Tools against tumors

One of the reasons tumor-associated macrophages fail in their task to eliminate cancer cells is because of the acidic nature of the tumor microenvironment.

OXFORD, UK—Pathios Therapeutics Ltd., an early-stage drug discovery company focused on developing macrophage conditioning to unlock the power of the innate immune system against cancer, has received a $475,000 Smart Grant from Innovate UK to accelerate its cancer immunotherapy program targeting the innate immune checkpoint known as GPR65. The company is targeting a genetically validated innate immune checkpoint as an approach to unleashing the power of macrophages in the fight against cancer.

Pathios, which was launched in 2017, will use the grant to collaborate with researchers from the Department of Oncology at The University of Oxford to develop tools to expedite the translation of small-molecule GPR65 inhibitors for use in cancer immunotherapy. The program will include the development of early clinical target engagement biomarkers as well as using bioinformatics techniques to identify patients who are most likely to benefit from Pathios’ GPR65-targeted approach.

According to Stuart Hughes, CEO of Pathios, “We are delighted to have secured this highly competitive funding from Innovate UK to accelerate our program against GPR65 and to continue to build our scientific links with cancer researchers at The University of Oxford. This award boosts our ongoing program and is a significant endorsement of our novel approach to targeting the innate immune system in hard-to-treat cancers. We look forward to developing the tools that will drive forward our GPR65-based Macrophage Conditioning technology and help deliver on the company’s goal to provide a first-in-class treatment approach for those melanoma patients who currently have limited treatment options.”

Hughes explained that the acidic tumor microenvironment found in many cancers suppresses infiltrating immune cells, disarming the anticancer immune response and negating the effectiveness of current immunotherapies. A key reason why some melanoma patients do not respond well to anti-PD-1 therapies relates to the disarming of innate immune cells called tumor-associated macrophages (TAMs) by the acidic microenvironment that is inherent to advanced tumors. This is especially obvious in TAMs, where acidity is sensed by the cell-surface receptor, GPR65, leading to an induction of the transcriptional repressor, ICER (inducible cAMP early repressor), and the widespread suppression of pro-inflammatory mediators such as TNFα, IL-6, and IL-12. 

Activation of the pH-sensing receptor, GPR65, on TAMs by acidic pH leads to the suppression of a host of pro-inflammatory genes, shifting the characteristics of these cells from immune-stimulating to immunosuppressive. The importance of the GPR65 pathway in cancer is underscored by a small proportion of the population with inactivating polymorphisms showing stratified association with survival when analyzed in The Cancer Genome Atlas.

Pathios is developing drugs to block GPR65 and prevent this signaling, thus conditioning macrophages toward a pro-inflammatory, immune-stimulating phenotype that can reignite an effective antitumor immune response and harness the power of the innate immune system against cancer. Pathios and researchers from the Department of Oncology at the University of Oxford will collaborate on developing the key tools required to enable the rapid translation of small-molecule GPR65 inhibitors for treatment-resistant melanoma. The advent of immunotherapy agents targeting T cell checkpoints (PD-1/CTLA-4) has brought about significant improvements in the long-term survival of many melanoma patients, but only a subset of patients receive sustained benefit from these treatments, and it remains an ongoing challenge to identify additional therapies for the remaining non-responsive population. 

Pathios’ Macrophage Conditioning approach deploys small-molecule GPR65 inhibitors to reverse pH-dependent immunosuppressive signaling in patients who do not carry this genetic change.

Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs, and clinicians. To date, the company has secured a total of $13.2 million in Series A funding from the leading venture capital firms Canaan Partners and Brandon Capital.

Pathios Therapeutics Limited https://pathiostherapeutics.com/

The University of Oxford https://www.ox.ac.uk/