ROR Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: … · 2018. 1. 29. · efficacy and...

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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 Hu 1 1 Lycera Corp., Ann Arbor, MI; 2 Celgene Corp., Seattle, WA; 3 Lycera 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. RORγ t expression across tumor types Figure 5. Correlation between RORγ t 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 RORγ t 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). Healthy Donor NSCLC -5 0 5 10 15 RO RC2 Relative Expression Healthy Donor NSCLC 0 2 4 6 8 IL17A IL17A Relative Expression A. 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 B. Healthy Donor NSCLC 0 1 2 3 4 5 IL26 IL-26 Relative Expression D M SO Agonist 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 patients 2,3 * 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 1 RORγ agonists activate a transcriptional program to modulate dual immuno- oncology pathways 2 Immune system killing of tumor cells & generation of anti- tumor memory 3 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

Transcript of ROR Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: … · 2018. 1. 29. · efficacy and...

Page 1: ROR Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: … · 2018. 1. 29. · efficacy and levels of TILs in the tumor microenvironment.5,6 o Analysis of TCGA RNA sequencing

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).

H e a l t h y D o n o r N S C L C

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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

B.

H e a l t h y D o n o r N S C L C

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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

*

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

1

RORγ agonists activate a transcriptional program to

modulate dual immuno-oncology pathways

2

Immune system killing of tumor cells &

generation of anti-tumor memory

3

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