Impact of relacorilant, a selective glucocorticoid receptor antagonist, on the immunosuppressive effects of endogenous cortisol.

Abstract

3091 Background: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, and immune cell trafficking. By selectively antagonizing GR, relacorilant may reverse the immunosuppressive effects of cortisol in solid tumor cancers. Methods: Immune cells and GR expression were assessed by IHC and calculated based on The Cancer Genome Atlas (TCGA) data. Human PBMCs were stimulated with αCD3+IL-12 +/- cortisol or cortisol + relacorilant. EG7 tumor-bearing mice were treated with anti-PD1 (RMP1-14) ip Q5D +/- relacorilant QD. Whole blood mRNA was measured via Nanostring, hematology was performed using standard complete blood count assays, and cytokines were assessed by immunoassays in study NCT02762981. Results: GR expression was observed in human tumor and immune cells. Its abundance was positively correlated with tumor infiltration of TH2, Treg, and PDL1+ cells ( P< .001) and negatively correlated with TH1 cells ( P< .001). In PBMCs, cortisol inhibited, and relacorilant restored, CD8+ T-cell activation ( P< .001) and pro-inflammatory cytokine secretion (TNFα P= .006, IFNγ P< .05). In the EG7 syngeneic model, relacorilant increased αPD1 efficacy ( P= .007) and decreased circulating IL-10 ( P< .002). In patients with advanced solid tumors, relacorilant + nab-paclitaxel systemically suppressed the expression of canonical GR-controlled genes ( ptgs2 P< .001) and genes encoding candidate-immunomodulatory drug targets ( cxcl8, ptger4, ido1; P< .001). In a small subset of patients (n = 11), sustained clinical response was associated with increased T-cell count ( P= .06) and IFNγ ( P= .03), as well as decreased Tregs ( P= .06) and IL-10 ( P= .03). Conclusions: Evidence of T-cell activation by relacorilant was observed in PBMCs, syngeneic mouse tumors, and patients with sustained response in a Phase 1 study. This supports the hypothesis that relacorilant can reverse immune suppression by endogenous cortisol in solid tumor cancers. Clinical studies with immune checkpoint inhibitors and relacorilant are planned.