Combinatorial treatments with immunotherapy

Transcription

1 Combinatorial treatments with immunotherapy Alessandra Curioni-Fontecedro, MD, PD Department Hematology and Oncology Clinic of Oncology Cancer Center Zurich University Hospital Zurich

2 My disclosures Consulting and advisory services, speaking or writing engagements, public presentations: Astra Zeneca, BMS, MSD, Pfizer, Roche, Takeda Research Grants Novartis

3 Types of resistance: Ab initio Anti PD1

4 Types of resistance: After initial response Anti PD1 Anti PD1

5 HOW TO OVERCOME: COMBINATORIAL TREATMENTS? IDO

6 Chemotherapy can induce immunogeneic cell death L Glalluzzi, Nat Rev Immunology 2017

7 Chemotherapy can induce immunogeneic cell death L Glalluzzi, Nat Rev Immunology 2017

8 Immunomodulatory effect of chemotherapy L. Zitvogel, Nat Rev Immunology 2008

9 Immunomodulatory effect of chemotherapy L. Zitvogel, Nat Rev Immunology 2008

10 Gemcitabine: Effect on cancer cells Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor Int Mol Med; 2012 Sept 2

11 Gemcitabine Effect on MDSC Eliminates myeloid-derived suppressor cells Clin Cancer Res Sep 15; 11(18):

12 Gemcitabine Effect on Tregs Int. J. Cancer: 133, (2013

13 Overcoming resistance: on mouse model

14 Overcoming resistance: on mouse model P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

15 HE (40X) CD3 (40X) CD3 (100X) Untreated 10x Gem 10x Gem + ICI Gem + ICI + Dexa 10x 10x P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

16 Timepoint A B C D E Pembro Carbo+PMT Carbo+Gem Gem Pembro+Gem Week Overcoming resistance: In patients P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

17 Timepoint A B C D E Pembro Carbo+PMT Carbo+Gem Gem Pembro+Gem Week P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

18 Timepoint A B C D E Pembro Carbo+PMT Carbo+Gem Gem Pembro+Gem Week A B C D E

19 Timepoint A B C D E Pembro Carbo+PMT Radiotherapy Gem Pembro+Gem Week P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

20 Timepoint A B C D E Pembro Carbo+PMT Radiotherapy Gem Pembro+Gem Week P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

21 Timepoint A B C D E Pembro Carbo+PMT Radiotherapy Gem Pembro+Gem Week * * * A B C * * D E

22 Pleural effusion A B C D 20% 75% CD4 CD8 CD3 P Tallon de Lara.A.Curioni-Fontecedro Clinical Cancer Research Aug 2018

23 HOW TO OVERCOME: COMBINATORIAL TREATMENTS? IDO

24 Radiotherapy modulates the immunophenotype of cancer cells Immunomodulators Adapted from A. Sharabi et al Lancet Oncology 2015; 16: e

25 Radiotherapy engages the immune system through a danger signal Local: increase of TILs On DCs upregulation of CD86 and CD70 (co-stimulatory signals) A danger signal is needed to induce an immune response However, chronic inflammation will lead to unresponsivness Adapted from A. Sharabi et al Lancet Oncology 2015; 16: e

26 Radiotherapy overcomes resistance to immunotherapy Tumormetastases C. Britschgi A. Curioni-Fontecedro Radiat Oncol May 31;13(1):102

27 Radiotherapy overcomes resistance to immunotherapy Tumormetastases New metastases Response of the other metastses 6 cycles anti-pd-1 Anti-PD-1= Nivolumab: 3 mg/kg every two weeks C. Britschgi A. Curioni-Fontecedro Radiat Oncol May 31;13(1):102

28 Radiotherapy overcomes resistance to immunotherapy Tumormetastases New metastases Response of the other metastses 6 cycles anti-pd-1 Radiotherapy Additional 6 cycles anti-pd-1 Anti-PD-1= Nivolumab: 3 mg/kg every two weeks RT: 3 x 6 Gy C. Britschgi A. Curioni-Fontecedro Radiat Oncol May 31;13(1):102

29 Radiotherapy overcomes resistance to immunotherapy Tumormetastases New metastases Response of the other metastses 6 cycles anti-pd-1 Radiotherapy Additional 6 cycles anti-pd-1 Anti-PD-1= Nivolumab: 3 mg/kg every two weeks RT: 3 x 6 Gy C. Britschgi A. Curioni-Fontecedro Radiat Oncol May 31;13(1):102

30 STIMULI: SCLC limited disease

31 The NICOLAS trial Stage IIIA-IIIB NSCLC

32 HOW TO OVERCOME: COMBINATORIAL TREATMENTS? IDO

33 How to overcome resistance? Combination treatments Hellmann Lancet Oncology 2017

34 Acquired resistance to PD-1 blockade (melanoma) Adapted from JM Zaretsky et al: NEJM 2016: 375;9

35 Acquired resistance to PD-1 blockade (melanoma) JAK1 Adapted from JM Zaretsky et al: NEJM 2016: 375;9

36 Mutations occurring in JAK 1 and JAK 2 impair the tumor-intrinsic effect of IFN Type I IFN Type II IFN LC Platanias, Nature Reviews Immunology 5, (May 2005)

37 Mutations occurring in JAK 1 and JAK 2 impair the tumor-intrinsic effect of IFN Type I IFN Type II IFN Adapted from BS Parker Nature Reviews Cancer 132, (March 2016) LC Platanias, Nature Reviews Immunology 5, (May 2005)

38 Mutations occurring in JAK 1 and JAK 2 impair the tumor-intrinsic effect of IFN Type I IFN Type II IFN Adapted from BS Parker Nature Reviews Cancer 132, (March 2016) LC Platanias, Nature Reviews Immunology 5, (May 2005)

39 The role of STING in the crosstalk with NK cells

40 Targeting STING

41 HOW TO OVERCOME: COMBINATORIAL TREATMENTS? IDO

42 ESMO IMMUNOONCOLOGY MEETING, GENEVA DEC 2017: PEGYLATED HUMAN IL-10 (AM0010) IN COMBINATION WITH AN ANTI-PD-1 IN ADVANCED NSCLC Deborah Wong, Medicine, Hematology/Oncology, UCLA - School of Medicine, Los Angeles, CA, USA BACKGROUND IL10, immune-suppressant during infections Nature Reviews Immunology12, (November 2012) Martin Oft Cancer Immunol Res 2014;2: IL10, immune-stimulator during cancer growth

43 PEGYLATED HUMAN IL-10 (AM0010) IN COMBINATION WITH AN ANTI-PD-1 IN ADVANCED NSCLC Deborah Wong, Medicine, Hematology/Oncology, UCLA - School of Medicine, Los Angeles, CA, USA RESULTS mos: 19.7 months 1-year survival: 71%

44 PEGYLATED HUMAN IL-10 (AM0010) IN COMBINATION WITH AN ANTI-PD-1 IN ADVANCED NSCLC Deborah Wong, Medicine, Hematology/Oncology, UCLA - School of Medicine, Los Angeles, CA, USA RESULTS Ab: 22C3 Dako

45 Targeting the network

46 Combination Targets Across Lung Cancer FRACTION-Lung Combinations with nivo: CTLA-4, BCR-ABL, LAG-3, IDO1 Morpheus-Lung Combinations with atezo: MAPK/MEK, CD3/CEA, CXCR4, Ezh2, ADORA2A HUDSON Combinations with durva: PARP, STAT3, ATR, mtor TGF-B 1 IDO1 9 CCR4 11 Cytokines (eg, IL2) 13 PI3K 15 ALK 17 T-cell Checkpoints (eg, CD137, CD27, GITR, OX40, LAG3, TIGIT, CD73, A2aR) 2-8 CTLA-4 3 I-O NK Cell Modulation (eg, SLAMF7, KIR) 9,10 Oncolytic Viruses 12 Vaccines 14 Antibody-Drug Conjugates 16 Glypican-3 18 Over 225 trials evaluating nivolumab in combination with novel agents are ongoing cmet 19 PARP 17 Chemo 21,22 BET 20 Epigenetic Modifiers (HDAC, HMT) 4,7,23 EGFR 19 Immune Stimulation/Modulation BCR-ABL 24 Tumor Cell Targeted Pathways Chemotherapy

47 Department of Hematology and Oncology Markus Manz Rolf Stahel Christian Britschgi Svenja Bihr Raphael Delaloye Stefanie Hiltbrunner Department of Radio-Oncology Matthias Guckenberger Niklaus Andratschke Robert Forster Department of Thoracic Surgery Walter Weder Isabelle Schmitt-Opitz Emanuela Felley-Bosco Institute of Pathology Holger Moch Alex Soltermann Bart Vrugt Institute of Experimental Immunology Maries van den Broek Christian Münz Paulino Tallon de Lara Virginia Cecconi Sophien-Stiftung zur Förderung der klinischen Krebsforschung