Abstract A019: Chimeric antigen receptors (CARs) as a low-impact treatment of pediatric ependymomas
Notice bibliographique
Résumé
Abstract Ependymoma is the third most common paediatric brain tumor and can occur anywhere along the neuroaxis, the most common location being the posterior fossa (PF). Surgery followed by radiation therapy (>4 years of age) is to date the most effective treatment regimen; chemotherapy is not part of the current standard of care as multiple clinical trials have failed to show any survival benefits. Despite extensive characterization of ependymoma, few credible oncogenes and tumor suppressor genes have been identified, in fact, up to 50% of PF ependymoma cases exhibit a balanced and bland genomic profile. Consequently, actionable mutations are not currently identifiable in the vast majority of cases. We are investigating candidate chimeric antigen receptor (CAR)- strategies to treat posterior fossa-A ependymoma (PFA) — a subtype that has the worst associated prognosis and is found predominately in infants. Probing of our extensive ependymoma gene expression dataset has identified several potential CAR target antigens, including HER2, EPHA2 and IL13Rα2, these have been further verified with tissue microarrays (TMAs). Using our orthotopic xenograft models of PFA ependymoma, we are confident from our preliminary analysis that HER2-positive PFA ependymomas respond to HER2-specific CAR treatment. Furthermore, the use of a TRI-CAR, tailored to target cells expressing EPHA2, IL13Rα2 and HER2, both collectively and independently, increases the efficacy and specificity as a therapy for both primary and recurrent ependymoma. To ensure we are using the most effective negative controls when confirming the therapeutic response of our CARs, we are silencing our genes of interest in our patient-derived ependymoma lines using shRNA and CRISPR-technology for HER2, EPHA2 and IL13Rα2. Whole-genome and whole-exome sequencing has demonstrated, that in comparison to PFB ependymomas, PFA tumors have more methylated CpG sites, and more genes that are transcriptionally silenced by CpG hypermethylation. To reduce this silencing and potentially improve therapeutic response to our CARs, we are using Azacitadine in combination with our CAR therapies. In parallel with our pre-clinical trials, we are performing safety trials to assess the administration of intravenous versus intrathecal HER2 CAR delivery. Patients presenting with a brain tumor frequently present with a leaky blood-CSF and blood-Brain barrier, therefore we aim to observe whether CARs injected intrathecally can be found within the blood and vice versa. Using a HER2 Copy Number Assay, we observed two significant results: firstly, HER2 CARs injected intrathecally, in the presence of a HER2-positive brain tumor, remain within the central nervous and are not found within the blood; secondly, HER2 CARs administered intraventrically in the presence of a HER2-positive brain tumor, migrate to the CSF (P = 0.009). Results from this project have the potential to create a paradigm shift in our approach to the treatment of ependymoma, including the initiation of a clinical trial for children with PFA ependymoma. This technology has the real potential to improve cure rates whilst also dramatically improving the quality of life for surviving patients by reducing the impact that current treatments have on normal brain development. Citation Format: Laura K. Donovan, Kevin J. Bielamowicz, Alex Manno, Nabil Ahmed, Michael D. Taylor. Chimeric antigen receptors (CARs) as a low-impact treatment of pediatric ependymomas [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A019.
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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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
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; les deux têtes enseignantes s’accordent sur ce qui est montré ici.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».