Abstract A176: Efficacy and safety of allogeneic double negative T cell as anti-AML therapy and its underlying mechanism
Notice bibliographique
Résumé
Abstract Acute myeloid leukemia (AML) is the most common form of adult acute leukemia that is associated with a low long-term survival rate. While chemotherapy achieves remission in the majority of AML patients, many relapse due to residual chemotherapy-resistant AML populations. Allogeneic hematopoetic stem cell transplantation is a potential curative treatment for AML that demonstrates the efficacy of a cell-mediated treatment for chemotherapy-resistant disease. However, its wide application is limited by suitable donor availability and associated toxicity such as graft-versus-host disease (GvHD). Hence, there is a need for a new treatment approach that targets chemotherapy-resistant AML blasts with minimal side effects. The goals of this study were to characterize allogeneic CD3+CD4-CD8- double negative T (DNT) cells as a potential new target of treatment for AML patients, including ones that are resistant to chemotherapy, and to dissect its underlying mechanisms. Using two-hour flow cytometry-based in vitro killing assay, we demonstrated that the allogeneic DNT cells expanded from healthy volunteers were cytotoxic against 23/29 primary AML patient blasts in a dose-dependent manner. Of those, 13 blasts were obtained from chemotherapy refractory or relapsing AML patients and nine of them were susceptible to DNT cells. The anti-leukemia activity of DNT cells was further validated in a AML-NSG xenograft model: a single infusion of DNT cells into mice pre-engrafted with primary AML blasts from chemoresponsive, chemorefractory, and relapsed patients significantly reduced the leukemia burden. Although residual blasts were observed from DNT cell-treated group, they did not develop resistance to DNT cells, as they remained susceptible to DNT cells in ex vivo killing assay. Further, we demonstrated the safety of allogeneic DNT cells, as DNT cells did not target allogeneic peripheral blood mononuclear cells (PBMC) and hematopoietic stem/progenitor cells (HSPC) in vitro. In addition, administration of allogeneic DNT cells into NSG mice, engrafted with human HSPC, had no effect on the engraftment level of human hematopoetic cells and their differentiation into different lineages. Further, infusion of human DNT cells did not cause xenogeneic GvHD in mice, collectively demonstrating the safety of allogeneic DNT cells. Using blocking assays, we showed the roles of HLA-class I, NKG2D, and DNAM-1 in DNT cell-mediated cytotoxicity against AML, whereas HLA-class II and T cell receptor were not involved. While IFNγ release correlated with cytotoxicity of DNT cells, IFNγ treatment alone did not induce AML cell death. Neutralizing IFNγ reduced susceptibility to DNT cell-mediated cytotoxicity while pretreating AML with recombinant IFNγ increased their susceptibility by inducing higher expression of NKG2D and DNAM-1 ligands, where NKG2D- and DNAM-1-blocking antibodies abrogated the effect of IFNγ pretreatment. Cytolytic activity of DNT cells was mediated in perforin-granzyme-dependent fashion, which subsequently activated caspase-8 and caspase-9 pathways in AML cells to induce AML cell death. Collectively, these studies demonstrated the safety and efficacy of allogeneic DNT cell therapy as a potential treatment for AML patients, including those with chemotherapy-resistant leukemia, and revealed important molecules for the anti-leukemia activity of DNT cells. Citation Format: Jong Bok Lee, Claire Weihsu Chen, Mark D. Minden, John E. Dick, Li Zhang. Efficacy and safety of allogeneic double negative T cell as anti-AML therapy and its underlying mechanism. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A176.
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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) | 0,002 | 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 ».