Three years ago, Dr. Harry Dolstra, associate professor and head of the cell therapy facility at Radboudumc in Nijmegen, was awarded a KWF grant to test the safety and effectiveness of a treatment with natural killer (NK) cells grown from stem cells in patients with metastatic ovarian cancer. The first seven patients have now received their NK cells. A similar study has also been started in patients with acute myeloid leukemia.
In 2003, Italian researchers confirmed the role of allogeneic NK cells after hematologic stem cell transplantation in the treatment of acute myeloid leukemia (AML). Since then, the possibilities of using NK cells in haematological cancers have been investigated. But solid tumors are also becoming increasingly common.1
Growing methods
Immunologist and associate professor Harry Dolstra specializes in translational immunohematology and within Radboudumc he works together with hematologists and oncologists to bring new treatment concepts to the clinic, including treatment with NK cells. “We have developed special culture methods to isolate blood-forming stem cells from various sources, namely bone marrow, mobilized blood or umbilical cord blood, and to multiply those stem cells in special culture media with different growth factors and allow them to mature into NK cells.” he explains. “That culture process takes five weeks, during which each stem cell can eventually be multiplied to about 1,000 NK cells. The yield of stem cells from umbilical cord blood is on average 2-5 million per isolation, so that yields about 2-5 billion NK cells in a volume of 300-500 ml.” An important component of the culture media is a small molecule, the purine derivative StemReginin 1 (SR1). “That can bind to a transcription factor, the aryl hydrocarbon receptor (AHR). American researchers published in 2010 that this AHR antagonist stimulates the outgrowth of CD34-positive hematopoietic stem cells. We subsequently found that SR1 can also stimulate differentiation of immune cells.”
Start clinical studies
Depending on the composition of the culture medium with added growth factors, very diverse cellular products can be generated by blocking AHR. “In our lab we focus on plasmacytoid and myeloid dendritic cells2 and NK cells.3 The dendritic cells can be loaded with tumor antigens and then administered as a vaccine. This research is still in a preclinical phase, although we have developed the entire production process. However, we have already further developed the NK cell culture method into a so-called Good Manufacturing Practice (GMP) production process. To this end, a validated production protocol had to be drawn up, an Investigational Medicinal Product Dossier (IMPD). After approval of this IMPD by the Central Committee on Human Research (CCMO), we were able to start clinical studies with it.”
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