IFN-gamma signature-driven neoadjuvant domatinostat, nivolumab and ipilimumab in stage III melanoma – the DONIMI trial

Low baseline Interferon gamma (IFNg) response signature is associated with lack of response to neo-adjuvant anti-PD1 + anti-CTLA4 therapy in patients with melanoma. Domatinostat, a class I specific histone deacetylase inhibitor is known to induce IFNg response in patients with advanced stage melanoma. Thus, addition of domatinostat to anti-PD1 + anti-CTLA4 might result in increased response to treatment. However, the effect of this combination therapy on tumor growth has not been evaluated in the pre-clinical setting. We therefore evaluated whether addition of domatinostat results in immune modulation and tumor growth control in the MeVa2.1.dOVA murine melanoma model. We provide pre-clinical evidence to use this combination in melanoma patients. Overall design: 8-week-old female C57BL/6 mice were injected s.c with MeVa2.1.dOVA cell line in the right flank. When average tumor volume reached 100 mm3, mice were randomized into treatment arms based on tumor volume. Mice received vehicle control, domatinostat, antiPD1 + anti-CTLA4, or domatinostat + antiPD1 + anti-CTLA4. Domatinostat (20 mg/kg) was administered twice daily via oral gavage. Anti-PD1 (100 ug per mouse) and anti-CTLA4 (50 ug per mouse) were administered two times per week intraperitoneal. Mice were sacrificed after 13 days of treatment and tumors were harvested for RNA seq analysis (n=4 mice per arm were used for RNA seq analysis).