Nieuwe ontwikkelingen binnen de immuuntherapie. John Haanen

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1 Nieuwe ontwikkelingen binnen de immuuntherapie John Haanen

2 My disclosures Institutional Research Grants: BMS; MSD; Novartis; Consultancy role: BMS; MSD; Roche; Pfizer; Novartis; NEON Therapeutics

3 Wat zijn de belangrijkste open vragen? 1. Biomarkers voor selectie (C. Blank) 2. Ontsnapping aan immuuntherapie Intrinsieke resistentie Adaptieve resistentie 3. Hoe kan de ORR en overleving verbeterd worden?

4 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle CTLA4 PD1/PDL1 CTLA4

5 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle Capacity to infiltrate T cell repertoire CTLA4 Foreignness of tumor Sensitivity PD1/PDL1 of tumor for T cell CTLA4 killing

6 Waarschijnlijkheid van respons op immuuntherapie is gecorreleerd met mutational burden Schumacher & Schreiber. Science 2015

7 PD-1 Blockade in Mismatch Repair Deficient Cancer Independent of Tumor Histology Presented By Lawrence Fong at 2016 ASCO Annual Meeting

8 Slide 12 Presented By Lawrence Fong at 2016 ASCO Annual Meeting

9 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle Capacity to infiltrate T cell repertoire CTLA4 Foreignness of tumor Sensitivity PD1/PDL1 of tumor for T cell CTLA4 killing

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11 Patients with clinical benefit to ipilimumab had a richer and more evenly distributed TCR repertoire Postow et al., J Immunother Cancer 2015

12 Translational research on patients treated in the Phase II IMvigor 210 Study of Atezolizumab (anti-pd-l1) in Metastatic Urothelial Carcinoma Rosenberg et al., Lancet 2016 Presented By Samuel Funt at 2016 ASCO Annual Meeting

13 Pretreatment T cell clonality in the blood inversely correlated with overall survival (n=29) * Log-Rank Presented By Samuel Funt at 2016 ASCO Annual Meeting

14 Openstaande vragen: Hoe verandert het perifeer bloed T cel repertoire onder invloed van de eerdere therapieën? Chemotherapie Chemoradiotherapie Targeted therapie Immuuntherapie

15 Welters et al., Sci Transl Med 2016

16 Depletie van circulerende myeloide cellen tijdens carboplatin/paclitaxel voor cervixcarcinoom Welters et al., Sci Transl Med 2016

17 Inductie van HPV 16 E6 en E7 specifieke T celresponsen na chemotherapie icm peptide vaccinatie Welters et al., Sci Transl Med 2016

18 Openstaande vragen: Hoe verandert het perifeer bloed T cel repertoire onder invloed van de eerdere therapieën? Chemotherapie Chemoradiotherapie Targeted therapie Immuuntherapie

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20 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle Capacity to infiltrate T cell repertoire CTLA4 Foreignness of tumor Sensitivity PD1/PDL1 of tumor for T cell CTLA4 killing

21 Tumor Infiltrating Lymphocyten (TIL) (HNSCC) Diffuse infiltration with CD8+ TILs in HNSCC Absence of TILs in HNSCC Keck et al., Clin Canc Res 2014

22 Inflamed vs non-inflamed tumoren Inflamed TILs CD8+ T cells Foreignness PD-L1 expression gene signature IFN-γ Pre-existing immunity Non-inflamed

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24 Spranger et al., Nature 2015

25 Tumoren met b-catenine pathway activatie in non-inflamed subset Presented By Lawrence Fong at 2016 ASCO Annual Meeting

26 Loss of PTEN promotes resistance to T cell mediated immunotherapy Peng et al., Cancer Disc 2015

27 b-catenin activatie en PTEN loss en non-inflamed tumoren Peng et al., Cancer Disc 2015

28 Inflamed vs non-inflamed tumoren Inflamed Inflamed Non-inflamed Respondeert slecht op checkpoint inhibitie Respondeert goed op checkpoint inhibitie Zeer onws om op checkpoint inhibitie te reageren Hoe kan T cell function verder worden verbeterd? Hoe kunnen deze tumoren in inflamed tumoren worden geconverteerd? Schmid et al. ECC 2015; Herbst et al. Nature 2014 Tumeh et al. Nature 2014; Ji et al. Cancer Immunol Immunother 2012

29 Hoe kunnen we onze kennis van de tumor microenvironment gebruiken om de juiste therapie te kiezen? RECRUIT / INFILTRATE (vasculature) Non-Inflamed CEA IL-2V* IL-2 ACTIVATE (central) Non-Inflamed KILL CANCER CELLS (tumor) Inflamed Chen and Mellman. Immunity 2013 CSF1R acsf1r*

30 Hoe kunnen we non-inflamed tumoren converteren naar inflamed? CEA Chemotherapie IL-2V* IL-2 Immunogenic cell death ACTIVATE (central) Non-Inflamed RECRUIT / INFILTRATE (vasculature) Non-Inflamed KILL CANCER CELLS (tumor) Inflamed Chen and Mellman. Immunity 2013 CSF1R acsf1r*

31 Combineren van immuuntherapie met chemotherapie: the desirable immunological side effects of chemotherapy Immunogenic cell death induced by anthracyclines Increasing the immunogenicity of malignant cells Established tumour Therapy with anthracyclines Established tumour Chemotherapy (gemcitabine) Immunogenic cell death TAA uptake TAA-specific immune response Immature DC and T cell recruitment DC maturation and T cell priming Incomplete immunostimulation Immunotherapy (CTLA4-blocking antibody) Optimal therapeutic effects Tumour eradication DAMPs=damage associated molecular patterns; DC=dendritic cell; PRRs=pattern recognition receptors; TAA=tumour associated antigen Galuzzi et al. Cancer Cell 2015

32 Combinatie strategieën om een non-inflamed naar inflamed tumor te converteren: chemotherapie Non-inflamed PD-L1 expression CD8+ T cells Genomic instability Chemotherapy combinations with atezolizumab in CRC 2 CD8 IHC Pre-treatment Post FOLFOX + bevacizumab + atezolizumab CD8 IHC PD-L1 PD-L1 IC0 IC2 Bendell et al. ASCO GI 2015

33 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle Capacity to infiltrate T cell repertoire CTLA4 Foreignness of tumor Sensitivity PD1/PDL1 of tumor for T cell CTLA4 killing

34 Intrinsieke of verworven resistentie Kelderman, Schumacher and Haanen, Mol Oncol 2015

35 (MSD) PD-L1 NSCLC Sample IHC staining PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive Negative Weak Positive (1%-49%) Strong Positive (50%-100%)

36 OS of pembrolizumab vs docetaxel in pretreated PDL1+ NSCLC (KN-010) 50% PDL1 expression Herbst et al., Lancet 2015

37 OS in Checkmate-066 according to PDL1 expression Atkinson et al. abstract 3774 SMR 2015

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39 Wel of geen benefit IT gecorreleerd met genetische immuunsignatuur Seremet et al. J Transl Med 2016

40 Intrinsieke of verworven resistentie Kelderman, Schumacher and Haanen, Mol Oncol 2015

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42 Saha et al., Cytokine 2009

43 Response upon anti-pd1 treatment

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45 Mutation in b2m gene

46 Kim and Chen, Ann Oncol 2016 Cancer immunity cycle Capacity to infiltrate T cell repertoire CTLA4 Foreignness of tumor Sensitivity PD1/PDL1 of tumor for T cell CTLA4 killing

47 Inflamed vs non-inflamed tumoren Inflamed Inflamed Non-inflamed Respondeert slecht op checkpoint inhibitie Respondeert goed op checkpoint inhibitie Zeer onws om op checkpoint inhibitie te reageren Hoe kan T cell function verder worden verbeterd? Hoe kunnen deze tumoren in inflamed tumoren worden geconverteerd? Schmid et al. ECC 2015; Herbst et al. Nature 2014 Tumeh et al. Nature 2014; Ji et al. Cancer Immunol Immunother 2012

48 Hoe kan T cell function worden verbeterd? RECRUIT / INFILTRATE (vasculature) Non-Inflamed CEA IL-2V* IL-2 ACTIVATE (central) Non-Inflamed Tumour immune escape IDO KILL CANCER T cell CELLSexhaustion (tumor) Inflamed Chen and Mellman. Immunity 2013 CSF1R acsf1r*

49 Rol van indoleamine 2,3-dioxygenase (IDO) in tumor immune escape IDO, PD-L1/B7-H1, and FoxP3 + regulatory T cells might serve as negative feedback mechanisms that follow CD8 + T cell infiltration Spranger et al. Sci Transl Med 2013

50 Median tumour volume (mm 3 ) Percent survival Approaches to overcoming T cell exhaustion: anti-tigit CT26 tumour inoculation Antibody treatment 3x/week n=10 Day 14 Day 0 Day 21 Day 60 TIGIT and PD-L1 co-blockade induce syngeneic CT26 tumour rejection Isotype Anti-PDL1 Anti-TIGIT Anti-PDL1 + anti-tigit Complete remission (CR) Day Day Johnston et al. Cancer Cell 2014

51 Hoe kan de tumor microenvironment de toekomst van immuuntherapie van kanker richting geven? We hebben een betere kennis van welke factoren bijdragen aan respons (tumor infiltrerende lymfocyten, PD-L1 expressie, mutational load) Ons toegenomen begrip van tumorbiologie en escape mechanismen helpt de meest veelbelovende pathways voor toekomstige immuuntherapie opties te identificeren We zullen deze kennis moeten inzetten om de uitkomst voor patiënten te verbeteren

52 Welke nieuwe immuuntargets kunnen we verwachten? Blank Curr Opin Oncol 2014

53 Welke combinaties voor welke patient? acd137 agitr TCE BiSpe mabs IDOi aox40 akir actla4 Chemotherapie apd-1/apd-l1 Herpes oncolytic virus Vaccinia oncolytic virus Radiotherapie TLR ago TKI RIG ago STING ago

54 Marit van Buuren Mireille Toebes Sander Kelderman Carsten Linneman Riccardo Mezzadra Laura Bies Daisy Philips Wouter Scheper Maarten Slagter Joost Beltman Pia Kvistborg Ton Schumacher Clinical translation Nienke van Rooij Raquel Gomez Joost van den Berg Christian Blank MSKCC Chemical Biology Huib Ovaa Sanger Institute Sam Behjati Mike Stratton AIMM Therapeutics Remko Schotte Hergen Spits Oslo University Erlend Strønen Johanna Olweus LUMC Els Verdegaal Sjoerd van der Burg Naiyer Rizvi Matt Hellman Alexandra Snyder Vlad Makarov Jonathan Havel Taha Merghoub Jedd Wolchok Tim Chan Utrecht University Can Keşmir Molecular Oncology Xinyao Huang Juliana Kenski Judith Muller Thomas Kuilman Daniel Peeper Cancer Immunotherapy Dream Team