gainor JF, Patel MR, Weber JS et al (2024) T-cell responses to individualized neoantigen therapy mRNA-4157 (V940) alone or in combination with pembrolizumab in the phase 1 KEYNOTE-603 study. Cancer Discov 14:2209–2223. https://doi.org/10.1158/2159-8290.Cd-24-0158 source
- cites [20] Rojas LA, Sethna Z, Soares KC et al (2023) Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618:144–150. https://doi.org/10.1038/s41586-023-06063-y source
May combine two claims.
PremisecitationDespite standard of care treatment, GBM recurrence is inevitable and there is no agreed salvage therapy post-recurrence.
“Despite standard of care treatment, GBM recurrence is inevitable and there is no agreed salvage therapy post-recurrence [4, 5].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [4] Wen PY, Weller M, Lee EQ et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol 22:1073–1113. https://doi.org/10.1093/neuonc/noaa106 source
- cites [5] Weller M, van den Bent M, Preusser M et al (2021) EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 18:170–186. https://doi.org/10.1038/s41571-020-00447-z source
In the section on IDH-wild-type glioblastoma (page unavailable), the guideline says standard-of-care treatments for recurrent glioblastoma are not well defined, supporting the claim that there is no agreed salvage therapy. It discusses recurrence but does not state that recurrence is inevitable after standard treatment. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationBoth the GAPVAC-101 and IMA950 immunotherapeutics were well tolerated and induced epitope-specific CD8+ T-cell responses.
“Both immunotherapeutics, which shared some peptides, were well tolerated and induced epitope-specific CD8+ T-cell responses [14, 15].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] Hilf N, Kuttruff-Coqui S, Frenzel K et al (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–245. https://doi.org/10.1038/s41586-018-0810-y source
- cites [15] Migliorini D, Dutoit V, Allard M et al (2019) Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol 21:923–933. https://doi.org/10.1093/neuonc/noz040 source
Classified as probably not a substantial claim.
PremisecitationAntigen-based immunotherapies are designed to induce cytotoxic T-cell responses against antigens expressed by the tumour, such as TAAs over-expressed in tumours compared with healthy tissue, resulting in tumour cell death.
“Antigen-based immunotherapies are designed to induce cytotoxic T-cell responses against antigens expressed by the tumour, for example, tumour-associated antigens (TAAs) that are over-expressed in tumours compared with healthy tissue, resulting in tumour cell death [8, 11].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [8] Desbaillets N, Hottinger AF (2021) Immunotherapy in glioblastoma: a clinical perspective. Cancers (Basel) 13:3721. https://doi.org/10.3390/cancers13153721 source
Section 5.1 (Vaccine Approaches; page unavailable) says tumour-antigen vaccines aim to induce immune responses and that dendritic-cell vaccines can induce antigen-specific T-cell responses. Section 5.4 (Adoptive Cell Transfer and CAR T Cells; page unavailable) describes T cells attacking cancer cells bearing tumour antigens. The copy does not establish the claim’s specific description of TAAs as over-expressed relative to healthy tissue or explicitly state that these responses result in tumour-cell death. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [11] Awuah Andrew W, Shah MH, Tan JK et al (2024) Immunotherapeutic advances in glioma management: the rise of vaccine-based approaches. CNS Neurosci Ther 30:e70013. https://doi.org/10.1111/cns.70013 source
The Glioma Vaccines section says antigen-based vaccines activate cytotoxic CD8+ T cells that can kill tumour cells presenting the targeted antigen. It also identifies tumour-associated antigens as vaccine targets. Our copy does not establish the claim that those antigens are over-expressed in tumours compared with healthy tissue. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationThe cytosolic C-terminal E5 degron has been described to increase protein turnover and proteasomal degradation in the cytosol.
“Additionally, MHC class I loading might be enhanced by the cytosolic, C-terminal E5 degron, which has been described to increase protein turnover and proteasomal degradation in the cytosol [30].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Varshavsky A (2019) N-degron and C-degron pathways of protein degradation. Proc Natl Acad Sci USA 116:358–366. https://doi.org/10.1073/pnas.1816596116 source
The Eukaryotic C-Degron Pathways section describes C-terminal degrons as degradation signals and says that a protein whose C-degron remains exposed faces an increasing probability of destruction. It does not identify an E5 degron or establish that this specific cytosolic degron increases protein turnover and proteasomal degradation. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationImmune evasion can also occur by loss of the required HLA allele or defects in the HLA presentation pathway, although this is less common in GBM than other tumour types.
“However, immune evasion can also occur by loss of the required HLA allele or defects in the HLA presentation pathway, although this is less common in GBM than other tumour types [40].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] Dhatchinamoorthy K, Colbert JD, Rock KL (2021) Cancer immune evasion through loss of MHC class I antigen presentation. Front Immunol 12:636568. https://doi.org/10.3389/fimmu.2021.636568 source
The Introduction and the section on mutation or deletion of structural genes explain that cancers can evade CD8 T cells through loss of MHC I antigen presentation, including loss of MHC I genes. Figure 4 includes GBM among cancers assessed for MHC I loss, but the text of our copy does not establish that loss of a required HLA allele or presentation-pathway defects are less common in GBM than in other tumour types; its frequency comparison concerns MHC I expression more generally. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCTLA-4 is a membrane protein that is targeted by its signal peptide via the ER to the cell surface; from there it is rapidly internalised to endosomes and lysosomal vesicles due to the cytoplasmic domain.
“CTLA-4 is a membrane protein that is targeted by its SP via the ER to the cell surface; from here it is rapidly internalised to endosomes and lysosomal vesicles due to the cytoplasmic domain [42].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] Valk E, Rudd CE, Schneider H (2008) CTLA-4 trafficking and surface expression. Trends Immunol 29:272–279. https://doi.org/10.1016/j.it.2008.02.011 source
The model of CTLA-4 trafficking describes movement to the cell surface followed by rapid AP-2-mediated internalisation to endosomal or lysosomal compartments. The membrane-retention section links this internalisation to a motif in CTLA-4’s cytoplasmic tail. The post-translation section mentions a signal peptide and processing in the endoplasmic reticulum, but does not say that the signal peptide targets CTLA-4 via the ER to the cell surface. Page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationGBM has a low mutational burden, and patients' tumours express only few tumour-specific antigens.
“The use of TAA-derived epitopes has the advantage of allowing development of an off-the-shelf product for a tumour indication with low mutational burden such as GBM, where patients’ tumours express only few tumour-specific antigens [38].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Alexandrov LB, Nik-Zainal S, Wedge DC et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477 source
The Results section ('Mutational catalogues'; page unavailable) reports that certain childhood cancers had the fewest mutations, but does not identify GBM as one of them. Searches for GBM, glioblastoma, and tumour-specific antigens found no passage addressing GBM’s mutational burden or the number of antigens its tumours express. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOne peptide of the CTLA-4 transmembrane domain has been described as present on thymic tissue.
“Indeed, one peptide of the CTLA-4 transmembrane domain has been described as present on thymic tissue [45].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [45] Marcu A, Bichmann L, Kuchenbecker L et al (2021) Hla ligand atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy. J Immunother Cancer 9:e002071. https://doi.org/10.1136/jitc-2020-002071 source
The Results section describes HLA-presented peptides from benign tissues, and the Methods section confirms that thymus samples were analyzed. However, searches for CTLA-4, its alternative name, and transmembrane peptides found no passage identifying a CTLA-4 transmembrane-domain peptide in thymic tissue. (LLM, conf=0.73)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationA murine model system using an HLA-A*02:01-transgenic murine GBM tumour cell line can be transfected with human TAAs and implanted intracranially into immunocompetent HLA-A*02:01-transgenic mice, circumventing the limitation of xenografts.
“Recently, a murine model system was developed that circumvents this limitation by using an HLA-A*02:01-transgenic murine GBM tumour cell line, which can be transfected with human TAAs and implanted intracranially into immunocompetent HLA-A*02:01-transgenic mice [46].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [46] Kilian M, Friedrich M, Sanghvi K et al (2022) T-cell receptor therapy targeting mutant Capicua transcriptional repressor in experimental gliomas. Clin Cancer Res 28:378–389. https://doi.org/10.1158/1078-0432.Ccr-21-1881 source
The Methods sections ‘Mice and cell lines’ and ‘Intracranial tumor cell inoculation’ describe an HLA-A*0201-transgenic murine glioma cell line implanted into the brains of matching mice; the Discussion describes the model as fully immunocompetent and contrasts it with xenografts in immunodeficient mice. The ‘Generation of CicR215W-expressing cell lines’ section shows that the glioma cells were transfected, but with mutant murine Cic, not a human tumour-associated antigen. Page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAdministration of CVGBM to mice induced CD8+ and CD4+ T-cell responses, demonstrating functionality in vivo.
“Administration of CVGBM to mice demonstrated functionality of the immunotherapeutic in vivo by inducing CD8+ and CD4+ T-cell responses.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHEK293T cells transfected with CVGBM mRNA had stronger antibody staining for HBV-001:HLA-A*02:01 complexes than mock-transfected cells, confirming presentation of the HBV-HLA class I epitope derived from the CVGBM fusion protein.
“HEK293T cells, which endogenously express HLA-A*02:01 (Supplementary Table 1), had stronger antibody staining for HBV-001:HLA-A*02:01 complexes after transfection with CVGBM mRNA than mock-transfected cells, confirming presentation of the HBV-HLA class I epitope derived from the CVGBM fusion protein (Fig. 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenCVGBM encodes eight unmutated TAA-derived epitopes selected to cover a large proportion of patients with GBM and concatenated into a fusion protein for optimal epitope presentation.
“CVGBM encodes eight unmutated TAA-derived epitopes that have been selected to cover a large proportion of patients with GBM and are concatenated into a fusion protein for optimal epitope presentation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenThe CVGBM-encoded epitopes comprise five HLA-A*02:01-restricted class I and three HLA-DR-restricted class II T-cell epitopes, as well as a class I reporter epitope.
“These epitopes comprise five human leukocyte antigen (HLA)-A*02:01-restricted class I and three HLA-DR-restricted class II T-cell epitopes, as well as a class I reporter epitope.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe eight TAA-derived epitopes encoded by CVGBM comprise five HLA-A*02:01-restricted class I epitopes and three HLA-DR-restricted class II epitopes.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGBMr-OtherLoc showed ample intracellular HA staining but no Eα presentation.
“This is exemplified by GBMr-OtherLoc, which showed ample intracellular HA staining but no Eα presentation.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationIn an HLA-A*02:01+ patient population, epitopes of the expressed TAAs will also be presented on the tumours of most patients to the immune system, because CVGBM encodes HLA-A*02:01-restricted epitopes for three of the TAAs and a pan-DR-restricted epitope for the fourth TAA (Survivin), which is presented by many HLA class II molecules.
“Importantly, in an HLA-A*02:01+ patient population, epitopes of the expressed TAAs will also be presented on the tumours of most patients to the immune system, as CVGBM encodes HLA-A*02:01-restricted epitopes for three of the TAAs (BCAN, NLGN4X, PTPRZ1) and a pan-DR-restricted epitope for the fourth TAA (Survivin), which is presented by many HLA class II molecules [29].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Widenmeyer M, Griesemann H, Stevanović S et al (2012) Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of vaccinated cancer patients. Int J Cancer 131:140–149. https://doi.org/10.1002/ijc.26365 source
- Rests on an assumption: Epitope processing and presentation observed in human cell lines reflects that in GBM patients.
May combine two claims.
Interpretationnone givenEach CVGBM epitope is present within an antigen segment of 29 amino acids, flanked by amino acid sequences that surround the epitope in the source proteins, allowing similar processing and presentation of the epitopes as per the full-length protein they are derived from.
“Each epitope is present within an antigen segment of 29 aa, flanked by aa sequences that surround the epitope in the source proteins; allowing similar processing and presentation of the epitopes as per the full-length protein they are derived from (Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenThe CVGBM core fusion protein contains an HLA-A*02:01-restricted epitope of HBV as a viral marker peptide, which is expected to induce more robust T-cell responses than the selected self-antigens and can serve as a sensitive reporter for CVGBM immunogenicity.
“The core fusion protein also contains an HLA-A*02:01-restricted epitope of HBV as a viral marker peptide, which is expected to induce more robust T-cell responses than the selected self-antigens and can therefore serve as a sensitive reporter for CVGBM immunogenicity.”
Quote in the paperNot a substantial claim- Rests on an assumption: The HBV reporter epitope induces more robust T-cell responses than the selected self-antigens.
May combine two claims.
InterpretationreasoningPresenting CVGBM-encoded epitopes of multiple TAAs might increase efficacy of the immunotherapeutic and reduce the risk of immune evasion by antigen loss.
“As a result of the frequent overexpression of the selected TAAs and the restriction to HLA-A*02:01-positive patients, a high percentage of eligible GBM patients will have tumours presenting CVGBM-encoded epitopes of multiple TAAs, which might increase efficacy of the immunotherapeutic and reduce the risk of immune evasion by antigen loss.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe potential to induce strong CD8+ T-cell responses is particularly relevant for an antigen-based immunotherapeutic for GBM, where chemotherapy and radiotherapy remain standard of care and induced T cells must cross the blood-brain barrier to invade the immunologically cold tumour.
“Since cytoreductive therapy significantly impairs the immune system [37], the potential to induce strong CD8+ T-cell responses is particularly relevant for an antigen-based immunotherapeutic for GBM, where chemotherapy and radiotherapy remain the standard of care, and induced T cells must cross the blood–brain barrier to invade the immunologically “cold” tumour.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe absence of detected CVGBM-derived HLA class II epitopes is likely due to low expression of HLA class II molecules on THP-1 cells or the overall lower number of recovered HLA class II than HLA class I epitopes.
“likely due to low expression of HLA class II molecules on THP-1 cells or the overall lower number of recovered HLA class II than HLA class I epitopes (Supplementary Table 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIn vivo functionality of CVGBM was confirmed in mice, with epitope-specific CD8+ and CD4+ T-cell responses induced.
“Finally, in vivo functionality of CVGBM was confirmed in mice, with epitope-specific CD8+ and CD4+ T-cell responses induced.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe epitope-specific T-cell responses in mice, although directed against epitopes presented on mouse MHCs that differ from human HLAs, confirm the accurate translation of CVGBM mRNA into the encoded fusion protein and presentation of epitopes from different parts of the fusion protein on MHC class I and II molecules.
“While these responses were directed against epitopes presented on mouse MHCs that differ from the epitopes presented on human HLAs, they confirm the accurate translation of CVGBM mRNA into the encoded fusion protein and presentation of epitopes from different parts of the fusion protein on MHC class I and II molecules.”
Quote in the paperSubstantial claim
The paper relies on this without support.
CVGBM requires an intact immune system for its mode of action.
“As CVGBM requires an intact immune system for its mode of action, it could not be tested in xenograft models.”
The paper relies on this without support.
Anti-tumour efficacy of the surrogate B16 immunotherapeutic predicts anti-tumour efficacy of CVGBM in GBM.
“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.”
The paper relies on this without support.
Epitope processing and presentation observed in human cell lines reflects that in GBM patients.
“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.”
The paper relies on this without support.
The HBV reporter epitope induces more robust T-cell responses than the selected self-antigens.
“The core fusion protein also contains an HLA-A*02:01-restricted epitope of HBV as a viral marker peptide, which is expected to induce more robust T-cell responses than the selected self-antigens and can therefore serve as a sensitive reporter for CVGBM immunogenicity.”
The paper relies on this without support.
Human GBM xenografts cannot be established in immunocompetent mouse models.
“The anti-tumoural efficacy of CVGBM could not be tested in immunocompetent mouse models as they do not allow human GBM xenografts.”
The paper relies on this without support.
CVGBM requires immunocompetent animals for its mode-of-action.
“while CVGBM requires immunocompetent animals for its mode-of-action.”
The paper relies on this without support.
The syngeneic B16.F10 melanoma model is a valid surrogate for assessing the anti-tumoural potential of the mRNA and protein designs used for CVGBM.
“For the present study, however, the syngeneic murine B16.F10 melanoma model was used instead to test the anti-tumoural potential of the mRNA and protein designed used for CVGBM.”
The paper relies on this without support.
LNP-formulated mRNAs with unmodified nucleotides also induce CD4+ T-cell responses.
“They primarily induce CD8+ T-cell responses [22], which can exceed those induced by LNP-formulated mRNAs with modified nucleotides [34, 35], as well as CD4+ T-cell responses.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
GBMr variant count changes from six to five
MinorThe design section says six GBMr fusion protein variants were generated, but the results describe five different GBMr proteins. The design section also names only five variants.
“The core fusion protein was used to generate six different fusion protein variants with reporters (GBMr), enabling in vitro evaluation of protein translation and epitope presentation (Supplementary Fig. 2b).”
“Flow cytometry results demonstrated similar staining of SIINFEKL/MHC class I complexes on the surface of BMDCs 9 h after transfection with mRNAs encoding the five different GBMr proteins (Fig. 2a).”
HLA restriction summary omits BCAN class II epitope
MinorThe discussion assigns BCAN epitopes to the HLA-A*02:01-restricted group and identifies BIRC5 as the HLA-DR-restricted source, but Table 1 also lists a pan-DR-restricted BCAN epitope.
“the epitopes selected for CVGBM were either restricted to HLA-A*02:01 (BCAN, PTPRZ1, NLGNX4) as the most frequent MHC class I allele in the Caucasian population (up to 50% of individuals bearing this allele according to the allele frequency net database [39]), or to various HLA-DR alleles (BIRC5).”
“| BCAN | Q96GW7 | VKVNEAYRFRVALPAYPA | BCA-005 | pan-DR | II | VARGVR(VKVNEAYRFRVALPAYPA)SLTDV | aa 92–120 |”
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Immunotherapy in Glioblastoma: A Clinical Perspective
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- Authors
- Lutz, J., Feist, R. K., Sonntag, T., Peguero-Sánchez, E., Wolter, K., Bick, R., Bauer, J., Walz, J. S., & Heidenreich, R.
- Affiliations
- CureVac (Germany) (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Lutz, Johannes
- ORCID
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2025-10-06
- Volume
- 74
- Issue
- 11
- Pages
- 329-329
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC12500496
- OpenAlex
- W4414854158
- Semantic Scholar
- 4b5a8c524488ccff67e8b9b11cde58f57fab3b76
- Cited by
- 9
- References
- 47
- Citations by year
- 2026: 9
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cancer Immunology Immunotherapy (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- PubMed Central (submittedVersion, cc-by)
- Funders
- CureVac SE
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- glioblastoma, tumor-associated antigens, lipid nanoparticles, HLA-A*0201, HLA class II epitopes, immunopeptidomics, CD8+ T cell responses, CD4+ T cell responses, B16F10 melanoma, MGMT unmethylated
- MeSH terms
- Animals, Antigens, Neoplasm, Brain Neoplasms, Female, Glioblastoma, Humans, Immunotherapy, Mice, Inbred C57BL, RNA, Messenger, Epitopes, T-Lymphocyte, Cancer Vaccines, Cell Line, Tumor, Mice, Nanoparticles
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