Immuno-oncology and immunotherapy resistance
Over the last decade, cancer treatment has been revolutionized by immunotherapy such as anti-PD-1 immunotherapy that results in significant and lasting clinical responses for a variety of refractory cancers. However, despite their game-changing potential, immunotherapy drugs benefit only to a small proportion of the cancer population and most patients do not respond to or ultimately experience immunotherapy resistance. The mechanisms underlying this resistance are very complex and often involve multiple aspects such as gene dysregulation, metabolic dysfunction, inflammation, and neovascularization.
Immunotherapy resistances are mediated by multiple immunosuppressive pathways and are classified in two forms: the primary and the acquired resistances. The first one consists in the clinical situation where a patient does not respond to immunotherapy, the second one in a situation where a tumor can initially respond to immunotherapy but relapses after a period.
Immunotherapy resistance programs at Domain Therapeutics
Domain’s objective is to identify novel GPCR-based mechanisms of immunotherapy resistance and to develop new drug candidates targeting these mechanisms. To that end, Domain Therapeutics has set-up a unique platform for the identification and validation of GPCRs involved in resistance against immune checkpoint inhibitors and based on a cross validation between preclinical and clinical data. This platform includes mouse models treated with immune checkpoint inhibitors and early biopsy analysis, as well as clinical information to cross-validate novel GPCR targets. Of note, Domain Therapeutics has already launched two programs based on immunotherapy resistance: the A2AR-A2BR dual antagonist with candidate M1069 licenced to Merck KGaA and the EP4R-antagonist with candidate DT-9081.