Novel small-molecule RORγ agonist immuno-oncology agent LYC-55716: Tumor selection and evaluation of renal cell and bladder cancer for inclusion in phase 2a expansion
| Autor: | Laura L. Carter, Brian Fox, Xikui Liu, H. Jeffrey Wilkins, Xiao Hu, Hongxiu Li, Yilin Gao, Garry Alan Weems, Elizabeth Zawidzka |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 36:424-424 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2018.36.6_suppl.424 |
| Popis: | 424 Background: The master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ) controls Type 17 effector T cell differentiation and function. Synthetic RORγ agonists modulate gene expression to enhance immune effector functions and decrease regulatory T cell (Treg) development and expression of checkpoint pathways. RORγ agonists have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics analyses were performed to evaluate renal cell carcinoma (RCC) and bladder cancer (BC) for inclusion in a Phase 2a expansion trial of the investigational RORγ agonist LYC-55716 (NCT02929862). Methods: A gene signature was identified through transcriptional profiling of murine and human T cells treated ± RORγ agonists. Bioinformatics analyses were then conducted using data on RCC and BC patients from The Cancer Genome Atlas (TCGA) to determine (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, biomarkers for endogenous RORγ ligands, and correlations with patient survival rates; and (c) tumor microenvironment (TME) immune profiles. Results: Expression: RNA sequencing analysis identified RORγ+ cells in a significant fraction of RCC and BC samples. RORγ-inducing cytokines IL6, IL23a, and IL1b as well as other genes that support Type 17 differentiation were highly expressed in RCC and BC. Biology: Low expression of sterol efflux genes in RCC and BC tumors suggested low levels of endogenous RORγ ligands in the TME. Importantly, analysis revealed a positive correlation between patient survival and expression of RORγ (or the RORγ signature gene IL17A) for RCC. Immune profile: Analysis of RCC and BC tumors indicated high infiltration of CD3+, CD4+, and CD8+ T cells and high mutation burden, which are associated with immunotherapy efficacy. Conclusions: Translational and bioinformatics studies of RORγ expression, biology, and tumor immune profiles support the inclusion of RCC and BC patients in an ongoing Phase 2a expansion trial of LYC-55716. |
| Databáze: | OpenAIRE |
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