Work

Development of a Therapeutic Natural Killer Cell Product Generated from Cord Blood CD34+ Cells Expanded on Notch Ligand

Year: 2019

Type: article

Abstract: Natural killer (NK) cells are a critical component of the innate immune system’s toolbox in fighting cancer. NK cells can kill tumor cells without priming or prior activation through their complement of activating and inhibitory surface molecules. In comparison with T cell therapies, NK cells are emerging as a safer, more clinically accessible and cost effective allogeneic cellular therapy, because they do not cause graft-versus-host disease nor cytokine release syndrome. We are developing an allogeneic, cryopreserved, off-the-shelf NK cell product for the treatment of hematological malignancies. Our NK cell product is generated from cord blood-derived CD34+ cells, which first undergo expansion and priming on a proprietary Notch ligand cell culture platform followed by a second NK cell differentiation phase. Cells and final product are characterized by immune phenotyping, cytokine expression, RNA sequencing, and functionality by in vitro cytotoxicity against a panel of different AML tumor targets. Anti-tumor activity has been evaluated in a mouse tumor model of glioblastoma (GBM). A commercially and clinically viable number of NK cell doses per manufacturing run can be produced using this platform with ~5,000 NK cells generated per starting CD34+ cell. Furthermore, the use of this product as an off-the-shelf product has allowed for scaled-up manufacturing, reduced costs of goods, and improved lot-to-lot consistency among manufacturing runs. The NK cell product’s expression profile is indicative of a less mature but highly active NK cell phenotype expressing a range of cell markers associated with functional cytotoxic NK cells. RNA sequencing analysis has shown a cytotoxic gene signature similar to that observed in adult NK cells, and numerous proinflammatory cytokines are secreted in response to tumor target cells, which may help to recruit host immune cells for further antitumor activity. Potent in vitro cytotoxicity has been observed across several acute myeloid leukemia (AML) tumor target cells, as has antitumor activity in an aggressive and immunosuppressive mouse GBM tumor model. Additional xenograft studies are planned, as is initiation of clinical trials using this product to treat patients with hematologic malignancies to assess the safety and potential efficacy of the product.

Source: Stem Cells Translational Medicine

DOI: 10.1002/sctm.12582