Combinations with cytotoxics, targeted agents and molecular therapy

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1 Combinations with cytotoxics, targeted agents and molecular therapy Alfred Zippelius Medical Oncology Laboratory of Cancer Immunology & Biology University Hospital Basel Department of Biomedicine, University Basel SAMO Immunotherapy 18./

2 PDLoma the spectrum of PD-1 and PD-L1 antibodies in many types of cancer OS benefit ORR 15% OS benefit OS benefit ORR 20% ORR 25% ORR 12-25% ORR 20% ORR 15% ORR 65-85% ORR 60% Modified, Michot, Eur J Cancer 2015

3 Yet only a minority of patients respond. > 70% Rizvi et al., Lancet Oncology 2015

4 Limitations of Cancer Immunotherapy Limited CTL activation and expansion Insufficient T Cell Homing Low Frequency of Tumor Antigen-specific T cells Chen&Mellman, Immunity 2013 Lack of Antigen Recognition Suboptimal Antigen Presentation Immune Suppressive Milieu (e.g. Treg, MDSC, IDO, VEGF, IL-10, PGE2, TGF-β) Insensitivity to pro-apoptotic signals from immune cells

5 Improving efficacy evolving synergistic immunotherapy combinations with conventional anti-cancer therapies Elimination Escape Equilibrium Immunoediting Oncogenesis and tumor progression along with failing immunosurveillance Reinstatement of immunosurveillance by anti-cancer therapy On-target & off-target effects breaks the barrier between molecular (tumor cell centered) and immune-mediated (tumor stroma centered) approaches!

6 Improving efficacy evolving synergistic immunotherapy combinations with conventional anti-cancer therapies Galluzzi, Cancer Cell 2015

7 What do we want to achieve with combinations? Survival? Control Targeted therapies / chemotherapies Immune checkpoint blockade Combination therepies Time -> increase the percentage of patients achieving durable responses

8 Evolving synergistic immunotherapy combinations with standard of care to reprogram the tumor environment Non-inflamed cancer no/limited response to treatment Inflamed cancer Active response to treatment CD8 PD1 low high Th1 chemokines, CCL4 and T cells low high Neoantigens low high PD-L1 expression high low Immunosuppression (Tregs, MDSCs) high low Stemness (cancer stemlike, EMT type) Melero, Nat Rev Cancer 2015; Zou, Science Transl Med 2016 provided by L. Bubendorf, Pathology USB

9 Choices...the Arabic Bazaar!

10 Scientific rationale.consider major pathways of the anti-tumor immune response Targeting microbiota Beneficial transplantation Detrimental inhibition/depletion Targeting Ag, APC, and innate immune signal Neo-antigen vaccine, oncolytic virus Targeting type I and II IFN signaling Targeting tumor (stem) cells and stroma Angiogenesis VEGF, CXCL12/CXCR4 blocker Tumor RTK inhibitor, anti- HER2/neu Cancer stem cell pathway IL-6, IL-8, IL-22 Anti-inflammation COX-2 inhibitor Fibroblast Chen&Mellman, Immunity 2013 Targeting TNF family CD40/CD40L, OX40/OX40L, 4-1BB Targeting T cells Trafficking Epigenetic drugs Survival Metabolism regulator Activation CD40/CD40L, OX40/OX40L, 4-1BB Therapy CAR-T, TILs Targeting immunosuppressive networks Tregs CTLA-4, TGFβ, CCR4/CCL22, CD39/CD79 MDSCs IDO Inhibitor B7 family members B7-H4, Tim-3, LAG3, TIGIT

11 Chemotherapy

12 Evolving synergistic immunotherapy combinations with standard of care to reprogram the tumor environment Patients undergoing adjuvant anthracycline Treatment with loss-of-function mutations TLR4 P2RX7 Melero, Nat Rev Cancer 2015 Apetoh, Nature Medicine 2007; Ghiringhelli, Nature Medicine 2009

13 Ipilimumab plus dacarbazine for previously untreated melanoma Robert, NEJM 2011

14 Ipilimumab Phase 2 CA in NSCLC Concurrent Phased Lynch et al, JCO 2012

15 Chemotherapy combination trials in NSCLC Carb = carboplatin; Cis = cisplatin; Gem = gemcitabine; ORR = objective response rate; OS = overall survival; Pac = paclitaxel; Pem = pemetrexed; PFS = progression-free survival; Q3W = every three weeks

16 CA (CheckMate 012): Nivolumab in Combination With Chemotherapy in NSCLC mos = median OS Antonia, ASCO 2015

17 Tumor Immune Profile to understand the immune mode of action of immunotherapy and combined approaches Serial on-treatment biopsies Neoadjuvant trials (worldwide) Durvalumab in NSCLC stage IIIA (SAKK 16/14) mrna vaccine in resectable NSCLC (Basel) Nivolumab in Stage II-IV RCC Pembrolizumab in TNBC Pembrolizumab in Stage III/IV melanoma Pembrolizumab in rectal cancer

18 Inhibitors of tubulin polymerization e.g. auristatins (MMAE), Maytansinoids (DM1) Müller, Cancer Immunol Res 2014 Martin, Cancer Immunol Immunother 2014 Müller, Oncoimmunology 2014

19 Antibody-Drug-Conjugates - Mechanism of Action - Brentuximab vedotin (Adcetris ) Trastuzumab emtansine (Kadcyla ) Disease HL, ALCL breast Target CD30 HER2 Linker Dipeptid Thioether Cytotoxic compoun d Cytotoxic class MMAE Auristatin = dolastatin 10 analogue DM1 Maytansinoid = ansamitocin P3 analogue Sievers & Senter, Annu Rev Med 2013

20 Therapeutic Efficacy of T-DM1 critically requires Adaptive Immunity Müller et al, Science Translational Medicine, 2015

21 Therapeutic Synergy with Checkpoint directed Maneuvers in an Orthotopic Breast Cancer Model A B Müller et al, Science Translational Medicine, 2015

22 Therapeutic Synergy with Checkpoint directed Maneuvers in an Orthotopic Breast Cancer Model A B Müller et al, Science Translational Medicine, 2015

23 A T-DM1 and checkpoint directed maneuvers Induction of anti-tumor immunity B C

24 T-DM1 and checkpoint directed maneuvers Induction of regulatory T cells A B

25 Treg depletion leads to autoimmunity B A

26 WSG-ADAPT Trial

27 Therapeutic Synergy with Checkpoint directed Maneuvers in an Orthotopic Breast Cancer Model

28 T-DM1 plus second generation ICI Submitted to CVC-CRI

29 Targeted and molecular therapy

30 Targeted/molecular combinations may target: - Immune cell pathways ( off target ) - tumor cell pathways ( on target )

31 PI3K-Akt-mTOR signaling regulates T cell differentiation Akt/PKB regulates CD4+ T cell differentiation into T helper 1, T helper 2, regulatory T cells and Th17 lineage Xue, JNCI 2015

32 PI3K p110δ inactivation in Tregs unleashes CD8 T cells responses and induces tumor regression (B. Vanhaesebroeck) Ali, Nature 2014

33 The BTK inhibitor Ibrutinib exerts potent anti-tumor activities through multiple mechanisms (L. Soucek, R. Levy) Potentiating Th-1 based immune responses by irreversibly inhibiting ITK Disrupting the tumor microenvironment by systemic mast cell inhibitory effects Dubovsky et al., Blood 2013; Masso-Valles et al, Cancer Res 2015; Sagiv-Barfi, PNAS 2015

34 Targeted/molecular combinations may target: - Immune cell pathways ( off target ) - tumor cell pathways ( on target )

35 PTEN loss impairs anti-tumor immunity PI3K inhbitors augment immunotherapy (P. Hwu) Anti- PTEN Anti- CD8 Peng et al., Cancer Discovery 2015

36 BRAF inhibition and immunotherapy Ag TILs Wilmott, Clin Cancer Res 2012; Frederick, Clin Cancer Res 2013; Ribas, NEJM 2013

37 CA : a single-arm phase II study to evalute the sequential administration of VEM followed by IPI in BRAF V600 melanoma Amin, ASCO 2015

38 Combining BRAF and MEK inhibition with PD(L)1 blockade (A. Ribas) Hu-Lieskovan; Science Transl Med 2015

39 Phase 1 Dabrafenib/Trametinib/anti-PDL1 (MEDI4736) Ribas, ASCO 2015

40 Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy (W. Zou) Peng, Nature 2015

41 Epigenetic therapy followed by anti-pd-l1: an example of response 10/ /2011 Pt History 64 y/o Diagnosed with IIIB adenoca Rx with XRT+ Tax/carbo, pemetrexed + carbo Entinostat + 5aza x 6 cycles provided by J. Brahmer

42 Anti-PD1 Epigenetic Priming Study (NCT ) Study population Epigenetic priming Immunotherapy Metastatic NSCLC 1 2 prior therapies ECOG PS 0-1 R Azacitidine 40 mg/m2 SC d 1-6, 8-10 Entinostat 7mg PO days day cycle 2 CC mg PO d day cycle 2 Nivolumab 3 mg/kg IV q 2 weeks Until progression Nivolumab 3 mg/kg IV q 2 weeks Until progression Biopsy Biopsy (CC-486 is an oral azacytidine) Sidney Kimmel Comprehensive Cancer John Hopkins

43 The evolving treatment landscape of combination therapies Timing, sequencing, dosing Tolerability Improved understanding of the tumor immunome (i.e. immune ignorance vs. evasion) Improved understanding of the immune mechanisms (to define biologically rational approaches) Patient selection (i.e. individual`s immune milieu)..the remaining..!

44 A view on T cell dysfunction in cancer T cell exhaustion Freeman et al, J Exp Med, 2006 Wherry et al, Nat Rev Immunol 2013

45 T cell exhaustion in NSCLC A B PD-1 subsets C PD-1 subsets co-express distinct levels of additional inhibitory receptors: Thommen et al, Cancer Immunology Research, 2015 Schreiner et al, Oncoimmunology, in press

46 The response to T cell bispecific antibodies depends on the level of PD-1 expression CD3 x FolR1 TCB: T cell TCR Tumor cell CD3 Tumor antigen Bispecific antibody Expression of folate receptor e.g in NSCLC Thommen et al, Cancer Immunology Research, 2015 Schreiner et al, Oncoimmunology, in press

47 T cell exhaustion in NSCLC PD-1 hi abundant PD-1 hi scarce PD-1 hi 82.3% PD-1 hi 22.0% PD-1 int 15.0% 2871 PD-1 int 58.8% 3147 PD-1 neg 2.70% 89.4 PD-1 neg 19.2% 343 PD-1 int PD-1 hi PD-1 hi PD-1 int

48 Overcoming T cell exhaustion therapeutic approaches Rapid activation of effector functions upon low-dose IL-2 Zippelius et al., JEM 2002; Zippelius et al, Cancer Res 2004

49 Percent survival Therapeutic efficacy of the F8-IL2 immunocytokine in a metastatic mouse model of lung adenocarcinoma Wieckowsi, Lung Cancer 2015

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51 Selective Targeting to the tumor stroma to provide co-stimulation Tumor-associated antigen T cell costimulation molecule Epithelial ovarian cancer: PD-1 TIM-3 BTLA 4000 IFN-γ IFNg 250 IL TNF-α TNFa IFNg (pg/ml) IL-2 (pg/ml) TNFa (pg/ml) unst acd3 FolR1/TCB+costimulation 0 unst acd3 FolR1/TCB FolR1/TCB+costimulation 0 unst acd3 FolR1/TCB FolR1/TCB+costimulation Uhlenbrock, unpublished in collaboration with Roche

52 Ex vivo cultured tumor blocks: a model to decipher the activity of immunotherapeutics DAPI Exogenously added antibodies are able to penetrate into ex vivo cultured tumor blocks 10x EpCAM Alexa647 EpCAM PE 40x Thommen, unpublished

53 Viability and T cell activation in tumor single cell suspensions and ex vivo cultured tumor blocks A B Thommen, unpublished

54 Our challenge: to make the right choices!