Browsing by Subject "NK cells"
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Item Engineering human pluripotent stem cells for enhanced lymphocyte development and function(2012-10) Knorr, David ArthurHuman embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide accessible, genetically tractable and homogenous starting cell populations to efficiently study human blood cell development. These cell populations provide platforms to develop new cell-based therapies to treat both malignant and non-malignant hematological diseases. Our group has previously demonstrated the ability of hESC-derived hematopoietic precursors to produce functional natural killer (NK) cells. hESCs and iPSCs, which can be reliably engineered in vitro, provide an important model system to study human lymphocyte development and produce enhanced cell-based therapies with potential to serve as a "universal" source of anti-tumor lymphocytes for novel clinical therapies. My studies have focused on the generation of NK cells from hESCs and iPSCs, their function both in vitro and in vivo against a variety of different tumor types, and modification of these cells with genetic constructs to enhance their anti-tumor capabilities.Item Harnessing Natural Killer Cells for Improved Therapeutic Potential(2021-08) Kim, HansolCellular immunotherapy provides durable control for infected and transformed cells. However, current Natural Killer (NK) cell therapy products are limited by effector persistence. To this end, three strategies to improve the efficacy of NK cell-based therapies are discussed. Killer immunoglobulin-like receptors (KIR) are developed during maturation of NK cells. It showed that KIR develops primarily between CD56brightCD94high and CD56dimCD94high stages. Major demethylation activities were observed during the development of KIR at its proximal promoter region. Ascorbic acid showed to facilitate the development of KIR in collaboration with Ten-eleven translocation (TET) enzymes. NK cells with adaptive immunological properties persist and expand in response to cytomegalovirus (CMV) infection. The levels of intracellular metabolites were analyzed and showed that adaptive NK cells have relatively higher levels of metabolites associated with glycolysis, purine, and pyrimidine metabolism. This supports the notion that adaptive NK cells have upregulated metabolic profiles, and have capacity to expand upon reactivation of CMV which is similar to the characteristics of memory T cells. To address challenges associated with inconsistencies of the manufactured product, and treatment cost, we developed a triple gene-edited induced pluripotent stem cell (iPSC) platform for broad patient-based adoptive cell therapy. First edit is to introduce non-cleavable CD16 which prevents reduced efficacy by antibody-dependent cellular cytotoxicity (ADCC). Second edit allows iPSC-derived NK cells, termed iNK, to persist without supplementation of exogenous IL-15 by introducing IL-15 receptor fusion. The last edit was to avoid daratumumab-induced fratricide by knocking out CD38 on the surface of the iNK cells. These engineered iNK cells persisted in vivo without supplementation of exogenous cytokine and could be combined with daratumumab for enhanced treatment of multiple myeloma. The gene-edited iNK cells exhibited metabolic features and gene expression profiles similar to those of adaptive NK cells which has broad off-the-shelf potential for the treatment of advanced cancer.