Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches.
Amanda C PrzespolewskiScott PortwoodEunice S WangPublished in: Leukemia & lymphoma (2021)
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-β. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased in vivo disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.
Keyphrases
- acute myeloid leukemia
- dendritic cells
- regulatory t cells
- immune response
- cell cycle arrest
- allogeneic hematopoietic stem cell transplantation
- cell death
- endoplasmic reticulum stress
- innate immune
- dna damage
- induced apoptosis
- oxidative stress
- cell cycle
- high fat diet induced
- risk factors
- pain management
- working memory
- magnetic resonance imaging
- stem cells
- wild type
- toll like receptor
- cell therapy
- mesenchymal stem cells
- cell proliferation
- signaling pathway
- contrast enhanced
- bone marrow