Abstract 3972: Carpet bombing with CARs: Influence of dose, timing, lymphodepletion and costimulatory domain on efficacy of mRNA engineered anti-CD19 Chimeric Antigen Receptor T cells in preclinical xenograft models.
Notice bibliographique
Résumé
Abstract T cells engineered to express chimeric antigen receptors (CARs), consisting of an anti-tumor targeting domain fused to Signal 1 and 2 activation domains, are a promising approach to cell therapy. We compared T cells engineered to stably express CARs using integrating viral vectors with T cells transiently expressing CARs via direct transduction with non-integrating mRNA. In early clinical testing, this CAR design using lentiviral transduction has been tested in patients with advanced CLL and relapsed ALL. Dramatic clinical responses have been observed in these refractory patients, speaking to the power of this approach. Transient expression has several advantages: i) short-term expression may allow initial clinical testing while limiting toxicity, and ii) RNA is easier to manufacture and modify, expediting manufacturing and scaling to GMP of changing CAR designs, allowing rapid iterative testing of and improvements to CAR design. To evaluate the in vivo efficacy of mRNA CAR+T cells compared to permanently modified (lentiviral transduction) T cells, we used xenograft models of human ALL (Nalm-6 and a primary patient leukemia, both CD19+) and high-level human T cell engraftment. NSG mice were injected with ALL at a dose producing 100% BM engraftment by 5d with 100% mortality by 25d (Nalm-6) or 36d (Primary). T cells were expanded ex vivo using CD3/CD28 beads and underwent lentiviral gene transfer or mRNA electroporation. Short-term efficacy of a single dose of mRNA vs. lentiviral CAR+ T cells was similar, and unlike permanently modified CAR T cells the costimulatory domain (CD28, 41BB or both) in mRNA engineered cells had no effect on efficacy in this model. Interval lymphodepletion with cyclophosphamide (CTX, 60mg/kg1) significantly improved efficacy with subsequent infusions of RNA CAR T cells. Neither CTX nor untargeted repeat CAR T cells infusions alone had an effect on leukemia burden or survival. While lentiviral CAR+ T cells persisted and were able to demonstrate a memory response on leukemia rechallenge, median overall survival was not different between repeat mRNA CARs (80d) and a single dose of lentiviral transduced CARs (77d). Importantly, both models produced long term (>120 days) survivors, suggesting that repeat infusion of RNA CAR T cells with interval lymphodepletion may approximate the efficacy of permanently modified T cells in this liquid tumor model. In our clinical experience with permanently modified cells, disease clearance happens over 14-21 days, which correlates with the window of efficacy of mRNA CARs. This suggests that though they do not persist, mRNA CARs may have significant potential for clinical efficacy. These pre-clinical results demonstrate an important advance in T cell engineering, and are leading directly to clinical trials testing mRNA CAR CTLs. Citation Format: David M. Barrett, Yangbing Zhao, Xiaojun Liu, Shuguang Jiang, Gregor S D Reid, Alix E. Seif, Carl H. June, Stephan A. Grupp. Carpet bombing with CARs: Influence of dose, timing, lymphodepletion and costimulatory domain on efficacy of mRNA engineered anti-CD19 Chimeric Antigen Receptor T cells in preclinical xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3972. doi:10.1158/1538-7445.AM2013-3972
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) | 0,001 | 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) | 0,002 | 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 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 ».