Abstract A176: Efficacy and safety of allogeneic double negative T cell as anti-AML therapy and its underlying mechanism
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".