A Novel Immunotherapy: Lyc-55716, A Small-Molecule Ror Gamma Agonist, In Clinical Trials For Head And Neck Squamous Cell Carcinoma

Retinoic acid receptor–related orphan receptor γ-t (RORγ) is the master transcription factor for Type 17 effector T cell differentiation and function. Synthetic RORγ agonists augment the activity of this transcriptional regulator by modulating a gene expression program in immune cells, resulting in enhanced effector functions and decreased regulatory T cell (Treg) activity. LYC-55716 and other RORγ agonists have shown promise as monotherapy and combination therapy in preclinical syngeneic tumor models. In parallel with Phase 1 clinical testing (NCT02929862), preclinical and bioinformatics assessments were performed to evaluate the potential for head and neck squamous cell carcinoma (HNC) tumors to respond to RORγ agonist therapy, for possible inclusion in a Phase 2a trial. A RORγ agonist signature was derived from transcriptional profiling of primary murine and human T cells treated ±RORγ agonists. Using a panel of murine syngeneic models, The Cancer Genome Atlas (TCGA) dataset, and other public datasets, a series of bioinformatic analyses were conducted to provide information on HNC tumors with regard to (a) expression of RORγ and RORγ-inducing cytokines; (b) RORγ biology and surrogate indicators of endogenous RORγ ligands correlated with prognosis; (c) immune profiles within the tumor microenvironment. Tumor-infiltrating lymphocytes (TILs) and PBMCs from HNC patients were assessed for RORγ expression and the effects of a RORγ agonist. Target expression: Analysis of TCGA RNAseq data determined that HNC was one of 15 tumors types for which >20% of samples expressed the highest levels of RORγ. TCGA analysis also showed that RORγ-inducing cytokines IL-6, IL-23α, and IL-1β were highly expressed in HNC tumors. In a small cohort of HNC patients, a significant fraction of CD4+ TILs expressed RORγ. Target biology: TCGA analysis indicated low expression of sterol synthesis and efflux genes in HNC. Analyses of TCGA and public datasets found high expression of RORγ and agonist signature genes in HNC tumors was associated with improved survival. Immune profiles: In TCGA, HNC tumors are associated with high mutational burden and infiltration of immune cells. Preclinical data from syngeneic tumor models, bioinformatic analyses of TCGA dataset, and the expression of RORγ and its correlation with improved survival support the selection of HNC for inclusion in a Phase 2a clinical trial.