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Editing NK Cells Produces More Potent Cancer Killers

Sep 15, 2020 10:07:00 AM / by Stacy Matthews Branch, DVM, PhD

Strong woman in city with breast cancer awareness_AdobeStock_224562135-1Researchers at the University of California San Diego used natural killer cells in a study as immunotherapeutic agents. They found that the natural killer cells are effective in ridding tumor cells from the body. 

Immunotherapy for cancer treatment is rapidly emerging, and many studies are aimed at increasing the safety and efficacy of anti-tumor immunotherapy. Although T cells have been extensively studied, more research is being conducted on the use of natural killer (NK) cells as immunotherapeutic agents. NK cells are lymphocytes of the immune system capable of attacking and killing virus-infected and tumor cells. NK cells can lyse tumor cells without prior activation, but the potency of this effect limits its clinical use.

A group of researchers at the University of California - San Diego, developed a way to enhance the potency of NK-cell anti-tumor activity. The approach involved CRISPR/Cas9‐mediated targeting of a gene encoding the checkpoint molecule Cytokine-inducible SH2-containing protein (CIS). In NK cells, CIS is a negative regulator of interleukin-15 (IL-15) signaling. The deletion of the CIS gene (CISH) in NK cells removes a checkpoint that suppresses NK cell activity. 

The human CISH-knockout (CISH-/-) NK cells were created using induced pluripotent stem cell-derived NK cells. These edited stem cells have increased signal activity for IL-15-mediated JAK-STAT (elevated IL-15-mediated JAK-STAT signaling activity). The enhanced signaling activity led to improved expansion and cytotoxicity against tumor cell lines even with lower concentration levels with cytokine. The cells were shown to persist and display anti-tumor activity in a leukemia xenograft mouse model. Biochemically, the edited NK cells are more robust, as seen by an increase in cellular metabolic processes such as glycolysis and mitochondrial respiration.

The CISH-deleted iPSC-derived NK cells exhibited significant anti-tumor activity in the experimental mice leading to survival. The mice treated with unedited NK cells still died from leukemia. Using iPSC-derived NK cells provides a reliable platform for gene editing. Furthermore, NK cells can be allogeneic; therefore, the modified NK cells can serve as a promising off-the-shelf therapy available to numerous patients in a cost- and time-effective manner. The goal is to conduct clinical trials using this technology and apply it to treat other types of tumors, including solid tumors. 

HemaCare is a proud provider of high-quality NK cells used in research to further the advancement of medical technology and provide better treatment options for patients. 

References:

Gene editing turns immune cells into more potent cancer killers. (2020). Retrieved 14 July 2020, from https://www.fiercebiotech.com/research/gene-editing-turns-immune-cells-into-more-potent-cancer-killers 

Zhu, H., Blum, R., Bernareggi, D., Ask, E., Wu, Z., & Hoel, H. et al. (2020). Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity. Cell Stem Cell. doi: 10.1016/j.stem.2020.05.008

Topics: Cancer, NK Cells

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