Rapid translation of small molecule GPR65 inhibitors for cancer immunotherapy

**Pathios Therapeutics** is a company that specialises in developing molecules that alter the signalling of cell-surface receptors in the immune system that detect changes in pH. The company has particular expertise in the understanding of a receptor called GPR65 and is currently seeking to make drugs that block or 'switch off' the signalling of this receptor to treat diseases like multiple sclerosis and ankylosing spondylitis. Recent scientific evidence suggests that drugs that block GPR65 could also enable the immune system to attack certain types of cancers. Pathios now plans to team up with cancer researchers at the University of Oxford to further capitalise on its expertise around GPR65 and exploit this important additional therapeutic opportunity.

In recent years, immunotherapy agents that target so-called T-cell checkpoints have led to dramatic survival benefits in some cancer patients. However, the majority of patients still do not respond adequately to these new treatments. This is because tumours are able to put up multiple barriers to prevent immune system attack and many of these are not addressed by currently approved therapies. Therefore, new forms of treatment are needed that target these additional immune evasion mechanisms.

One of the key additional barriers to immune system attack that has come to light in recent years is the ability of tumours to disarm specialized cells in the innate immune system called tumour associated macrophages (TAMs), via the creation of a low pH (i.e. acidic) local microenvironment. It is well known that tumours can be more acidic than normal tissues because they rely on a different form of metabolism for growth and survival that creates lactic acid as a by-product. It has also long been known that this altered metabolism, which can be readily detected by a specialized blood test, strongly predicts that patients will respond poorly to current immunotherapy. This is particularly marked in advanced melanoma, a serious form of skin cancer. Recent ground-breaking data has now provided an explanation for this link by showing that tumour acidity disables TAMs by activating the GPR65 receptor and its signalling pathway, leading to significantly worse melanoma outcomes. Therefore, a drug that blocks GPR65 could achieve potentially game-changing results in melanoma. A collaboration between Pathios and the University of Oxford is ideally placed to progress such a drug into clinical development as it brings together cutting-edge knowledge of the GPR65 receptor with an unparalleled clinical understanding of treatment-resistant melanoma patients.