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Updated: Nov 28, 2025
Generation of Knock-out Primary and Expanded Human NK Cells Using Cas9 Ribonucleoproteins
Published on: June 14, 2018
Genetic and epigenetic modification of human primary NK cells for enhanced antitumor activity
Meisam Naeimi Kararoudi1, Brian P Tullius1, Nitin Chakravarti2
1Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute of Nationwide Children's Hospital, Columbus, OH.
Abstract:
Cancer immunotherapy using genetically modified immune cells such as those expressing chimeric antigen receptors has shown dramatic outcomes in patients with refractory and relapsed malignancies. Natural killer (NK) cells as a member of the innate immune system, possessing both anticancer (cytotoxic) and proinflammatory (cytokine) responses to cancers and rare off-target toxicities have great potential for a wide range of cancer therapeutic settings. Therefore, improving NK cell antitumor activity through genetic modification is of high interest in the field of cancer immunotherapy. However, gene manipulation in primary NK cells has been challenging because of broad resistance to many genetic modification methods that work well in T cells. Here we review recent successful approaches for genetic and epigenetic modification of NK cells including epigenetic remodeling, transposons, mRNA-mediated gene delivery, lentiviruses, and CRISPR gene targeting.
Insights
Genetically modifying natural killer (NK) cells enhances their cancer-fighting ability for immunotherapy. This review explores advanced methods to overcome challenges in genetically engineering these crucial innate immune cells.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for refractory and relapsed cancers.
- Natural killer (NK) cells offer potent anticancer activity with fewer toxicities, making them ideal for immunotherapy.
- Genetic modification of NK cells is crucial for enhancing their therapeutic potential but faces technical hurdles.
Purpose of the Study:
- To review recent advancements in genetic and epigenetic modification techniques for NK cells.
- To highlight methods overcoming challenges in primary NK cell engineering.
- To discuss the potential of modified NK cells in cancer immunotherapy.
Main Methods:
- Epigenetic remodeling strategies.
- Gene delivery using transposons.
- mRNA-mediated gene transfer.
- Viral vector-based methods (lentiviruses).
- CRISPR-Cas9 gene editing technology.
Main Results:
- Successful genetic and epigenetic modifications of NK cells have been achieved using various innovative techniques.
- These methods enable enhanced expression of therapeutic molecules and improved NK cell function.
- Overcoming resistance to genetic manipulation in primary NK cells is becoming increasingly feasible.
Conclusions:
- Advanced genetic and epigenetic engineering approaches are vital for unlocking the full potential of NK cell immunotherapy.
- Successful modification strategies pave the way for developing next-generation NK cell-based cancer therapies.
- Continued research in NK cell engineering promises more effective and safer treatments for a broad range of malignancies.
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