ROR Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: … · 2018. 1. 29. · efficacy and...
Transcript of ROR Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: … · 2018. 1. 29. · efficacy and...
o Retinoic acid receptor–related orphan receptor γ (RORγ) is the master transcription factor responsible for type 17 effector T cell differentiation and function.
o Synthetic RORγ agonists can modulate immune cell gene expression by enhancing type 17 helper (Th17) and cytokine (Tc17) T cells, stimulating a potent antitumor response that includes increased immune activity and decreased immune suppression (Figure 1).1
o RORγ agonists have shown promise as monotherapy and combination therapy in syngeneic tumor models.
o LYC-55716 is a first-in-class, oral, small-molecule investigational agent that selectively activates RORγ.
o Phase 1 clinical testing of LYC-55716 identified a pharmacodynamically active dose and demonstrated that this agent was well tolerated in cancer patients.
o Preclinical and bioinformatics assessments were conducted to support the inclusion of patients with non–small cell lung cancer (NSCLC) in a Phase 2 expansion trial (NCT02929862).
RORγ Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: Rationale for Clinical Evaluation in Non–Small Cell Lung Cancer Based on Translational and Bioinformatic Evaluation
Laura Carter,1 Xikui Liu,1 Hongxiu Li,1 Elizabeth Zawidzka,1 Yilin Gao,1 Brian Fox,2 Garry Weems,3 H. Jeffrey Wilkins,3 Xiao Hu1 1Lycera Corp., Ann Arbor, MI; 2Celgene Corp., Seattle, WA; 3Lycera Corp., Plymouth Meeting, PA.
o Studies have shown a positive correlation between immunotherapy efficacy and levels of TILs in the tumor microenvironment.5,6
o Analysis of TCGA RNA sequencing data indicated a high expression of T cell markers such as CD3e in NSCLC samples (Figure 7).
o Certain sterols can function as RORγ ligands and partially activate RORγ,4 but sterol levels are likely low in exhausted T cells and can be influenced by cancer cells in the tumor microenvironment. o TCGA analysis of sterol efflux gene expression (a surrogate for
endogenous ligand levels) revealed differential expression across tumor types (Figure 6).
o Tumor types with low sterol efflux may respond better to RORγ agonist therapy. o NSCLC tumors from TCGA dataset expressed low levels of sterol efflux
genes; this suggested that levels of endogenous RORγ agonists in the tumor microenvironment were also likely low (Figure 6).
Figure 6. Expression of sterol efflux genes across tumor types
o NSCLC tumors highly express RORγ and RORγ-inducing genes, and this expression is correlated with improved patient survival.
o High levels of TILs and high mutational burden, both associated with immunotherapy efficacy, occur in NSCLC.
o Bioinformatic analyses suggest that immune cells from NSCLC patients are likely to respond to RORγ agonist therapy. This was supported by experimental data showing PBMCs from NSCLC patients express increased IL-17A and IL-26 in response to RORγ agonist treatment
o These analyses support the inclusion of patients with NSCLC in an ongoing Phase 2 clinical trial of LYC-55716 (Table 1).
Figure 7. TILs across tumor types
1. Hu X, et al. Oncoimmunology. 2016;5:e1254854. 2. Punt S, et al. Oncoimmunology. 2015;4:e984547. 3. Zeng Y, et al. Int J Clin Exp Med. 2015;8:10515-
36. 4. Hu X, et al. Nat Chem Biol. 2015;11:141-7.
5. Alexandrov LB, et al. Nature. 2013;500:415-21. 6. Lawrence MS, et al. Nature. 2013;499:214-8. 7. Chen J, et al. Int J Biol Sci. 2011;7:53-60. 8. Lawrence MS, et al. Nature. 2013;499:214-8.
o Analysis of TCGA RNA sequencing data showed that approximately 35%-40% of NSCLC samples showed elevated RORγt (RORC2) expression, indicating infiltration of type 17 T cells into NSCLC tumors (Figure 3A).
Figure 3A. RORγt expression across tumor types
Figure 5. Correlation between RORγt expression and patient survival
o The immune system may recognize tumors with a high mutational burden; patients with such tumors have shown improved response to immunotherapy and longer progression-free survival.7,8
o High mutational burden has been noted in NSCLC tumors (Figure 8).
Figure 3B. Frequency of expression of genes that support RORγt expression
Figure 1. RORγ agonist as a novel immuno-oncology approach
Abstract #171
o TCGA analyses demonstrated a survival advantage for patients with NSCLC displaying high intratumoral expression of RORγ (Figure 5).
Figure 8. Mutational burden across tumor types
REFERENCES
DISCLOSURE: LYC-55716 is an investigational agent not yet approved by FDA: the safety and efficacy of LYC-55716 have not been established in patients. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster. CLINICAL TRIAL CONTACT: [email protected]
BACKGROUND & STRATEGY
INDICATION Non–small cell lung cancer
Gastroesophageal cancer Head and neck squamous cell carcinoma
Ovarian cancer Renal cell carcinoma Urothelial carcinoma
TARGET EXPRESSION
IMMUNE PROFILE
CONCLUSIONS
TARGET BIOLOGY
Table 1. Tumors selected for Phase 2a Expansion
o The Cancer Genome Atlas (TCGA) dataset was evaluated for (Figure 2): o Expression of RORγ and RORγ-inducing cytokines and correlations
between expression and survival; o Genes related to RORγ biology and biomarkers for endogenous RORγ
ligands; and o Immune profiles of the tumor microenvironment.
o IL6, IL1β, and IL23A support RORγt induction and the formation of type 17 cells; tumors that highly express these genes may be more responsive to RORγ agonist therapy. o Approximately 50% of NSCLC tumors highly expressed genes that support
RORγt expression (Figure 3B).
o Experimental data show that approximately 12% of CD4+ tumor infiltrating lymphocytes (TILs) expressed RORγ in lung cancer. In contrast, ~5% of PBMCs from healthy donors expressed RORγ (Figure 4A).
o PBMCs from patients with NSCLC showed increased expression of RORγt compared with healthy donors (Figures 4A/B).
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o RORγ agonist treatment of PBMCs from NSCLC patients increased expression of target genes IL17A and IL26 (Figures 9A/B).
o Taken together, these analyses suggest that immune cells from NSCLC patients express RORγ (Figures 4A/B) and may respond to RORγ agonists.
Figure 9. PBMC expression of target genes IL17A and IL26
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D M S O
A g o n i s t
NSCLC Renal
HNSCC Liver
GE Ovarian
Urothelial Cancer
Target Expression • RORγ expression • RORγτ−inducing
microenvironment • 25 tumor types
Clinical program identified tumor types that meet at least 2 of 3 categories
Target Biology • Endogenous ligand RORγ
expression & prognosis • RORγ agonist signature &
prognosis • 7 tumor types
Immuno-oncology Proof of Concept • Immunotherapy responsive tumors • Tumors with immune infiltrates • Mutation burden *green line= cutoff at the lowest 33% of the range
o Literature data indicate that high expression of RORγt target gene IL17A also has better prognosis in NSCLC patients2,3
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o As a result of these analyses NSCLC was selected as a potential expansion indication and additional testing was performed: o RORγ expression and the in vitro effects of a RORγ agonist on peripheral
blood mononuclear cells (PBMCs) were assessed from patients with NSCLC.
Figure 4. Expression of RORγt
NSCLC (adenocarcinoma)
A. TILs by Flow Cytometry B. PBMCs by qPCR GE, gastroesophageal; HNSCC, head & neck squamous cell carcinoma.
Figure 2. Factors considered in tumor selection for the clinical program
Targets RORγ nuclear receptor, the master
transcription factor for Type 17 T cells
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RORγ agonists activate a transcriptional program to
modulate dual immuno-oncology pathways
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Immune system killing of tumor cells &
generation of anti-tumor memory
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RORγ AGONIST DECREASES IMMUNE SUPPRESSION
• Decreases regulatory T cells • Lowers PD-1 expression and function • Decreases coinhibitory molecule expression
RORγ AGONIST INCREASES IMMUNE ACTIVITY
• Enhances expression of costimulatory receptors • Increases pro-immune chemokines and cytokines • Increases effector cells in tumors • Prolongs survival and memory responses of anti-
tumor T cells
RORγ activation by agonist regulates
transcription of target genes
Cancer cells
T cells Other immune cells
DNA/chromatin
T cell Agonist
Target gene
RORγ
RORγ
Target-driven responses produce beneficial anti-tumor effects