Synergistic combinations of targeted immunotherapy to combat cancer

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1 Synergistic combinations of targeted immunotherapy to combat cancer Myung Ah Lee, M.D., Ph. D Division of Medical Oncology, Hepato-biliary pancreatic cancer center Seoul St. Mary s hospital, The Catholic University of Korea

2 Current systemic treatment in advanced HCC sorafenib only approved standard 1 st line agent median survival months No longer survival beyond 10 months

3 No longer survival beyond 10 months Gong et al, World J Gastroenterol, 2016

4 Emerging systemic treatment immunotherapy oncolytic vaccine immunotherapeutic vaccine immune check inhibitor target delivery drug system cytotoxic agents various target agents

5 Emerging systemic treatment immunotherapy oncolytic vaccine immunotherapeutic vaccine immune check inhibitor target delivery drug system cytotoxic agents various target agents

6 Immunosuppressive microenvironment disappointing previous trials with immunotherapy reasons strong intrinsic immune suppressive microenvironment fail to effective anti-tumor activities induce intrahepatic tolerogenicity by liver cell induce anergic CD8+ T cell tolerogenic APC cells hepatocyte liver sinusoidal endothelial cells Kupffer cell liver dendritic cell

7 Immunotherapy in HCC Cellular immunotherapy Passive immunotherapy cytokine-induced killer cell NK or NKT cell adoptive cell transfer of tumor infiltrating lymphocytes (TILs) Active immunotherapy dendritic cells Non cellular immunotherapy peptide based vaccine oncolytic immunotherapy

8 Cytokine-induced killer (CIK) cells peripheral cell treated with IFN-r, anti-cd3 Ab, IL-2 expression of CD3 T cell & CD56 NK cell Li et al, Clin Res Hepatol Gatroenterol, 2014

9 Li et al, Clin Res Hepatol Gatroenterol, 2014

10 NK and NKT cells NK cells inhibited anti-tumor activity in advanced HCC reactivation by RFA or liver resection effective in HCC in preclinical study completed phase II trials waiting results NKT cells both immunosuppressive and immunoactive ongoing phase I trial in advanced HCC

11 adoptive TILs transfer autologous T cells activated and expanded ex vivo effect in immunogenic tumor with adequate host immune response ongoing phase I trial safe result in preliminary data

12 Dendritic cell vaccine immature phenotype and impaired function of DC in HCC fail to induction of anti-tumor immune response deletion an antigen specific cell expansion of regulatory T cell establishment of the HCC immunosuppressive microenvironment DC-based vaccine activating DC in vitro with Ag and reinfusion safe in current phase I/II but controversial efficacy

13 Immunotherapy in HCC Cellular immunotherapy Passive immunotherapy cytokine-induced safe killer & feasible cell treatment controversial NK or NKT cell effect to prevent recurrence or survival prolongation Active more immunotherapy effective with low burden of micrometastasis adoptive cell transfer of tumor infiltrating lymphocytes (TILs) dendritic cells Non cellular immunotherapy peptide based vaccine oncolytic immunotherapy

14 Peptide based cancer vaccine limited data for HCC no specific antigen or targeting to HCC telomerase reverse transcriptase (TERT) Wilms tumor 1(WT-1) candidate antigen glypican 3 (GPC3) MAGE-A SSX-2 NY-ESO-1

15 Oncolytic immunotherapy JX-594 (Pexa-Vec) phase II trial in advanced HCC similar response rate in low or high dose survival benefit in higher dose (14.1 vs. 6.7 months) ongoing trial with/without sorafenib

16 Immunotherapy in HCC Cellular immunotherapy Passive immunotherapy cytokine-induced killer cell NK or NKT cell adoptive cell transfer of tumor infiltrating lymphocytes (TILs) Active immunotherapy dendritic cells Non cellular immunotherapy peptide based vaccine oncolytic lack of HCC immunotherapy specific Tumor associated antigen

17 Immune check point inhibitors anti-ctla-4 antibody RR 18%, DCR 76%, TTP 6.48 months in 21 patients combination with TACE or RFA in 10 patients 4 PR, PFS 7.4 months anti-pd-1 antibody upregulated PD-L1, L2 in HCC ongoing trials as 1 st or 2 nd line treatment promising data in interim analysis

18 Immune stimulatory approach induce immunogenic microenvironment in HCC tumor ablation cytotoxic chemotherapy target agents

19 Tumor ablation 1st treatment option for early HCC high temperature RFA heat induced necrosis release immunogenic intracellular substrates - nucleic acid, heat shock proteins, cytokines, high mobility group protein B1. induce significant immune infiltrates in tumor transition zone induce activation of circulating DCs increased GPC3-specific cytotoxic T cells local therapy and immunotherapy to induce TAA specific cytotoxic T cell

20 cytotoxic chemotherapy temporary immunosuppressive rebound replacement of active immune cell generating immune environment potentiate effects of anti-cancer vaccines

21 CRT Calreticulin; HMGB1 high mobility group box 1 Kroemmer et al, Annu Rev Immunol, 2013

22 gemcitabine induced CD4 T cell Plate et al, Cancer Immunol Immunother 2005

23 chemotherapy induce MHC class I expression Liu et al, Br J Cancer 2010

24 platinum increase T cell proliferation Lesterhuis et, J Clin Invest 2011

25 Tyrosine kinase inhibitor targeting multicomponent of tumor microenvironment induce immunogenic modulation Tumor infiltrating immune cell recruit by vascular change expect synergistic effect with immunotherapy

26 Tagliamonte et al, Curr Opin Immunol, 2016

27 Considering point underlying liver function drug interaction of combination in vivo sequence duration response metabolism co existing various factors viral infection, chronic inflammation

28 Summary No promising regimen as single treatment modality effective combination regimen based on immunologic response current standard local treatment + immunotherapy target agents + immunotherapy cytotoxic chemotherapy + immunotherapy require clinical trial with combination based on research data