image: IFNβ-induced AML-cell cytotoxicity is enhanced with anti-CD38 antibody daratumumab. (A-C) AML cell lines (MV-411, n = 9 experiments and OCI-AML3, n = 7 experiments) and primary AML apheresis samples (n = 3) were treated with or without 1000 U/mL IFNβ for 24 h and then incubated with opsonized sheep red blood cells. Phagocytosis was evaluated via microscopy in a blinded fashion. The phagocytic index represents the number of red blood cells ingested by 100 AML cells for each respective cell line. (D) OCI-AML3 cells (n = 7 experiments) were treated with or without anti-CD38 antibody (α-CD38, 20 μg/mL), IFNβ (500 U/mL), or α-CD38 + IFNβ for 48 hours. Cytotoxicity was then measured using a Lactate Dehydrogenase Assay. (E and F) MV4-11 cells (n = 6 experiments) were treated with IFNβ (500 U/mL) for 48 hours. Cells were then plated on methocult™-media-containing plates for 10 days, then colonies counted in a double-blinded fashion. (G) Current working model, as described in the text. *p ? 0.05.
Oncotarget published "Activation of plasmacytoid dendritic cells promotes AML-cell fratricide" which reported that Interferons have been previously shown to aid in the clearance of AML cells. Type I interferons are produced primarily by plasmacytoid dendritic cells. However, these cells exist in a quiescent state in AML.
In addition, the authors showed increased expression of the immune-stimulatory receptor CD40. Then they next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab.
These Oncotarget findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.
These Oncotarget findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed
Dr. Jonathan P. Butchar and Dr. Susheela Tridandapani both from The Ohio State University said, "Acute Myeloid Leukemia (AML) is associated with defective innate and adaptive immune responses, as is seen with other malignancies."
Type I and Type II interferons have previously been tested in clinical trials for AML.
However, Type I interferons have not been examined as a dual-treatment with anti-CD38 within the context of AML.
Type I and Type II interferons signal through distinct pathways but there is also sufficient overlap to suggest that they may be of benefit when combined with daratumumab, and with fewer potential toxicities.
pDCs express TLR 7-9 and are able to produce many cytokines including TNF-α, CXCL8, and IL-6, but most importantly Type I Interferons after TLR stimulation.
In agreement with previous studies we found that R848 led to higher expression of CD40.
Notably, it also increased IFNβ production by AML-patient pDCs, and this induced an upregulation of CD38 in AML cells.
The Butchar/Tridandapani Research Team concluded in their Oncotarget Research Output, "we report a novel mechanism of inducing the effector-like AML cell phenotype by reprogramming AML-patient pDCs to produce IFNβ through TLR stimulation. This can lead to upregulation of CD38 on AML cells and can enhance antibody-mediated fratricide of AML cells. These findings suggest that the use of either IFNβ or IFNβ-inducing agents in combination with an anti-CD38 therapeutic antibody could likely offer a new therapeutic option for AML."