Our optimally engineered NK cell therapy platform leverages unique proprietary cell modifications to maximize the cytotoxic potential, metabolic health and persistence of the engineered cells.
We have an overarching goal to create next generation off-the-shelf, optimally engineered NK cell therapies with broad applicability across a wide range of targets and tumor types.
Our unique approach to optimally engineering NK cell therapies
We have a strong research pipeline exploiting gene editing techniques, to explore mechanisms by which NK cell functionality and NK cell based therapies can be optimized, including:
- Enhancement of persistence and metabolism e.g. knockout (KO) of the CISH gene
- Ensure tumor homing by exploiting natural chemokine receptor expression of expanded cord blood NK cells
- Overcome exhaustion and immune invasion through KO of inhibitory receptors e.g. PD-1, TIGIT, CD96, LAG3, TIM3, CTLA-4, Siglec-7 and Siglec-9
- Maximize antigen independent killing by harnessing TRAILv and overcome microenvironmental inhibition by blocking IL-6.
In addition to gene editing, we are exploring the use of adjunctive therapies such as antibodies to enhance NK cell cytotoxicity within the tumor microenvironment e.g. IL-6 antagonism.
CISH gene KO
The CISH gene encodes Cytokine Inducible SH2 protein (CIS), a member of the suppressor of cytokine signaling (SOCS) family of proteins and a potent checkpoint in NK cell-mediated tumor immunity. CISH KO confers beneficial properties on NK cells, including:
- Increased sensitivity to IL-15, IL-2, which leads to greater cell proliferation
- Improved metabolic fitness with enhanced glycolysis and oxidative phosphorylation
- Increased in-vivo persistence
- Enhanced responsiveness to NK cell cytotoxicity receptors
- Enhanced anti-tumor activity.
CISH KO is a key capability of our core platform, and we have an exclusive global license to IP from The Walter and Eliza Hall Institute of Medical Research for CISH KO in human NK cells for their use in cancer therapies.
Targeting the Death Receptor Pathway
The role of the death receptor pathway in inducing apoptosis via the extrinsic pathway has been well characterized in NK cells.
We have engineered a high affinity, membrane bound TNF-related apoptosis-inducing ligand variant (TRAILv), targeting death receptors DR4 or DR5 in cancer cells.
In addition to CAR mediated granzyme killing, TRAIL activation of the death receptor pathway adds a second driver of efficacy as it is a:
- Key component of NK cell cytotoxicity
- Facilitator of concurrent antigen independent killing
Our CAR Construct
Initial product candidates incorporate the well validated CD28/CD3ζ CAR backbone.
We are also exploring the incorporation of novel co-stimulatory domains within the construct.
Our goal is also to ensure efficient tumor targeting, including the use of optimized affinity and tumor specific engagers to mitigate on-target off-tumor toxicity.