USPTO Grants ONK Therapeutics’ Foundational Patent for CISH Knockout in NK Cells for Use in Cancer Therapies

  • The US Patent and Trademark Office (USPTO) has granted ONK Therapeutics’ patent for CISH knockout (KO) in Natural Killer (NK) cells based on the earliest scientific discoveries
  • The patent, under exclusive global license from WEHI, gives ONK key IP for CISH KO in human NK cells for their use in cancer therapies, irrespective of cell origin
  • The CISH IP adds to ONK’s broad and growing IP estate covering the optimization of persistence, metabolic profile and cytotoxic potential of its NK cell therapy platform

Galway, Ireland and San Diego, USA, 9 September 2021 – ONK Therapeutics Ltd, an innovative NK cell therapy company, today announced that the US Patent and Trademark Office (USPTO) has granted its licensed patent that covers CISH knockout (KO) in NK cells, irrespective of the source of the NK cells, including, for example, human cord blood-derived and human induced pluripotent stem cell (iPSC)-derived cells (Patent No. 11104735).

Earlier this year ONK entered into an exclusive global patent license agreement with Australia’s Walter and Eliza Hall Institute of Medical Research (WEHI) providing it rights to CISH KO in the field of human NK cells for the treatment of cancer, with the right to sublicence.

“We are excited to have this unparalleled opportunity to explore the potential of CISH KO in human NK cells. We believe this is the foundational patent, based on the earliest scientific discoveries which cover CISH KO NK cells from any source, and we intend to evaluate this edit in both umbilical cord blood and iPSC-derived NK cells,” said ONK Therapeutics’ CEO Chris Nowers.

CISH KO has been shown to improve the persistence, metabolic profile, and cytotoxic potential of NK cells. While several other companies and academic centers are exploring the potential of a CISH KO on NK cells, the research team at WEHI, in 2015, was the first to show the critical role CIS, the protein encoded by CISH, plays in negatively regulating the function of NK cells.

Prof. Michael O’Dwyer, founder and CSO of ONK Therapeutics said, “Editing of NK cells to knock out CISH has the potential to improve the potency of the NK cell-based therapies and provide greater benefit to patients.”

We are building an unrivaled and broad IP estate against multiple NK cell checkpoint receptors, including extracellular proteins CD96, TIGIT, Siglec-7 and PD-1 as part of our innovative strategy to engineer a highly differentiated NK cell therapy platform that has broad potential across both hematological malignancies and solid tumors.”

WEHI’s Head of Biotechnology and Commercialisation Dr Anne-Laure Puaux said, “Cell-based therapies have demonstrated their enormous potential as disease-modifying therapies in oncology.  By licensing our intellectual property to ONK Therapeutics we are supporting the opportunity to develop more potent cell-based therapies for the future benefit of cancer patients.”

In addition to this granted CISH KO US patent, ONK Therapeutics has filed a US continuation patent application. Parallel filings are also under review in the EU by the European Patent Office (EPO) as well as in China, Japan, Australia and New Zealand, thus providing excellent coverage for the company’s commercial interests.


About CISH and the WEHI patent

CIS (encoded by the gene CISH) is a member of the suppressor of cytokine signaling (SOCS) family of proteins. 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).

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)

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

Caption: CISH gene knockout confers enhanced metabolic profile on NK cells, created with

Copyright: ONK Therapeutics Ltd

About ONK Therapeutics

ONK Therapeutics Ltd is an innovative cell therapy company dedicated to developing the next generation of ‘off-the-shelf’, dual-targeted NK cell therapies targeting solid and hematological cancers.

The company was founded in 2015, by Prof. O’Dwyer MD, of NUI Galway, an expert in translational multiple myeloma research, the tumor microenvironment, and exploitation of NK cells as cellular immunotherapy. Its core proprietary off-the-shelf cell therapy platform is based on a dual-targeted NK cell expressing both a chimeric antigen receptor (CAR) targeting a known tumor antigen and a TNF-related apoptosis-inducing ligand variant (TRAILv) targeting the death receptor pathway (i.e., DR4 or DR5). This unique approach has the potential to enhance efficacy by addressing both intrinsic (e.g., CAR engagement of a tumor-specific antigen) and extrinsic (e.g., signaling through the death receptor pathway) apoptotic pathways and to reduce the susceptibility to possible target antigen escape through the engagement of tumor antigen-independent TRAILv.

Its pre-clinical pipeline comprises four programs:

  • ONKT101 is a dual-targeted NK cell therapy incorporating a CD19 CAR and TRAILv targeting DR5, intended for the treatment of relapsed/refractory B cell malignancies. This program is partnered with Avectas, with the company having responsibility for development to Phase 1
  • ONKT102 combines an optimized affinity CD38 CAR and a TRAILv targeting DR5, intended for the treatment of patients with relapsed/refractory multiple myeloma
  • ONKT103 combines a TA-MUC1 CAR with a TRAILv targeting DR5, for the treatment of solid tumors
  • ONKT104 combines a CLL-1 CAR with a TRAILv targeting DR4, for the treatment of AML

In addition to the unique off-the-shelf, dual-targeted NK cell therapy platform, the company has a strong focus on engineering strategies to enhance tumor homing and persistence in-vivo, and overcome exhaustion in the tumor microenvironment, including the exploration of proprietary gene edits, such as the deletion of checkpoint receptors in NK cells.

ONK Therapeutics is headquartered in the med-tech hub of Galway, Ireland, with a wholly-owned US subsidiary, ONK Therapeutics, Inc. based at JLabs @ San Diego. Shareholders include Acorn Bioventures, ALSHC (principally Seamus Mulligan), and Enterprise Ireland.

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Ray Gordon, Gordon MRM – +353 87 2417373