The PD-1 pathway of T cell exhaustion

Transcription

1 The PD-1 pathway of T cell exhaustion SAMO

2 Overview T cell exhaustion Biology of PD-1 Mechanism Ligands expressed on tumor cell and on non-tumor cells other receptor pairs Biomarkers for apd-1/pd-l1 therapy Expression of PD-L1 Antigen Activated T cells

3 T cell exhaustion in viral infections non-cytopathic virus (LCMV, HBV, HIV) persist in the host in the presence of T cells cytotoxic T cells lose effector function cytotoxic T cells induce the disease immunopathology Gallimore A, J Exp Med 1998 Zajac AJ, J Exp Med 1998 Virgin HW, Cell 2009

4 Molecular Mechanisms of T cell exhaustion Werry EJ, Immunity 2007

5 Immunecheckpoints: T cell Exhaustion Werry EJ, Nature Immunology 2011

6 Exhaustion Repetitive stimulation of T cells leads to exhaustion Exhausted T cells express immune inhibitory receptors such as PD-1, LAG-3, 2B4

7 Exhaustion of cancer-specific T cells Baitsch L, J Clin Invest 2011

8 Molecular Mechanisms of T cell exhaustion

9 Blocking PD-1 / PD-L1 interaction The oncologists view Topalian SL, N Engl J Med 2012 Brahmer JR, N Engl J Med 2012

10 PD-1/ PD-L1 interaction with tumor cells Disease Citation n Detection Method Pathological Observations Prognosis. Non-Small Cell Lung Cancer Melanoma Mu CY, Paraffin IHC PD-L1+ cells in adenocarcinoma were more numerous than those in squamous cell carcinoma (65.2% vs 44.4%, P = 0.032) Konishi J Frozen IHC No correlation of PD-L1 or PD-L2 expression with clinicopathologic characteristics Hino R, Paraffin IHC PD-L1 was higher in larger tumors and in lymph node positive cancer (P <.0001) Taube JM Paraffin IHC PD-L1 was expressed on a proportion (57/150) of various MEL lesions, most commonly in close juxtaposition to TILs (P =0.033). Chapon Paraffin IHC, FACS 66% of mmel biopsies were PD-L2+ whereas 58% of metastatic MEL biopsies were PD-L1+ PD-L1 positivity correlated with survival shorter than 3 years after lobectomy (P = 0.034) No correlation between PD-L1 and PD-L2 expression and patient survival OS and PFS rate were lower in the PD-L1 hi expression group compared with the PD-L1 lo expression group (P = , respectively) Patients with PD-L1+ metastatic MEL (mmel) had longer survival than those with PD-L1- metastatic MEL (P = 0.032) N/A

11 Co-localisation of TIL with PD-L1 expression Anti-PD-L1 Anti-PD-L1 Taube JM, Science Transl Med. 2012

12 PD-L1 expression is regulated by IFNg T T T adoptive Immunotherapy with specific CTL (P14) H8-CML Riether C, Leukemia 2015

13 Dynamic regulation of PD-L1 expression PD-L1 is upregulated during inflammation: IFNg IL-2, IL-7, IL-15, IL-21 Type I IFNs

14 Assistentencurriculum Universitätsklinik für Medizinische Onkologie, Inselspital Bern Genetic Aberrations that induce PD-L1/2 Ansell SN, N Engl J Med

15 Role of PD-1 expressed on non-tumour cells Nguyen and Ohashi, Nature Reviews Immunology 2015

16 PD-1/PD-L1 signalling pathway The immunologists view Universitätsklinik für Medizinische Onkologie, Inselspital Bern Nguyen and Ohashi, Nature Reviews Immunology 2015

17 Relevance of PD-L2 expression? APC (monocytes, macrophages, DCs) tumor cells, tumor stroma expansion cytokine production + PD-L1 + PD-L2 blocking PD-L2 augments T cell responses (Th2) controversial results in preclinical tumor models Latchman Y, Nat Immunol 2001

18 Relevance of PD-L2 expression? significant correlation between PD-L2 and PD-L1 expression discordant staining was present in many individual samples: some presented PD-L1 expression in the absence of PD-L2 (and vice versa) Yearley, ECC 2015 Rozali E, 2012

19 PD-1 targeting antibodies PD-1 targeting antibodies Agent Description Kd Binding Affinity Nivolumab (Optivo) Human IgG4 3 nm Pembrolizumab (Keytruda) Humanized IgG4 kappa 28 pm Pidilizumab Humanized IgG1 kappa 20 nm AMP-24 B7-DC/IgG1 fusion protein NA PD-L1 targeting antibodies Agent Description Kd Binding Affinity Atezolizumab, MPDL3280A ADCC reduced, engineered IgG1 NA Durvalumab, MEDI4736 ADCC reduced, engineered IgG1 kappa NA Avelumab, MSB C fully human IgG1 NA

20 Overview T cell exhaustion Biology of PD-1 Mechanism Ligands expressed on tumor cell and on non-tumor cells other receptor pairs Biomarkers for apd-1/pd-l1 therapy Expression of PD-L1 Antigen Activated T cells

21 Nivolumab versus Docetaxel in Advanced Squamous-Cell Non Small-Cell Lung Cancer (CheckMate 017) NSCLC St IIIB, IV, squamous cell PS 0 1 (n=272) R 1:1 Nivolumab 3mg/kg q 2wk Docetaxel 75mg/m2 q3wk Bramer J, NEJM 2015

22 Bramer J, NEJM 2015

23 Nivolumab versus Docetaxel in Advanced Non-Squamous-Cell Non Small-Cell Lung Cancer (CheckMate057) NSCLC St IIIB, IV, nonsquamous cell Failed 1 prior platinum doublet PS 0 1 (n=582) R 1:1 Nivolumab 3mg/kg q 2wk Docetaxel 75mg/m2 q3wk H. Borghaei H, NEJM 2015

24 OS according to PD-L1 expression Paz-Ares, ASCO 2015

25 PD-L1 expression and response to PD-1 checkpoint blockade

26 PD-L1 expression on immune cells (IC) versus tumor cells (TC) PD-L1 pos NSCLC (> 5%): Immune cells: 26% Tumor cells: 24% Herbst RS. Nature 2014

27 Objective response to anti-pd-l1 Ab atezolizumab according to PD-L1 expression on IC and on TC Immune cells p=0.015 Tumor cells p=0.920 Herbst RS. Nature 2014

28 Predictive biomarker study from a randomized phase II study atezolizumab versus docetaxel (POPLAR) PD-L1 expression on tumour cells and on tumour-infiltrating immune cells were both independent predictors of survival improvement with atezolizumab Vansteenkiste. ECC 2015

29 PD-L1 expression and response to PD-1 checkpoint blockade (Keynote001) < 1 % 23.2% screened population PD-L1+>50. ORR 45.2% 1-49 % > 50% Garon EB. NEJM 2015

30 Biomarker study from phase I/II study with durvalumab(medi4736) Patients positive for PD-L1 had better response than patients negative for PD-L1 Similarly, patients who were IFNg mrna positive had better overall response than IFNg mrna negative patients Patients positive for both IFNg and PD-L1 were even more likely to benefit from treatment with durvalumab than patients negative for these biomarkers Higgs, ECC 2015

31 Overview T cell exhaustion Biology of PD-1 Mechanism Ligands expressed on tumor cell and on non-tumor cells other receptor pairs Biomarkers for apd-1/pd-l1 therapy Expression of PD-L1 Antigen Activated T cells

32 Mutational Rate and Clinical Response Alexandrov LB, Nature 2013

33 High mutational burden predicts response to pembrolizumab in NSCLC Predicted neo-epitopes: Mutant nanomers with < 500nM binding affinity to HLA alleles n=17 Cut off :178 mutations HR 0.19, p=0004 p=0.002 n=17 Rizvi NA, Science 2015

34 But: Antigens have to be presented on MHC-I Ferrone S

35 Overview T cell exhaustion Biology of PD-1 Mechanism Ligands expressed on tumor cell and on non-tumor cells other receptor pairs Biomarkers for apd-1/pd-l1 therapy Expression of PD-L1 Antigen Activated T cells

36 Predictive correlates of response to anti-pd-l1 antibody atezolizumab responder Ignorance non-responder non-functional Immune response Exclusion pre-existing anti-tumor immune response is predictive! Herbst RS. Nature 2014

37 Predictors for Response to PD-1 Blockade Antigen Mutational burden predictive for neoantigens presented on MHC-class I T cells T cell infiltration in tumors (IFNg) clonal T cell expansion PD-L1 expression dynamic (archieval tissue?) on immune cells / on tumor cells / or both which antibody / test treshold role of PD-L2?