- 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.
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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