Abstract IA015: GD2-specific CAR T cell therapies for pediatric solid cancers
Notice bibliographique
Résumé
Abstract Glycolipid GD2 is an attractive immune target in neuroblastoma. Monoclonal antibodies against GD2 are approved agents for the consolidation of remissions but can not eradicate measurable disease. GD2 was the first target for CAR-engineered T cells addressed in a pediatric cancer, with a reassuring safety profile and individual remissions in first-in-human clinical investigation and durable complete responses with advanced CAR designs. However, the activity of GD2 CAR T cell therapy remains limited to proportions of patients with low burden disease. Major hurdles are local barriers in the tumor microenvironment that impede therapeutic immune responses. One potential solution are CAR T cell designs with engineered secretion of activating cytokines that increase numbers of tumor-infiltrating T cells, enhance their potency within an immunosuppressive tumor milieu and activate and/or reprogram bystander cells for a concerted antitumor immune response. Our group has developed a novel investigational medicinal product, GD2-specific autologous CAR T cells with CAR-inducible secretion of cytokine IL-18, a potent danger signal with an important physiological role in antiviral immune defense. This product had superior in vivo antitumor activity compared to a control construct without IL-18 in preclinical work and has now entered clinical investigation in pediatric cancer patients (EU CT 2022-501725-21-00). Besides neuroblastoma, further cancers can express GD2 at antigen densities sufficient to trigger CAR-induced effector cell responses. In the pediatric population, this includes bone sarcomas (Ewing sarcoma, osteosarcoma) and various CNS cancers such as diffuse midline gliomas and medulloblastoma. To enable selection of patients with adequate GD2 expression for inclusion into GD2 CAR T cell trials, we have established an immunofluorescence-based assay that allows reproducible and robust detection of the glycolipid in paraffine-embedded tissue sections. Moreover, we have found that epigenetic modulation with a clinically approved inhibitor of methyltransferase EZH2 can selectively upregulate GD2 in Ewing sarcoma to high, targetable densities both in vitro and in vivo, potentially extending the applicability of GD2-targeted immunotherapies to patients with initially GD2-negative or low disease. Still, to advance GD2-targeted CAR T cell therapies to their full potential, advanced designs and combination strategies are needed to enable higher and prolonged performance. Early clinical trials with insights into the pre- and posttherapeutic tumor microenvironment will allow to gain knowledge on the biological effects of novel CAR T cell designs to inform future improvements. While the safety and preliminary efficacy of innovative cell-therapeutic agents are being evaluated in early-phase trials, investigators in the well-established international Pediatric Oncology networks must begin to consider academia-driven solutions for the subsequent development and distribution of these complex cell-based therapeutics for the benefit of all patients. Citation Format: Claudia Rossig. GD2-specific CAR T cell therapies for pediatric solid cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA015.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,004 | 0,002 |
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 source (Gemma direct ou Codex distillé), 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 ».