Harry Dolstra, Jeannette Cany and Michel Schaap, from the departments of Laboratory Medicine and Hematology have received a 567 kE KWF Grant for translational NK cell research.
Adoptive NK cell transfer combined with DNA methyltransferase inhibition: a double attack against acute myeloid leukemia.
Incidence of acute myeloid leukemia (AML) increases with age, with more than 60% of patients being older than 60 years. Complete remission can be achieved after intensive chemotherapy, but prognosis remains poor due to high relapse rate. Especially, in the older AML population many patients relapse and a minority of the patients are still alive after 5 years. Although, allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning is increasingly adopted for the treatment of older patients with AML, the incidence of relapse as well as non-relapse mortality are still high. Natural killer (NK) cell-based immunotherapy is a promising adjuvant, relatively non-toxic therapy approach for AML. In the setting of allo-SCT, NK cell alloreactivity has proven to decrease relapse rate and to improve survival. Furthermore, it has been shown that allogeneic NK cell infusion following lymphodepleting conditioning can result in successful in vivo expansion and promising clinical activity. However, further enhancement of its therapeutic effect is warranted.
In this project, we will investigate an integrated approach of NK-cell based immunotherapy combined with DNA methyltransferase (DNMT) inhibitors to combat residual or persistent AML following consolidation therapy. We have developed a novel culture system to generate NK cell products from hematopoietic progenitor cells (HPC). Trafficking studies in mice demonstrated that these HPC-NK cells migrate to the bone marrow (BM) as well as to lymphoid organs where in vivo expansion and maturation can take place. A single NK cell infusion inhibited leukemic cell growth and prolonged survival of leukemia-bearing mice. Recently, we demonstrated that alternative culture protocols and modulation by the DNMT inhibitors result in improved NK cell cytoxicity against AML cells. These observations warrant assessment of the optimal HPC-NK cell product and choice of the most enhancing DNMT inhibitor treatment for the development of a subsequent clinical trial. The goal of this project is to maximize the anti-AML effect of allogeneic HPC-NK cell therapy by a) demonstrating improved efficacy of alternative NK cell products that more efficiently expand, target and eradicate AML cells in the BM and b) combining NK cell infusion with DNMT inhibitor therapy that augments NK cell responsiveness to AML cells and exerts a direct anti-AML effect.
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