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

CISH gene knockout pathway in NK cells

CISH gene knockout confers enhanced metabolic profile on NK cells, created with
CISH gene knockout confers enhanced metabolic profile on NK cells, created with
  • The European Patent Office (EPO) has granted WEHI a patent for CISH knockout (KO) in Natural Killer (NK) cells which is exclusively licensed to ONK Therapeutics for cell immunotherapy purposes, giving ONK key IP for CISH KO in human NK cells for use in cancer therapies, irrespective of cell origin
  • The CISH IP forms part of 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, June 27, 2023 (GLOBE NEWSWIRE) — ONK Therapeutics Ltd, an innovative NK cell therapy company, today announced that the European Patent Office (EPO) has granted its licensed patent covering CISH knockout (KO) in NK cells, irrespective of the source of the NK cells, including human cord blood-derived, peripheral blood-derived, and NK cells derived from induced pluripotent stem cells (iPSCs).

The patent granted to ONK’s licensor, WEHI (Walter and Eliza Hall Institute of Medical Research), by the EPO is part of a portfolio which includes granted US, Australian, New Zealand and Japanese patents as well as pending applications in several other countries.

ONK licensed the patent family relating to the KO of CISH in NK cells in an exclusive global patent license agreement from WEHI in 2021. CISH KO has been shown to improve the persistence, metabolic profile, and cytotoxicity of NK cells. The patent granted by EPO specifically covers CISH KO NK cells per se, and cancer therapies that utilize NK cells with CISH KO as well as NK cells engineered with the foundational CISH KO in combination with IL-15 (soluble or engineered), TGFβR2 KO, or TGFβR2 KO and IL-15 (soluble or engineered).

ONK and WEHI continue to prosecute the CISH patent portfolio in a way to maximize its depth and breadth of scope. It forms part of ONK’s broad and growing IP estate covering the optimization of persistence, metabolic profile and cytotoxic potential of its NK cell therapy platform.

ONK Therapeutics’ CEO, Chris Nowers, said, “Editing of NK cells to knockout CISH has the potential to improve the potency and persistence of NK cell-based therapies and provide greater benefit to patients. We are actively exploring the merits of CISH KO alone or in combination with other gene edits such as TGFβR2 KO and IL-15 knock-in. We believe this is the foundational CISH KO patent, based on the earliest scientific discoveries and covers CISH KO NK cells from any source. We are excited to have this broad and evolving patent estate which underpins our scientific efforts in the field.”

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. Partnerships and collaborations are key to advancing WEHI’s drug discovery and development programs, to help us take our research from the lab to the clinic. Through this license agreement with ONK Therapeutics, we are excited to support the opportunity to develop more potent cell-based therapies for the future benefit of cancer patients.”

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). Later studies found that removing CIS improved the metabolic fitness of NK cells, optimizing their ability to kill tumor cells(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 137(5), 624-636, 2021
  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 27(2), 224-237.e6, 2020

ONK Therapeutics Ltd

About ONK Therapeutics –
ONK Therapeutics is an innovative cell therapy company dedicated to developing the next generation of optimally engineered off-the-shelf, natural killer (NK) cell therapies. With a growing pre-clinical pipeline targeting both hematological malignancies and solid tumors, ONK is advancing multiple cell therapy candidates towards the clinic, including its lead program, ONKT102, an optimized affinity CD38 CAR-NK product, intended for the treatment of patients with relapsed/refractory multiple myeloma. Read about the pipeline here.

The company’s optimally engineered NK cell therapy platform utilizes a suite of proprietary gene edits and cell modification strategies to optimize NK cell metabolic health, persistence and anti-tumor effect of NK cells, while reducing the potential for their exhaustion in the tumor microenvironment. These include CISH knockout (KO); the expression of high affinity, membrane bound, TNF-related apoptosis-inducing ligand variants (TRAILv) targeting DR5 or DR4; and the deletion of inhibitory receptors, including extracellular proteins for example CD96, and Siglec-7. Read about the platform here.

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Ray Gordon, Gordon MRM – +353 87 2417373

An infographic accompanying this announcement is available at

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