Abstract PR010: Developing a safe and potent tumor-targeting gated CAR-T cell therapy for DIPG: A deadly pediatric brain tumor
Notice bibliographique
Résumé
Abstract Background: DIPG (Diffuse Intrinsic Pontine Glioma) is an aggressive pediatric brain tumor that infiltrates the pons and is uniformly fatal. Curative surgery is not possible, radiation therapy provides only temporary relief, and chemotherapy is not effective. There is a great interest in applying Chimeric Antigen Receptor (CAR) expressing T cells and CAR-T cell strategies to solid tumors like DIPG; however, doing so will require novel approaches in CAR-T cell design to make this therapy effective. We recently identified CD99 as a highly expressed antigen in DIPG cells and an immunotherapy target in DIPG. A major obstacle in CAR-T cell therapy for solid tumors is the absence of true “tumor only” antigens, as most antigens are shared among multiple normal cells. CD99 is expressed in other normal cells. Therefore, combinatorial targeting of numerous antigens has the potential to overcome the lack of tumor-specific antigens. Hypothesis: Given that DIPG cells uniquely express the combination of B7-H3 and CD99 at high levels, we propose that CAR-T cells capable of specifically recognizing this combination will offer specificity to DIPG cells while safeguarding normal tissues expressing either antigen alone. We then developed a novel bicistronic CAR construct that employs Boolean logic to 'gate' the function of CAR-T cells according to 'AND' rules, where two distinct antigens are necessary for CAR-T cell activation. In our model, we used our novel CD99 CAR (based on 10D1-antibody-based ScFv) in conjunction with B7-H3 CAR (enoblituzumab antibody-based scFv). We created two 'AND' CAR-T cells using different co-stimulatory domains and successfully tested the specificity and functionality of our 'AND' CARs. Results: The “AND” CAR-T cells 1) showed enhanced tumor cell killing when co-cultured with DIPG tumor cells; 2) demonstrated no functionality against either single antigen-expressing cells, suggesting the specificity of the AND CAR-T in targeting dual-antigen-expressing tumor cells and 3) a single low dose of “AND” CAR-T cells delivered either IV or intrathecally completely cleared DIPG in the murine models with a significant increase in animal survival while either antigen targeting monovalent CAR-T cells showed only temporary clearance of tumor as the tumor relapsed after treatment. In addition, during the meeting, we will discuss the results obtained concerning the potency of the “AND” CARs developed against DIPG tumors. Topics will include the engineering design of the “AND” CAR-T cells to overcome CD99-driven fratricide, increased CAR-T persistence in vivo, and the mechanism behind the enhanced efficacy of our “AND” CAR-T cells against heterogeneously expressed tumor target antigens. Conclusion: The results from this study will significantly advance the development of effective immunotherapy for patients with DIPG. It emphasizes the importance of target antigen density heterogeneity and employs logic-gating to enhance tumor clearance and increase specificity, thereby reducing the risks associated with targeting shared antigens. Citation Format: Sujatha Venkataraman, Ilango Balakrishnan, Lillie Leach, Krishna Madhavan, Angela Pierce, Joshua Michlin, Joshua Obrecht, Breauna Brunt, Terry Fry, Rajeev Vibhakar, Eric.M Kohler. Developing a safe and potent tumor-targeting gated CAR-T cell therapy for DIPG: A deadly pediatric brain tumor [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 PR010.
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 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) | 0,001 | 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; 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 ».