PROJECT SUMMARY

MDS and AML are myeloid malignancies associated with disease initiating stem cells that are not eliminated by conventional therapies. We and others recently demonstrated that hematopoietic stem cells (HSC) are aberrantly expanded in MDS/AML, can persist during phenotypic remissions and can predict relapse. Thus, novel therapeutic targets against such (pre-)leukemic stem cells need to be identified for potentially curative strategies. In preliminary studies, we found Interleukin 8 (IL8) to be consistently overexpressed in stem cells from MDS patients. The receptor for IL8, CXCR2, was also significantly increased in a large cohort of MDS stem cells (N=183) and was predictive of increased transfusion dependence, a key clinical feature of patients with MDS . High CXCR2 expression was also associated with worse survival in a large cohort of patients with AML. Importantly, inhibition of the IL8/CXCR2 pathway with a chemical drug selectively inhibited immature stem cells from MDS/AML samples without an effect on healthy stem cells.

In the last two year we tested the efficacy of a clinically applicable IL8 antibody (HuMax-IL8) against a large number of primary MDS/AML marrow samples. We determined that treatment with this antibody led to inhibition of MDS stem cells and encouraged differentiation to mature cells. We also saw encouraging effects in mouse models of MDS that were treated with this antibody. Furthermore, we showed that high levels of IL8 correlate with stage of the disease. Based on these exciting data, we now propose to test the efficacy of this antibody in a large number of MDS samples both in vitro and in vivo. Responses will be correlated with clinical and mutational subtypes to identify subsets that will be sensitive to IL8/CXCR2 inhibition. Since Hu Max IL8 is safe for human use we hope that these studies may lead to clinical trials in MDS that will target disease initiating stem cells in this disease.