The acidic tumour microenvironment inherent to all solid cancers causes a profound immunosuppression of infiltrating immune cells. This disarms the anti-cancer immune response and negates and renders current immunotherapies ineffective. This is particularly evident in tumour associated macrophages (TAMs), where acidity is sensed by the cell-surface receptor, GPR65, leading to a host of transcriptional changes in these cells that can explain many of the defining features of the immunologically hostile tumour microenvironment (TME). These include an upregulation of angiogenic and wound healing factors, a reduction of key chemokines and cytokines and a suppression of interferon and antigen presentation genes.
Pathios is developing drugs to block GPR65 signalling, thereby conditioning macrophages toward a pro-inflammatory, immune-stimulating phenotype that can reignite an effective anti-tumour immune response and harness the power of the innate immune system against cancer. Unlike most other novel approaches in immuno-oncology, targeting GPR65 has the potential to deliver profound monotherapy activity in a host of currently hard-to-treat myeloid-dominated tumours.
GPR65 inhibition counteracts low pH-induced immunosuppressive effects on immune cells and displays pronounced anti-tumor activity in mice: identification of PTT-4256 as a clinical drug candidate.