Both therapies employ a virally inserted CD19 CAR that allows T cells to recognize and kill malignant B cells expressing the CD19 antigen, including B cell acute lymphoblastic leukemia and non-Hodgkin lymphomas. There are currently two Food and Drug Administration (FDA)-approved CAR T cell therapies, tisagenlecleucel and axicabtagene ciloleucel. These cells are genetically modified to express antibody fragments fused to T cell signaling domains, providing antigen-specific cytotoxicity independent of the HLA. One approach to T cell therapies is to use autologous or human leukocyte antigen (HLA)-matched allogeneic T cells with an engineered chimeric antigen receptor (CAR). Progress with T cell therapies over the last decade has provided guidance for the development of NK cell therapies. While many of these are promising options (reviewed elsewhere ), this review will focus on natural killer (NK) cell-based approaches and their potential for off-the-shelf therapeutics. Immunotherapy, which seeks to harness and augment natural functions of the patient’s immune system to treat tumors, has now generated numerous approaches: antibodies, cytokines, dendritic cell vaccines, checkpoint inhibitors, adoptive cell transfer with tumor infiltrating lymphocytes (TIL) or genetically modified T cells, or some combination of these treatments. This review will highlight the current sources for NK therapies and their respective constraints, discuss recent developments in the manufacturing and genetic engineering of iPSC-NK cells, and provide an overview of ongoing clinical trials using NK cells.ĭespite recent advances in standard of care, cancers still account for more than 600,000 deaths annually in the USA alone, causing researchers to investigate alternative therapies. Moreover, genetic modifications targeting NK-mediated antibody-dependent cellular cytotoxicity capabilities, cytotoxicity, and checkpoint inhibitors may increase the therapeutic potential of iPSC-NK products. The development of a serum-free and feeder-free differentiation protocol allows for the manufacturing of clinically adaptable iPSC-NK cells that are equally as effective as primary NK cells and the NK-92 cell line for many indications. In contrast, NK cells differentiated from induced pluripotent stem cells (iPSC-NK cells) offer an off-the-shelf alternative that may overcome these bottlenecks. Alternative cell sources utilizing immortalized NK cell lines require irradiation and are dependent on systemic IL-2 administration, which has been associated with adverse effects. Current NK therapies using primary NK cells are prone to manufacturing issues related to expansion and storage. This model platform will pave the way for autologous coculture cross-talk assays, disease induction and subsequent drug testing.ĭifferentiation four-organ-chip induced pluripotent stem cells microphysiological system multi-organ-chip.Natural killer (NK) cells play a crucial role in host immunity by detecting cells that downregulate MHC class I presentation and upregulate stress ligands, as commonly seen in cancers. Only the renal model was overgrown by coexisting cells and did not further differentiate. Although there were no added growth factors present in the coculture medium, the intestine, liver and neuronal model maintained defined marker expression. The coculture of the four autologous tissue models in one common medium deprived of tissue specific growth factors was successful over 14-days. All four organ models were predifferentiated from induced pluripotent stem cells from the same healthy donor and integrated into the microphysiological system. Here, we designed a four-organ-chip interconnecting miniaturized human intestine, liver, brain and kidney equivalents. Microphysiological systems play a pivotal role in progressing toward a global paradigm shift in drug development.
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