On May 27, 2021 ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, reported that it has entered into an exclusive global patent license agreement with Australia’s Walter and Eliza Hall Institute of Medical Research (WEHI) providing rights to CISH KO in the field of NK cells for the treatment of cancer (Press release, ONK Therapeutics, MAY 27, 2021, View Source [SID1234580662]).
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"Deletion of CISH in NK cells leads to an improved metabolic profile, greatly enhancing their proliferation, cytotoxicity, and persistence. In-vivo models of cancer have shown that CISH KO NK cells are much more efficient in eliminating cancer cells, making such cells a very attractive prospect for future clinical development," said Prof Michael O’Dwyer, CSO of ONK Therapeutics.
"This patent agreement builds on and strengthens the broad IP we have created at ONK Therapeutics against multiple NK cell checkpoints," added Prof O’Dwyer.
CIS (encoded by the gene CISH) is a member of the suppressor of cytokine signaling (SOCS) family of proteins. The research team at WEHI, led at the time by Prof Nick Huntington and Assoc Prof Sandra Nicholson, was the first to show the critical role that CIS plays in negatively regulating the function of NK cells. When NK cells are stimulated with growth factors, such as interleukin 15 (IL-15), which encourage their growth, survival, and killing capability, there is an increase in the activity of CIS protein, which acts as a brake or checkpoint, on further NK cell growth and function.
The WEHI team found that when CIS was removed from NK cells by deleting the CISH gene, the NK cells were more responsive to growth factors and had improved survival and killing capacity(1). Improving the metabolic fitness of NK cells to enhance glycolysis and oxidative phosphorylation is important for optimizing the anti-tumor activity of NK cells, especially against solid tumors(2-3).
"Uncovering the role of CIS as an intracellular NK cell checkpoint has been an essential discovery to further the understanding of NK cell homeostasis and turnover," said Dr. Anne-Laure Puaux, Head of Biotechnology and Commercialisation, WEHI. "We believe that our invention has the potential to improve the potency of the NK cell-based therapy platform developed by ONK Therapeutics and provide greater benefit to patients."
Under the terms of the agreement, ONK Therapeutics has secured exclusive global rights to WEHI’s patent covering the use of human NK cells lacking CISH for the purposes of researching, developing, manufacturing and commercializing NK cell therapies. The financial terms of the agreement include milestone payments and royalties on sales, the specifics of which are not disclosed.
ONK Therapeutics’ CEO Chris Nowers said, "We are very pleased that via this agreement with WEHI we have the unique ability to produce therapeutic NK cells lacking CISH for the treatment of cancer. This is another example of our innovative strategy to engineer a highly differentiated NK cell therapy platform that has broad potential across both hematological malignancies and solid tumors."
ONK Therapeutics is optimizing a unique off-the-shelf, dual-targeted NK cell therapy platform, combining the expression of a chimeric antigen receptor (CAR) and a TRAIL variant (TRAILv) and anticipates using CISH KO as a core feature of this platform. The pipeline currently has four programs in pre-clinical development across hematological malignancies and solid tumors. The Company is also exploring engineering strategies to enhance tumor homing, to optimize persistence and metabolism, and to overcome exhaustion in the tumor microenvironment, including the exploration of proprietary gene edits, such as the deletion of checkpoint receptors in NK cells, including extracellular proteins CD96, TIGIT, Siglec-7 and PD-1.
1. Delconte, R., Kolesnik, T., Dagley, L. et al. CIS is a potent checkpoint in NK cell–mediated tumor immunity. Nat Immunol 17, 816–824 (2016) View Source
2. Daher et al., Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells Blood Sept 9, 2020
3. Zhu et al., Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity Cell Stem Cell Sept 3, 2020″