The unmet need: despite advances in detection and treatment, cancer remains a major killer. Whilst experimental evidence for immunological control of tumor growth is well established, it was only relatively recently accepted that avoiding immune detection also contributes to cancer development in humans. Tumors are now known to induce various defense mechanisms to subvert immune attack, many of which are now targeted by drugs that aim to reverse this immune inhibition. These drugs include the revolutionary T cell ‘checkpoint inhibitors’ that have resulted in durable responses in some cancer patients.
Unfortunately however, most patients fail to respond to such therapies, while others eventually develop resistance.
At oNKo-innate we believe that the next major advances in cancer immunotherapy will result from strategies that recruit, integrate and activate a more diverse immune response. With our leading understanding of Natural Killer “NK” cells as a key coordinator of efficient anti-tumor immunity, we are identifying and developing the next generation of immunotherapies.
NK cells represent a large proportion (10-15%) of your circulating lymphocytes and have an innate ability to detect and kill virally-infected and cancerous cells. The molecular ‘decision’ an NK cell makes to destroy a target cell results from the integration of an extremely complex array of activating and inhibitory inputs. These include certain ligands on the surface of the cancer cell, cytokines that the NK cells has experienced and the microenvironmental context of the interaction.
Together, the role of NK cells in cancer can be summarized into 6 key points:
- NK cells prevent metastasis
- Their infiltration into tumors predicts overall patient survival
- Their activity is inversely correlated with cancer relapse
- They are key drivers of a ‘hot’ tumour microenvironment
- Their infiltration enhances CD8 T cell tumor immunity and responsiveness to checkpoint blockade
- They are able to detect and kill tumour cells that have escaped T cell detection
NK cell-based therapies clearly promise better cancer outcomes, though clinical realisation of this potential has been far from optimal. The best current examples include cytokine infusions and CD16-binding antibodies, which are thought to partly function through activating and redirecting NK cells, respectively. Though effective in some cases, non-specific cytokine therapies are limited by significant toxicity, while most cancers also do not express good antigens to serve as antibody targets.
The challenge therefore remains: how can NK cells be therapeutically targeted and truly enter mainstream immunotherapy?
Effective therapeutic exploitation of NK cells has thus far eluded everyone’s best efforts, the real breakthroughs will come from revising our understanding of NK cells from simple effectors to key orchestrators of productive immunity.
At oNKo-innate we are truly modality agnostic. We discover and develop the most effective strategies for enhancing the NK cell response against cancer. Using this unbiased approach, our discovery platforms yield targets actionable by small molecules, biologics and cell therapies.
Our core discovery themes include:
- Innate tumour recognition
- NK cell trafficking
- The hierarchy of NK cell negative regulators
By developing unique NK-targeting therapies and rationalizing how combination immunotherapy should work, we are laying the foundations for the next revolution in cancer treatment.
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