Abstract 746P
Background
Retinoic acid-related Orphan Receptor gamma (RORγ) is a transcription factor that controls the differentiation and maintenance of Th17, Tc17, γδ T and innate lymphoid cells. Abundance of Th17+ cells and high levels of the Th17 cytokine IL-17 are associated with good clinical prognosis and outcomes in some cancers. RORγ is a master controller which tightly regulate the expression of genes, including Th17 cytokines, that are critical in enhancing antitumor immunity and inhibiting immune suppression.
Methods
Novel small molecule INV-71 RORγ agonists were discovered using structure-based drug design against the RORγ ligand-binding domain. Following an iterative medicinal chemistry campaign, promising INV-71 lead candidates were discovered with potent RORγ-inducing properties and antitumor activities.
Results
INV-71 lead compounds induce signature Th17 cytokines IL-17A, GM-CSF gene expression and protein production in mouse and human lymphoid cells. Direct antitumor activity is demonstrated by INV-71 impeding 3D spheroid growth & viability. A favorable pharmacokinetic profile and optimal ADMET properties of INV-71 compounds enabled oral dosing of a selected INV-71 clinical candidate compound in a mouse syngeneic 4T1 breast carcinoma model. BALB/c mice were dosed daily with INV-71 monotherapy p.o. and INV-71 in combination with anti-PD-1 (RMP1-14) administered i.p. b.i.w. versus vehicle controls after orthotopic implantation of 4T1 tumor cells in the mammary fat pad. INV-71 monotherapy inhibited tumor growth on sacrifice Day 21 [p<0.01] with enhanced efficacy observed in the combination treatment arm of INV-71 with anti-PD-1 [p<0.001] demonstrating synergistic effects on tumor growth inhibition versus controls. INV-71 was well-tolerated by tumor-bearing mice which exhibited normal body condition scores and body weight.
Conclusions
The data presented highlight the potential therapeutic utility of pharmacological RORγ activation with synthetic oral INV-71 new chemical entities as a single-agent monotherapy. The synergistic antitumor effects of INV-71 as a combination treatment with anti-PD-1 hold promise as a novel immunotherapeutic treatment modality for cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Innovimmune Biotherapeutics.
Funding
Innovimmune Biotherapeutics.
Disclosure
A. Gaweco: Financial Interests, Personal and Institutional, Ownership Interest: Innovimmune Biotherapeutics. All other authors have declared no conflicts of interest.