1435 Therapeutic mRNA cancer vaccine for GBM reaches complete response in a preclinical model
Notice bibliographique
Résumé
<h3>Background</h3> Glioblastoma (GBM) is a fatal cancer that has limited response to chemotherapy and radiotherapy. Immunotherapy for GBM has been challenging due to low frequency of neoantigens and immunosuppressive tumor microenvironment. Here we report the efficacy of a novel EGFRvIII mRNA vaccine formulated in next generation lipid nanoparticles (LNP). EGFRvIII is a cancer-driver mutation detected in approximately 30% of GBM patients, it appears as an in-frame epidermal growth factor receptor (EGFR) deletion generating a constitutively active oncogenic protein therefore considered a neoantigen driver mutation. <h3>Methods</h3> A GBM implantable cell line was generated from C3H/HeJ mice by <i>in vivo</i> electroporation to introduce genetic alterations of EGFRvIII-OE, CDKN2A-KO and PTEN-KO into periventricular cells of early postnatal mice. Resulting tumors were propagated in vitro to create cell lines. Following orthotopic implantation in 6-week-old C3H/He mice resulted in syngeneic tumors that recapitulate histologic features of GBM and caused mortality of mice by day 30. Using this GBM model, mice were intramuscularly vaccinated with either formulation buffer (fb) or EGFRv-III mRNA-LNP on day 7or 10 post tumor implantation. Four more immunizations were done before MR imaging. Mice were monitored until day 150. Brains were fixed for histological evaluation and immuno-histochemistry to determine lymphocytes, macrophages and tumor cells. T cells from spleen, and lymph nodes were analyzed to determine KLRG1, IL-7R, PD1, Ly108, CD44 and CD62L populations by flow. Anti-EGFRvIII abs were determined by ELISA. In situ spatial profiling with 10x Xenium was done in tissues for a panel of immunological markers. <h3>Results</h3> Vaccinated mice cleared tumors with no detection by histology or MRI and stayed tumor free until day 150. In contrast, control mice were diseased by day 36. Moreover, surviving vaccinated mice re-challenged on day 42 with the tumor cells, controlled the tumor with no evidence of tumor growth until day 150. The vaccination regimen induced specific EGFRvIII T cells, high numbers of Ly108+ T cells and high amounts of anti EGFRvIII antibodies. T cells are detected in brain tissue of vaccinated mice. LNP mechanism of action involved in the tumor control will be discussed. <h3>Conclusions</h3> An mRNA vaccine encoding a driver mutation in a new LNP induce an immune response that clears tumors in 100% of mice with a high-grade glioma. The vaccine induced strong T cell and antibody responses involved in controlling tumor progression. These new LNP will help progress the development of cancer vaccines for solid tumors and difficult to treat cancers.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».