Our long-term goal is to define a new mechanism of killing in the context of antibody therapy in Acute Myeloid Leukemia. Acute Myeloid Leukemia (AML) AML is the most common acute leukemia in adults, causing over 10,500 deaths in 2015 with more than 20,800 people diagnosed. The proposed research will help develop a new AML therapeutic that makes use of a novel mechanism of tumor-cell killing. AML blasts are of an immature phenotype but the possibility exists that these cells can be coaxed toward taking on phagocytic/cytotoxic properties. Here, we show that IFN? is able to drive AML blasts toward a more differentiated state, in which they express the M1-related markers CD80 and CD86, as well as Fc? receptor I (Fc?RI), which mediates effector responses to therapeutic antibodies. Additionally, IFN? is able to up-regulate CD38, the target of the therapeutic antibody daratumumab, which is now used for multiple myeloma and is in testing for AML. Because IFN? can up-regulate both Fc?RI and CD38 on AML cells and skew them away from a tumor-supportive role, we hypothesize that treatment of AML blasts with IFN? promotes cell-to-cell killing, or fratricide, within the context of antibody therapy. In support of this hypothesis, we have demonstrated that AML cells treated with IFN? could target one another after the addition of daratumumab, as measured by a chromium-release assay. Thus our aims are to 1) identify the molecular mechanism of CD38 up-regulation by IFN?, and the subsequent fratricide between AML cells and 2) test whether IFN? in the context of anti-CD38 antibody therapy can help treat AML in vivo. Successful completion of this project will significantly further our understanding of this novel mechanism of antibody-mediated killing, and will help to determine the possibility of pursuing this induced fratricide as a new AML therapeutic.
This application seeks to understand a novel mechanism of antibody-mediated killing wherein acute myeloid leukemia (AML) cells target and kill one another after treatment with the immune-stimulatory cytokine Interferon-?. We propose to interrogate the mechanisms behind this phenomenon and also test whether it can occur in vivo. Successful completion of these proposed studies will provide mechanistic and in-vivo evidence that may warrant the pursuit of this treatment as a potential therapeutic modality for AML.
| Fatehchand, Kavin; Santhanam, Ramasamy; Shen, Brenda et al. (2017) Active hexose-correlated compound enhances extrinsic-pathway-mediated apoptosis of Acute Myeloid Leukemic cells. PLoS One 12:e0181729 |
