CIT: from translational research to clinical application

Transcription

1 CIT: from translational research to clinical application John Haanen ESMO I-O preceptorship Lugano 2018

2 Cancer Immunotherapy fighting cancer but ignoring the tumor unleashing the immune system or harnessing the immune system to combat cancer

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5 What is the science behind CIT?

6 van Elsas et al., J Exp Med 1999

7 Prevention of outgrowth and rejection of aggressive B16 melanoma using CLTA-4 blockade and vaccine van Elsas et al., J Exp Med 1999

8 Combination of anti-ctla-4 + vaccine leads to rejection of pulmonary metastases and immune infiltrates van Elsas et al., J Exp Med 1999

9 Melanoma bearing mice successfully treated with anti-ctla4 and vaccine develop vitiligo van Elsas et al., J Exp Med 1999

10 Cancer immunity cycle CTLA4 PD1/PDL1 CTLA4 Chen & Mellman Immunity 2013

11 T cell signaling

12 Melero, Haanen. Nat Rev Cancer 2015 T cell activating and inhibiting molecules and signals

13 Checkpoint molecule CTLA4

14 CTLA4 plays a role during T cell priming Ribas. N Engl J Med 2012

15 Human CTLA4 blockade Ipilimumab, IgG1 human mab, selected for its lack of ADCC/CDC activity Administered every 3 weeks x 4, 3 mg/kg Showed improvement in mos of 4 months in metastatic melanoma Approved in 2011 Tremelimumab, IgG2 human mab Administered every 3 months, 15 mg/kg Failed to show improvement in mos

16 Efficacy of ipilimumab as first line treatment ORR: 11.9% Robert et al., NEJM 2015

17 CTLA-4 blockade (ipilimumab) can induce long-term survival (pooled overall survival analysis including Expanded Access Program data from 4846 patients) Proportion Alive Ipilimumab CENSORED Median OS (95% CI): 9.5 months ( ) 3-year OS rate (95% CI): 21% (20% 22%) Months Patients at Risk Ipilimumab Schadendorf D, et al. J Clin Oncol 2015

18 Treatment with anti-ctla-4 mab Maker et al., Ann Surg Oncol 2005

19 Auto-immune uveitis after anti-ctla-4 treatment After treatment

20 Immune related adverse events upon anti- CTLA-4 mab treatment colitis hypophysitis

21 How does CTLA4 blockade lead to anti-tumor immune responses? Two not mutually exclusive mechanisms have been proposed: 1. Priming of tumor-reactive T cells Against shared tumor associated antigens Against mutated (neo) antigens 2. Depletion of regulatory FoxP3+ T cells from the tumor microenvironment

22 What could tumor-specific cytotoxic T cells detect on human cancer? 1. Self antigens (to which tolerance is incomplete) Shared between patients 2. Neo-antigens, epitopes that arise as a consequence of tumor-specific mutations In large part patient-specific, hence generally ignored

23 Two models proposed Kvistborg et al., Science Transl Med 2014

24 Analysis of PBMC from 40 ipilimumab treated melanoma patients for 75 tumor associated antigens Kvistborg et al., Science Transl Med 2014

25 Generation of pmhc multimers by UV-induced peptide exchange Rescue Peptides Disintegration Peptide 1 Peptide 2 Peptide 3 Toebes et al. Nat. Med Bakker et al. PNAS 2008 Allows generation of 1000s of pmhc in parallel

26 Self-assembling molecular codes Generate fluorochrome conjugated MHC multimers Mix to create a collection of differentially encoded MHC multimers T cell T cell T cell Assembly of combinatorial codes on T cell surfaces Analysis by flow cytometry Allows detection of 47 T cell responses in parallel Hadrup et al, Nat Methods 2009, Andersen et al, Nat Prot 2012.

27 Kvistborg et al., Science Transl Med 2014 Flow results

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29 Ipilimumab treatment leads to broadening of the anti cancer IR Kvistborg et al., Science Transl Med 2014

30 T cell responses against shared tumor antigens Kvistborg et al., Science Transl Med 2014

31 What could tumor-specific cytotoxic T cells detect on human cancer? 1. Self antigens (to which tolerance is incomplete) Shared between patients 2. Neo-antigens, epitopes that arise as a consequence of tumor-specific mutations In large part patient-specific, hence generally ignored

32 Analyzing the neo-antigen-specific T cell repertoire in human cancer? Generate map of tumorspecific mutations (ExomeSeq) Determine which mutated genes are expressed (RNASeq) HLA-A2 HLA-B7 HLA-C2 MDLVLNELVISLIVESKLLE Predict epitopes for each mutation/ each HLA-allele in silico T cell Screen for T cell recognition of mutated epitopes

33 Pt 002: Partial response upon anti-ctla4 treatment pre-treatment post-treatment Van Rooij et al., J Clin Oncol 2013

34 Analyzing the neo-antigen-specific T cell repertoire in human cancer? % of Non-Synonymous mutations Resected tumor material Isolate tumor cells (n=1036) T > A / A > T T > G / A > C T > C / A > G C > A / G > T C > G / G > C C > T / G > A Identify tumor-specific mutations Mutation Type

35 Analyzing the neo-antigen-specific T cell repertoire in human cancer? Resected tumor material Isolate tumor cells Isolate tumor-infiltrating T cells Screen with MHC multimer technology Identify tumor-specific mutations Predict potential epitopes

36 Strong T cell response against an ATR S>L neo-epitope within the tumor Resected tumor material pmhc QD 625 (ATR S>L ) 3.3% pmhc PE-Cy7 (ATR S>L ) Isolate tumor cells Isolate tumor-infiltrating T cells Screen with MHC multimer technology Identify tumor-specific mutations Predict potential epitopes

37 Increased magnitude of neo-antigen-specific T cell response under anti-ctla4 pmhc QD 625 (ATR S>L ) 3.3% pmhc PE-Cy7 (ATR S>L ) van Rooij, van Buuren JCO 2013

38 Cancer exome-guided immunomonitoring Exome-based analysis of neo-antigen specific T cell responses in human cancer is feasible - Dissect the role of neo-antigen specific T cell reactivity in melanoma immunotherapy (TIL therapy, anti-ctla4, anti-pd1 etc.) The T cell based immune system commonly interacts with the consequences of DNA damage in human melanoma in 10 out of 12 pts CD8 neo-ag spec TIL in 5 out of 6 CD4 neo-ag spec TIL

39 Snyder et al. NEJM 2014 Mutational load and outcome to ipi

40 How does CTLA4 blockade lead to anti-tumor immune responses? Two not mutually exclusive mechanisms have been proposed: 1. Priming of tumor-reactive T cells Against shared tumor associated antigens Against mutated (neo) antigens 2. Depletion of regulatory FoxP3+ T cells from the tumor microenvironment

41 Vargas et al. Cancer Cell 2018

42 CD16 snp plus inflamed tumor associated with better outcome on ipilimumab in melanoma Vargas et al. Cancer Cell 2018

43 PD1 and PD-L1 checkpoint Freeman & Sharpe. Nat Immunol 2013

44 Programmed Death-1 receptor (PD1) Discovered in 1992 by Honjo and coworkers Upregulated gene in relation to apoptosis Member of the Ig superfamily Cytoplasmic domains with ITIM and ITSM Recruites phosphatases Inhibits PI3K and AKT activity Inducibly expressed by CD4 and CD8 T cells, NKT cells, B cells, monocytes and subtypes of DC Expressed by both effector and regulatory T cells PD1/PD-L1 interaction involved in tolerance and chronic inflammation PD1/PD-L1 contributes to functional T cell exhaustion during chronic infection and cancer

45 PD-1 pathway inhibits T cell response directly downstream of the TCR Freeman PNAS 2008

46 PD1/PD-L1 play a role at the tumor/effector phase Ribas. N Engl J Med 2012

47 Checkpoint molecules PD-1/PD-L1 Nivolumab: anti-pd1 Pembrolizumab: anti-pd1 Atezolizumab: anti-pdl1 Durvalumab: anti-pdl1 Avelumab: anti-pdl1

48 Expression of PD1 ligands Hematopoietic cells Non-hematopoietic cells PD-L1 (B7-H1) DC, macrophages, B cells, T cells, BM-derived mast cells Vascular endothelium, epithelia, muscle, liver, pancreatic islets, placenta, eye PD-L2 (B7-DC) DC, macrophages, B cells, Th2 cells, BMderived mast cells Few, airway epithelia Stimuli Interferons (α, β, γ) IL-4 + GM-CSG Binding partners PD1, B7.1 PD1 Expression by tumors Melanoma, RCC, HNSCC, ovary, NSCLC Expression also found on tumors

49 PD-L1 on human tumor cells mediates T cell inhibition Pardoll DM, Nat Rev Cancer 2012

50 Expression of PD-L1 co-localizes with TILs Taube et al. Science Transl Med 2012

51 Pembrolizumab Baseline: April 13, 2012 April 9, year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab Images courtesy of A. Ribas, UCLA. Ribas A ASCO 2013

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53 Design of CheckMate 066

54 Results of the CheckMate 066

55 Nivolumab improves PFS and OS compared to dacarbazine

56 Are there any predictive markers for PD1/PDL1 blockade?

57 Evolution of CD8+ T-cells, according to treatment outcome IHC Analysis of CD8+ T-cells in samples obtained before and during anti-pd1 treatment Tumeh et al. Nature 2014

58 PD-L1 expression and response in melanoma ORR PDL1+ ORR PDL1- Melanoma Pembrolizumab 1% cut-off: 49% 10% cut-off: 52% 1% cut-off: 13% 10% cut-off: 23% Daud, AACR 2014 Ghandi, AACR 2014

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

60 Correlation of PD-L1 Expression and Efficacy Borghaei H, ASCO 2016; Rittmeyer A, Lancet 2016; Herbst R, Lancet

61 Mutational burden and clinical benefit from anti-pd1 in NSCLC Rizvi et al., Science 2015

62 A neo-antigen specific T cell response induced during anti-pd1 treatment Rizvi et al., Science 2015

63 Anti-PD1 in mismatch repair deficient tumors Le et al., NEJM 2015

64 A neo-antigen repertoire may only be frequent in some human cancers Formation of neo-antigens Generally Regularly Occasionally Caveat: It is possible that a neglected repertoire of neo-antigens exists We may be underestimating Schumacher and Schreiber Science 2015

65 Paradigm shift: Cancer immunotherapy can be applied broadly Checkpoint blockade

66 Ayers et al. JCI 2017

67 Ayers et al. JCI 2017

68 Requirement for effective CIT High mutation burden increases chance for neo-antigen specific T cell response T cell infiltrate in tumor or invasive margin CD4 and/or CD8 PD-L1 expression (indicative of T celltumor interrogation) favors response IFN-γ gene signature favors response to CIT

69 Target cancer immunity cycle obstructions

70 Selection and optimization of immunotherapybased combinations Zappasodi et al. Cancer Cell 2018

71 Marit van Buuren Chemical Biology MSKCC Sander Kelderman Huib Ovaa Naiyer Rizvi Carsten Linneman Matt Hellman Laura Bies PDX models Alexandra Snyder Daisy Philips Kristel Kemper Vlad Makarov Mireille Toebes Daniel Peeper Jonathan Havel Pia Kvistborg Taha Merghoub Maarten Slagter Joost Beltman Sanger Institute Sam Behjati Mike Stratton Jedd Wolchok Tim Chan Cancer Immunotherapy Dream Team Clinical translation Nienke van Rooij Bianca Heemskerk Raquel Gomez AIMM Therapeutics Remko Schotte Hergen Spits Utrecht University Can Keşmir MD Anderson Joost van den Berg Maaike van Zon Noor Bakker Christian Blank LUMC Els Verdegaal Sjoerd van der Burg Laszlo Radvanyi Chantale Bernatchez Patrick Hwu