The Promise of Adjuvant Epigenetic Therapy in Early Stage Esophageal Cancer. Zhihao Lu M.D. Peking University Cancer Hospital

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1 The Promise of Adjuvant Epigenetic Therapy in Early Stage Esophageal Cancer Zhihao Lu M.D. Peking University Cancer Hospital

Current Treatment Strategies for Early Stage Esophageal Cancer Rate Prognosis Guideline About 10-30% of patients with stage I/IIA esophageal cancer will get

2 Current Treatment Strategies for Early Stage Esophageal Cancer Rate Prognosis Guideline About 10-30% of patients with stage I/IIA esophageal cancer will get recurrence after High recurrence rate Low survival rate (4-5%) No effective treatment (Chemotherapy, Target therapy ) resection. Cancer Stastatics

3 How Does Cancer Establish Metastasis? Nature Medicine 2014;

4 Establish HNM007 Tumor Tissue of Highly Metastatic Ability in C57BL/6 Mice P % recurrence rate Frozen tumor tissue (9-10 d) Resect the primary tumor(0.5cm) Median recurrence time: days. Median survival time after Resection: days. P4 Implant the tumor tissue subcutaneously All times for metastasis to appear Easy to track the metastasis: micro-ct scan, IVIS.

5 Why Adjuvant Epigenetic Therapy?

6 Current Treatment Strategies for Cancer Adjuvant Therapy Chemotherapy: Very low effect; High toxicity Target therapy: No use Radiotherapy: No use Immunotherapy: Uncertain effect; High cost; Severe toxicity

7 Why Epigenetic Therapy? Progression Free Survival Overall Survival Cancer Discov. 2011

8 Epigenetic therapy can prevent the recurrence and prolong the overall survival in HNM007 mouse mode Mock group: day 8 after resection 150 Mock 5mg/kg/d Percent survival mg/kg/d AE 5.0mg group: day 8 after resection survival time(d) Mock 5mg/kg/d 7.5mg/kg/d Mock, 7 mice; 5mg/kg/d group, 8 mice 7.5mg/kg/d group, 8 mice Mock AE 5.0mg AE 7.5 mg Medium survival (day) P value Relative body weight of mice P > Days after treatment 13

9 What is the Potential Target of Adjuvant Epigenetic Therapy

Relative tumor volume Relative body weight of mice The Target of Epigenetic therapy is not tumor cells but tumor microenvironment 4000 3000 2000 1000 20 15 10 5 0 0 Keeping the AZA Dosage constant,

10 Relative tumor volume Relative body weight of mice The Target of Epigenetic therapy is not tumor cells but tumor microenvironment Keeping the AZA Dosage constant, Optimize the dosage and schedule of Entinostat in NSG mice d0 d0 d4 d4 P> Mock d8 Days after treatment d8 Days after treatment * Each group had 5 mice d12 P>0.05 d12 Mock 1mg/kg/d 2.5mg/kg/d 5mg/kg/d 7.5mg/kg/d 1mg/kg/d 2.5mg/kg/d 5mg/kg/d 7.5mg/kg/d Nature Medicine 2014;

11 Nature Reviews cancer 2009; Explore the Target of Epigenetic therapy in tumor microenvironment (Lung tissue) FACS results Cancer Metastasis Tumor

12 CD11b Myeloid-derived Suppressor Cells (MDSCs) M-MDSC G-MDSC Gr-1 Nature Reviews 2009; Nat Immunol (3):

13 Immunosuppressive Mechanisms Employed by Myeloid-derived Suppressor Cells (MDSC) Immunosuppression Immunology Feb;138(2): Nature Medicine 2014; Immunological Investigations, 2012; 41(6 7):

Cells count Cells count T cell Proliferation Tumor bearing mouse spleen M-MDSC % proliferated T cells 80 *** ** *** 60 40 20 CFSE T cell alone 1:4 1:2 1:1 G-MDSC %

14 Cells count Cells count T cell Proliferation Tumor bearing mouse spleen M-MDSC % proliferated T cells 80 *** ** *** CFSE T cell alone 1:4 1:2 1:1 G-MDSC % proliferated T cells :1 1:4 1:2 1:1 M-MDSC: T cell ratio *** ** CFSE T cell alone 1:4 1:2 1:1 MDSC: CD8a T cell ratio 0 0:1 1:4 1:2 1:1 G-MDSC: T cell ratio Unpublished data

15 Cells count Unpublished data T cell Proliferation Human peripheral blood M-MDSC (CD14 + HLADR low/- ) CFSE T cell alone 1:4 1:2 1:1 MDSC: CD8a T cell ratio

16 What is the Role of MDSC in Tumor Recurrance? Unpublished data

17 Deplete MDSCs Can Prevent Lung Metastasis in Vivo Lung metastasis free mice (%) d3 d7 d10 Days after surgery d13 Mock(n=9) IgG(n=7) anti-pd1(n=5) AE(n=8) TIK(n=8) AE+anti-PD1(n=7) D3 d7 d10 d13 Mock 0/6(0%) 6/6(100%) 6/6(100%) 6/6(100%) IgG 0/7(0%) 6/7(85.7%) 7/7(100%) 7/7(100%) Anti-PD1 0/5(0%) 4/5(80%) 5/5(100%) 5/5(100%) Aza+Ent (AE) 0/8(0%) 2/8(25%) 7/8(87.5%) 7/8(87.5%) Anti-MDSC 0/8(0%) 3/8(37.5%) 6/8(75%) 7/8(87.5) Aza+Ent+anti-PD1 0/7(0%) 3/7(43%) 4/7(57.1%) 4/7(57.1%) Unpublished data

18 Deplete MDSCs Can Prolong Overall Survival in LLC Model Percent survival Mock IgG anti-pd1 AE ** TIK * AE+anti-PD1 ** Mock Days after surgery median survival(d) p value IgG Anti-PD AE TIK AE+anti-PD Unpublished data

19 Explore the Mechanism of Adjuvant Epigenetic Therapy to Prevent the Recurrence

20 Low Dosage of Epigenetic Therapy on MDSCs Percentage After 4 Days Culture of MDSCs in Vitro CD11b Mock 5-aza + Ent Gr-1 Unpublished data

21 CD11b Epigenetic Therapy Can Reduce MDSCs in Vivo (Mouse Lung) In Vivo (6 days after resection, mouse lung) 30.28% 6.12% Gr-1 Mock AZA + Entinostat** Unpublished data

22 F4/80 M-MDSC could differentiate to Macrophages after Aza plus Entinostat treatment at Day 4 -- In Vitro Mcok AZA+Entinostat Unpublished data MHC-II

23 CD11c Epigenetic Therapy Can Increase the Lung Macrophages Percentage After 6 Days treatment in Vivo CD68 Unpublished data

24 Gene Expression Array Shows Epigenetic Therapy Can Differentiate Lung Mono-MDSCs to Macrophages Up regulated genes (to macrophage): Mafb, c-maf, Egr-1 and Egr-2 Not for DCs: PU.1 and RelB Unpublished data

25 Epigenetic Therapy Can Differentiate M-MDSCs to Macrophages Immunosuppression Nat Immunol (3): ; Nature Reviews 2009;

26 Therapeutic strategies to re-educate or target the tumor microenvironment Epigenetic Therapy!

27 Future Directions Explore the epigenomic alterations in tumor bearing mice and human MDSCs before and after in vitro treatment with epigenetic modifiers. The Molecule Mechanism of Adjuvant Epigenetic Therapy on the differentiation of M-MDSC. Initialized a new prospective, randomized, phase II adjuvant epigenetic therapy clinical trial in patients with early stage ESCC.

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Supplementary Figure 1. Double-staining immunofluorescence analysis of invasive colon and breast cancers. Specimens from invasive ductal breast

Supplementary Figure 1. Double-staining immunofluorescence analysis of invasive colon and breast cancers. Specimens from invasive ductal breast carcinoma (a) and colon adenocarcinoma (b) were staining