Pancreatic cancer oral inverse agonist of RORgT receptor targets primary cancer cells and alters inflammatory mediators of the tumor microenvironment

Pancreatic cancer is the fourth deadliest cancer for both men and women. Current five-year survival rate is 12% increased to 44% for the 15% with localized disease and most patients prsent with advanced or metastatic disease. The backbone of therapy has been gemcitabine and more recently in combination with Nab-paclitaxel or FOLFIRINOX regimens however the incremental gains in survival range from 2-4.5 months 1,2 with a heavy cost of quality of life due to the side effects. The use of immune checkpoint inhibitors (ICI) have not been as effective in pancreatic cancer as some other malignancies. 3 This ICI resistance may be due to T cell exclusive tumor associated neutrophils and macrophages that have been shown to be induced by IL-17. New approaches that not only target primary tumor cells but also alter the tumor immune microenvironment (TIME) could prove beneficial. Translational work suggests the RORgT receptor is a promising target with patient-derived pancreatic cancer xenografts responsive to an inverse agonist. RORgT receptor is a ligand-dependent transcription factor that regulates multiple pro-inflammatory genes, including driving the differentiation of T helper cells to Th17 cells. Three healthy human volunteer studies have been conducted with the novel oral inverse agonist XT-0528.

Pre-clinical data review of a novel high-affinity RORgT inverse agonist and the results ofthree healthy human phase 1 studies.

Standard pre-clinical toxicology studies were conducted in Sprague-Dawley rats and beagles with both single and multiple day dosing up to 2000mg/kg dose of XT-0528 with no adverse events in body weight, food consumptions, cardiovascular, clinical, or gross pathology and no dose limiting toxicities identified. The drug demonstrated dose dependent pharmacokinetics and improvement in clinical score and locomotor activity as well as a reduction in IL-17 expression in a recognized autoimmune encephalitis model. Three healthy human volunteer studies have been performed with 78 subjects receiving drug in single and multiple ascending doses. The drug exhibited a linear dose response with 93% bioavailability of the s isomer. Adverse events were limited and mild with complete resolution. The half-life of the drug is 22.5 hours.

RORgT and the IL-17 pathway is a well-recognized target for inflammatory conditions, and increased expression is associated with a worse prognosis for various cancers. XT-0528 is a high-affinity RORgT inverse agonist with a demonstrated reduction in the key inflammatory cytokine IL-17 and a very good safety profile that is a promising agent for pancreatic cancer. Translational work demonstrates increased RORgT expression in human pancreatic cancer and RORgT inhibition led to tumor regression within a human xenograft tumor model. 4 Pre-clinical and healthy human data suggest that XT-0528 is very well tolerated and effective in blocking RORgT. XT-0528 could decrease Th17 induced inflammation shifting the pool of T cells to Th1 differentiation resulting in a more favorable TIME. A phase 1 study in an advanced and metastatic solid tumor population will use safety and biomarker activity to define the RP2 dose.

NCT03237832 NCT04514237 NCT03464058.

The authors.

Has not received any funding.

D. Johnson: Honoraria (self): Bristol Meyer Squibb, Xenthera; Speaker Bureau / Expert testimony: Bristol Meyer Squibb. D. Bearss: Shareholder / Stockholder / Stock options: Xenthera Inc. The author has declared no conflicts of interest.