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oRetinoic acid receptor–related orphan receptor g (RORg) is the master transcription factor responsible for type 17 effector T cell differentiation and function.
o Synthetic RORg 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 (Figures 1 & 2).1
oRORg agonists have shown promise as monotherapy and combination therapy in syngeneic tumor models.
LYC-55716, A Novel Small-Molecule RORg Agonist Immuno-oncology Agent: Rationale for Tumor Selection and Clinical Evaluation of Gastric and Esophageal Carcinoma in Phase 2a Expansion
Garry Weems,1 Xiao Hu,2 Xikui Liu,2 Hongxiu Li,2 Madhumita Bogdan,2 Yilin Gao,2 Brian Fox,3 H. Jeffrey Wilkins,1 Laura Carter2
1Lycera Corp., Plymouth Meeting, PA; 2Lycera Corp., Ann Arbor, MI; 3Celgene Corp., Seattle, WA.
o The infiltration of T cells into the tumor microenvironment is positively associated with immunotherapy efficacy.
o Analysis of TCGA RNA sequencing data indicated a high expression of T cell markers such as CD3e in both EC and GC (Figure 8).
o Certain sterols can function as RORg ligands and partially activate RORg,2 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 are expected to respond better to RORg agonist therapy.o TCGA data showed that GC and EC tumors express low levels of sterol
efflux genes, suggesting that the levels of endogenous agonists in the tumor microenvironment are also low (Figure 6).
Figure 3. Factors considered in tumor selection
Figure 6. Expression of sterol efflux genes across tumor types
o Bioinformatics assessments indicate high expression of RORg, and genes that support RORg expression, in GC and EC tumors.
o Analyses of RORg biology suggest that GC and EC tumors are likely to respond to RORg agonist therapy.o High intratumoral expression of RORg target gene is correlated with
improved survival for patients with GC and EC.
o Immunotherapy efficacy is correlated with high levels of TILs and high mutational burden, both of which occur in GC and EC.
o In summary, these analyses support the inclusion of GC and EC patients in an ongoing Phase 2 clinical trial of LYC-55716 (Table 2).
Figure 8. Tumor-infiltrating lymphocytes across tumor types
1. Hu X, et al. OncoImmunology. 2016;5:e1254854.2. Hu X, et al. Nat Chem Biol. 2015;11:141-7.3. Lv L, et al. PLoS One. 2011;6:e18219.4. Lu L, et al. J Immunother. 2013;36:451-8.5. Wang B, et al. Cancer Immunol Immunother.
2013;62:1575-85.
6. Lida T, et al. Oncol Rep. 2014;31:605-12.7. Chen J, et al. Int J Biol Sci. 2011;7:53-60.8. Lawrence MS, et al. Nature. 2013;499:214-8.9. Alexandrov LB, et al. Nature. 2013;500:415-21.
CONCLUSIONS
o Analysis of TCGA RNA sequencing data showed that 50% of EC and 70% of GC samples expressed moderate to high levels of RORgt (RORC2), indicating infiltration of Type 17 T cells into the tumors (Figure 4).
Figure 4. Frequency of RORgt expression across tumor types
Figure 7. Correlation between patient survival and IL-17 expression in published data 3,7
o A high mutational burden within the tumor microenvironment has also been associated with immunotherapy efficacy and progression-free survival (Figure 9).8,9
o TCGA analysis indicated a high mutational burden in both EC and GC.
Figure 5. Frequency of expression of genes that support RORgt expression
Figure 1. RORg agonist as a novel immuno-oncology approach
Abstract #67
o Genes such as IL6, IL17A, and IL23A also support RORgt induction and the formation of type 17 cells; tumors that highly express these genes may be more responsive to RORg agonist therapy.
o RORgt-supportive genes were highly expressed in ~75% of GC and EC tumors (Figure 5).
o A literature review indicated a significant survival advantage for EC and GC patients who have high intratumoral IL-17 expression and high levels of IL-17–producing tumor-infiltrating lymphocytes (TILs), compared with patients with low levels of IL-17+ TILs (Figure 7, Table 1).3-7
Figure 9. Mutational burden across tumor types
TARGET BIOLOGY
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
NSCLCRenal
HNSCCLiver
GEOvarian
Urothelial Cancer
Target Expression• RORg expression• RORgt-inducing microenvironment• 25 tumor types
Clinical program identified tumor types that meet at least 2 of 3 categories
Immuno-oncology Proof of Concept• Immunotherapy responsive tumors• Tumors with immune infiltrates• Mutation burden
Figure 2. RORg agonist LYC-55716 decreases coinhibitory molecules and increases costimulatory molecules
Table 2. Tumors selected for inclusion in Phase 2a expansion
o The first-in-class, oral, small-molecule LYC-55716 is an investigational agent that selectively activates RORg.
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 During Phase 1 testing, bioinformatics assessments were conducted to support the inclusion of patients with gastric carcinoma (GC) and esophageal carcinoma (EC) in a Phase 2a expansion trial (NCT02929862) (Figure 3).
• The Cancer Genome Atlas (TCGA), other public datasets, and literature review
• Expression of RORg and RORg-inducing cytokines, signature genes associated with RORg biology, surrogate biomarkers for endogenous RORg ligands
• Immune profiles of the tumor microenvironments• Correlates to patient prognosis/survival
Gastroesophageal (GE), Non–Small-Cell Lung Cancer (NSCLC), Head & Neck Squamous Cell Carcinoma (HNSCC)
Table 1. Published findings of the correlation between patient survival and IL-17 expression
TARGET EXPRESSIONIMMUNE PROFILE
-80 -40 0 40 80 120
PD1
TIGIT
CD160
LAIR1
TIM3
LAG3
CD73
CD39
CD226
CD27
CD137
IL17A
% Change from Control
80%
Tumor Type N Findings Reference
Esop
hage
al S
quam
ous
Cel
l Car
cino
ma
181
• Density of IL-17+ TILs was inversely correlated with T score
• EC patients with IL-17high TILs had significant survival advantage over those with IL-17low TILs
Lv T, et al.,20113
• IL-17A promoted immune cell recruitment in human EC and infiltrating dendritic cells
• High CD1a+ dendritic cells were associated with improved survival
Lu L, et al., 20134
215
• Density of IL-17+ cells in muscularis propriaserved as independent predictor of favorable survival
• Levels of IL-17+ cells in muscularis propriawere positively associated with CD8+ T cells and activated macrophages
Wang B, et al., 20135
Gas
tric
Car
cino
ma
79 • IL-17 in peritoneal lavage correlated with improved overall survival
Lida T, et al.,20146
192 • High levels of intratumor IL-17 showedsignificantly better 5-year overall survival
Chen J, et al., 20117
INDICATION
Non–small-cell lung cancer
Gastroesophageal cancer
Head and neck squamous cell carcinoma
Ovarian cancer
Renal cell carcinoma
Urothelial carcinoma
Targets RORg nuclear receptor, the master
transcription factor for Type 17 T cells
1
RORg agonists activate a transcriptional program
to modulate dual immuno-oncology
pathways
2
Immune system killing of tumor cells & generation of anti-
tumor memory
3
RORg AGONISTDECREASES IMMUNESUPPRESSION
• Decreases regulatory T cells• Lowers PD-1 expression and function• Decreases coinhibitory molecule expression
RORg AGONISTINCREASES IMMUNEACTIVITY
• 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
RORg activationbyagonistregulatestranscriptionoftargetgenes
Cancercells
TcellsOtherimmunecells
DNA/chromatin
TcellAgonist
Targetgene
RORg
RORg
Target-drivenresponsesproducebeneficialanti-tumoreffects
Target Biology• Endogenous ligand RORg
expression & prognosis• RORg agonist signature &
prognosis• 7 tumor types