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Generation of Natural Killer Cells from Human Expanded Potential Stem Cells
Published on: January 13, 2023
Genome engineering of induced pluripotent stem cells to manufacture natural killer cell therapies
Keerthana Shankar1, Christian M Capitini2,3, Krishanu Saha4,5,6
1Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
Abstract:
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. Current NK therapies using primary NK cells are prone to manufacturing issues related to expansion and storage. 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. In contrast, NK cells differentiated from induced pluripotent stem cells (iPSC-NK cells) offer an off-the-shelf alternative that may overcome these bottlenecks. 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. Moreover, genetic modifications targeting NK-mediated antibody-dependent cellular cytotoxicity capabilities, cytotoxicity, and checkpoint inhibitors may increase the therapeutic potential of iPSC-NK products. 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.
Insights
Induced pluripotent stem cell-derived natural killer (iPSC-NK) cells offer a promising, off-the-shelf cancer immunotherapy. These cells overcome manufacturing challenges of primary NK cells and reduce adverse effects associated with other NK cell therapies.
Area of Science:
- Immunology
- Stem Cell Biology
- Cancer Therapy
Background:
- Natural killer (NK) cells are vital for immune surveillance, identifying and eliminating cancerous cells.
- Current NK cell therapies face manufacturing hurdles and potential adverse effects from systemic IL-2 administration.
- Induced pluripotent stem cells (iPSC) offer a renewable source for generating NK cells (iPSC-NK cells).
Purpose of the Study:
- To review current NK cell therapy sources and their limitations.
- To discuss advancements in iPSC-NK cell manufacturing and genetic engineering.
- To provide an overview of clinical trials involving iPSC-NK cells.
Main Methods:
- Review of existing literature on NK cell sources and therapies.
- Analysis of iPSC-NK cell differentiation protocols, including serum-free and feeder-free methods.
- Examination of genetic engineering strategies to enhance iPSC-NK cell functions.
Main Results:
- iPSC-NK cells provide an effective, off-the-shelf alternative to primary NK cells and NK-92 cell lines.
- Serum-free and feeder-free protocols enable clinically adaptable iPSC-NK cell manufacturing.
- Genetic modifications can augment NK-mediated cytotoxicity and therapeutic potential.
Conclusions:
- iPSC-NK cells represent a significant advancement in cancer immunotherapy, overcoming limitations of current NK cell therapies.
- Optimized manufacturing and genetic engineering hold promise for enhancing iPSC-NK cell efficacy.
- Ongoing clinical trials will further elucidate the therapeutic value of iPSC-NK cells in cancer treatment.
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