ONK Therapeutics’ CSO Prof. M O’Dwyer and his Academic Group Present New Data Showing the Benefit of Knocking Out the Inhibitory Receptor CD96 on Human NK Cells in the Context of Multiple Myeloma at EHA 2021

  • The checkpoint inhibitor CD96 was shown conclusively to be an inhibitory receptor on human NK cells in the presence of multiple myeloma (MM) cells expressing CD155
  • CD96 knock out (KO) using CRISPR/Cas9 gene editing enhanced both NK cell cytotoxicity and cytokine release
  • Efficient engineering of NK cells to genetically eliminate inhibitory receptor expression has the potential to overcome exhaustion and immune evasion in the tumor microenvironment

Galway, Ireland and San Diego, USA, 11 June 2021 – ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, welcomes new data presented by John Daly from the academic lab of CSO, Prof. Michael O’Dwyer at the Annual European Hematology Association 2021 Virtual Congress illustrating the merit of knocking out the checkpoint inhibitory receptor for CD96 on NK cells in the context of MM.

The data is based on research studies carried out at the National University of Ireland, Galway (NUI Galway), College of Medicine, Nursing and Health Sciences, by Prof. O’Dwyer’s academic research group.

Contradictory data had previously shown that CD96 could be both an activating and an inhibitory receptor on human NK cells, depending on the tumor type being examined.  The data presented during the poster presentation demonstrate conclusively that in the case of MM cells expressing CD155, CD96 is a human NK cell inhibitory receptor, regulating both cytotoxicity and cytokine release. Experiments using CRISPR/Cas9-mediated KO of CD96 in primary NK cells resulted in enhanced cytotoxicity and cytokine release compared to controls. Studies carried out in parallel also demonstrated a similar beneficial effect of CRISPR/Cas9-mediated KO of TIGIT in primary NK cells.

Furthermore, NK cells obtained from MM patient bone marrow had particularly high levels of CD96 expression, suggesting NK cells in the bone marrow of MM patients are more likely to be susceptible to CD155 mediated immune-evasion.

These new insights support knocking out inhibitory checkpoint receptors, including CD96 KO and TIGIT KO as a promising approach to improving the functionality of off-the-shelf engineered NK cell therapies for the treatment of cancer.

E-poster presentation title: Knockout of CD96 or TIGIT using CRISPR/Cas9 enhances NK induced
cytotoxicity and cytokine production in the presence of CD155 expressing myeloma cells.

Author(s)/Presenters: John Daly, Mark Gurney, Michael O’Dwyer.

Session title: Myeloma and other monoclonal gammopathies – Biology & Translational Research.

Abstract number: EP941

Date and Time: Available on the virtual platform as an e-poster Friday, June 11 at 9:00 CEST.

Download a copy HERE.

Chris Nowers, ONK Therapeutics’ CEO said, “The studies carried out by Prof. O’Dwyer’s academic research group are expanding our deep understanding of NK cell biology and are helping to confirm certain gene constructs and edits that will enhance NK cell cytotoxicity, cytokine production and persistence in the tumor microenvironment.  Gene edited NK cells lacking CD96 and/or TIGIT could therefore be beneficial for treating CD155 expressing malignancies, such as Multiple Myeloma.”

ONK Therapeutics was formed based on technology and intellectual property developed at NUI Galway by Prof. O’Dwyer. The Company is developing off-the-shelf, optimized NK cell therapies for cancer that utilize dual-targeting of the death receptor pathway in addition to incorporating a CAR, along with further strategies that utilize novel gene editing approaches to enhance persistence, metabolic profile, and cytotoxic potential. ONK has exclusive licenses to a broad intellectual property (IP) against a wide range of NK cell checkpoints, including CD96 and TIGIT.

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ONK Therapeutics www.onktherapeutics.com

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:

  • The lead program, 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 inhibitory 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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Media enquiries (for ONK Therapeutics)

International

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ONK Therapeutics Secures Exclusive Global License to Patent for CISH Knockout in NK Cells for the Treatment of Cancer, from Australia’s WEHI

  • Cytokine Inducible SH2 containing protein (CIS; encoded by the gene CISH) is a potent checkpoint in NK cell-mediated tumor immunity
  • CISH knockout (KO) NK cells have been shown to be more efficient in eliminating cancer cells in in-vivo models
  • Exclusive global license to WEHI patent for CISH KO in the field of NK cells builds on and strengthens ONK Therapeutics’ broad intellectual property (IP) against a wide range of NK cell checkpoints
  • Will enable ONK Therapeutics to further optimize the persistence, metabolic profile and cytotoxic potential of its dual-targeted NK cell therapy platform

Galway, Ireland and San Diego, USA, 27 May 2021 – ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, today announced 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.

“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) https://www.nature.com/articles/ni.3470?proof=t

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″

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

Copyright: ONK Therapeutics Ltd

ONK Therapeutics www.onktherapeutics.com

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:

  • The lead program, 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.

Follow us on Twitter and LinkedIn.

International

Sue Charles, Charles Consultants – +44 7968 726585 sue.charles59@outlook.com

Ireland

Ray Gordon, Gordon MRM – +353 87 2417373 ray@gordonmrm.ie

 

Anthony Nolan Cell & Gene Therapy Services and ONK Therapeutics Announce Collaboration

  • Anthony Nolan Cell & Gene Therapy Services will provide umbilical cord blood and cord-derived NK cells to facilitate the development of ONK Therapeutics’ next-generation dual-targeted NK cell therapies
  • Collaboration supports a common mission to improve the lives of patients with hematological malignancies and solid tumors

London, UK and Galway, Ireland, and San Diego, USA 22 February 2021 – Cell therapy company ONK Therapeutics and blood cancer charity Anthony Nolan have entered into a collaboration to facilitate the development of the next-generation natural killer (NK) cell therapies to improve the lives of patients with hematological malignancies and solid tumors.

Anthony Nolan Cell & Gene Therapy Services will provide a consistent supply of umbilical cord blood and cord-derived NK cells as a choice of starting material for both ONK Therapeutics’ research activities and continued process development work. This source material is scalable and ethically-sourced from consenting donors.

The parties bring together their extensive experience in cell sourcing, cell processing, translational research, understanding of the tumor microenvironment, and exploration of NK cells as a foundation for cellular immunotherapy. In doing so they aim to expedite the development of much-needed new lifesaving cell therapies for patients with a broad range of cancers.

Diana Hernandez, Head of Immunotherapy at the Anthony Nolan Research Institute says: “Our innovative partnership with ONK Therapeutics will serve to accelerate vital research and development into hematological and solid cancer treatments.  We see this as an exciting opportunity which will ultimately lead to better treatments, improving the lives of many more cancer patients.”

Chris Nowers, CEO of ONK Therapeutics says: “Anthony Nolan has a rich heritage in stem cell therapy research, including an enviable understanding of the biology of NK Cells and their processing. We look forward to continuing to partner with their team and to benefiting from their extensive know-how as we drive our programs towards clinical trials and beyond.”

About Anthony Nolan Cell and Gene Therapy Services

Anthony Nolan is the pioneering charity that saves the lives of people with blood cancer and blood disorders who need a stem cell transplant. Anthony Nolan’s Cell and Gene Therapy Services aim to facilitate ethical research and development through the sourcing and supply of donor starting materials to researchers and developers. With a register of over 850,000 donors, a cord blood bank, and four decades of experience providing stem cells, Anthony Nolan has the infrastructure, the expertise, and the skills to support the needs of the cell and gene therapy industry.

Website: www.anthonynolan.org/clinicians-and-researchers/cell-and-gene-therapy-services

LinkedIn: www.linkedin.com/showcase/anthony-nolan-cell-&-gene-therapy-services/

Contact: katie.griffee@anthonynolan.org

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 hematological malignancies and solid tumors.

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 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:

  • The lead program, 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 research focus on strategies to enhance homing and persistence, and overcome exhaustion, including the exploration of proprietary gene edits, such as the deletion of checkpoint inhibitory 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.

Follow us on Twitter and LinkedIn.

Website: www.onktherapeutics.com

Ends

Media enquiries (for ONK Therapeutics)

International

Sue Charles, Charles Consultants – +44 7968 726585 sue.charles59@outlook.com

Ireland

Ray Gordon, Gordon MRM – +353 87 2417373 ray@gordonmrm.ie

Media enquiries (for Anthony Nolan)

For more information about the charity, please call the Anthony Nolan press office on 0207 424 1300 or email press@anthonynolan.org. For urgent out of hours media enquiries, call 07881 265 285.

NOTES TO EDITORS

About Anthony Nolan

Anthony Nolan saves the lives of people with blood cancer. The charity uses its register to match potential stem cell donors to blood cancer and blood disorder patients in need of stem cell transplants. It also carries out pioneering research to increase stem cell transplant success and supports patients through their transplant journeys. Every day Anthony Nolan gives three people a second chance at life. Find out more at www.anthonynolan.org

Note to sub-editors

Please note that Anthony Nolan changed its name in 2001 and is no longer known as Anthony Nolan Trust.

What is a stem cell transplant?

If a patient has a condition that affects their bone marrow or blood, then a stem cell transplant may be their best chance of survival. Doctors will give new, healthy stem cells to the patient via their bloodstream, where they begin to grow and create healthy red blood cells, white blood cells, and platelets.

Key statistics

  • About 2,000 people in the UK need a stem cell transplant from a donor every year
  • 90% of donors donate through PBSC (peripheral blood stem cell collection). This is a simple, outpatient procedure similar to giving blood
  • We need more young men to sign up, as they are most likely to be chosen to donate but make up just 18% of the register
  • We need more people from Black, Asian, and minority ethnic (BAME) backgrounds to sign up. Only 70% of transplant recipients receive the best match. This drops dramatically to around 37% if you’re from a Black, Asian, or ethnic minority background.
  • Blood cancer is the fifth most common type of cancer in the UK and the third biggest cancer killer. It accounts for 9% of all new cases of cancer diagnosed in the UK.
  • It costs £40 to add each new donor to the register so we always need financial support
  • To join the Anthony Nolan register, you must be 16-30 and healthy. Anthony Nolan’s world-leading Research Institute has shown younger donors offer better survival rates for patients.