Abstract 1518: Dose optimization and radiation dosimetry of CD45-targeting 225Actinium-armed antibody as a conditioning agent for adoptive cell therapy
Notice bibliographique
Résumé
Abstract Background: Bone marrow transplantation, ex vivo gene therapies targeting hematological disorders, and other forms of adoptive cell therapies (ACT) require complete or partial removal of the host immune cells by a process called conditioning. This is usually accomplished with total body irradiation (TBI) or chemotherapy, but both modalities can result in significant toxicities, especially in elderly patients. As a result, more effective and safe alternatives to TBI and chemotherapy for conditioning prior to ACT are therefore needed. We have recently demonstrated that the murine CD45-targeting antibody 30F11 armed with the beta emitters 131Iodine or 177Lutetium successfully eliminated various cohorts of immune cells in murine models and ensured effective tumor control during adoptive T cell therapy (Dawicki W., et al. Oncotarget 2020). Here we report the results of a dose optimization study and radiation dosimetry results for 30F11 antibody labeled with the powerful alpha emitter 225Actinium (225Ac). Methods: Female C57BL/6 mice were treated with a broad dose range of 225Ac-30F11 antibody (100-500 nCi per mouse). Survival of mice was observed for 25 days post treatment, and white blood cells (WBC), red blood cells (RBC) and hematopoietic stem cells (HSC) were enumerated by flow cytometry. The cellularity of bone marrow in surviving mice was assessed histologically. Radiation dosimetry calculations were performed to yield the doses delivered to the various organs including those with significant numbers of immune cells. Results: The survival study demonstrated that all mice receiving 100 and 250 nCi doses of 225Ac-30F11 survived, 40% survived with 300 nCi, and 0% with the 400 and 500 nCi doses. While the 500 nCi group showed signs of radiation toxicity, the 100-400 nCi doses had no effect on RBC and preserved liver and kidney function. Flow cytometry and histology revealed that up to 30% of WBC and HSC were lost in the 100-250 nCi group, up to 70% in the 300 nCi group and almost complete acellularity of bone marrow was observed in 400 nCi group. Radiation dosimetry calculations determined the absorbed doses to immune organs such as bone marrow and spleen were comparable to those for beta emitters, while the doses to other organs were lower than for beta emitters. Conclusions: This study demonstrates that low doses of an 225Ac-armed CD45-targeting antibody can safely and efficiently reduce the numbers of host immune cells which would be sufficient for gene therapy or adoptive T cell therapy while high doses can completely eliminate host immune cells, thus providing the conditions for bone marrow transplant engraftment and expansion. Citation Format: Ravendra Garg, Qing Liang, Eileen M. Geoghegan, Kevin J. Allen, Wojciech Dawicki, Dale L. Ludwig, Ekaterina Dadachova. Dose optimization and radiation dosimetry of CD45-targeting 225Actinium-armed antibody as a conditioning agent for adoptive cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1518.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».