Principles of tumour immunology

Transcription

1 Principles of tumour immunology Michele Teng Nov 20 th 2017, Singapore Cancer Immunoregulation and Immunotherapy Laboratory QIMR Berghofer MRI Brisbane, Australia

2 Disclosure Slide I have received speakers bureau honoria from Merck Sharp & Dohme.

3 Talk Outline 1. Hallmarks of Cancer 2. Cells of the Immune system 3. The Cancer Immunity Cycle - Tumor-associated antigens (TAA), Cellular and Humoral responses to TAA 4. Conceptual developments in the field of tumour immunology - Immunosurveillance and role of innate immunity, immune balance against cancer

4 Sources of slide Charles Janeway s Immunobiology text book Peer-reviewed articles (Pubmed) Online slides ( URL listed)

5 Cancer

6 Hallmarks of Cancer (2000) Hanahan and Weinberg, Cell 2000

7 Emerging Hallmarks and Enabling Characteristics Hanahan and Weinberg, Cell 2011

8 Hallmarks of Cancer (2017) In Vitrogen

9 Immunology (Study of the immune system)

10 Cells of the immune system ILCs innate lymphoid cells MAITs Mucosal associated invariant T cells gd T cells gamma delta T cells (ILCs) (gd, MAIT)

11 Cancer Immunology (Study of the response of the immune system to cancer)

12 The Cancer-Immunity Cycle Steps to generate an effective anti-tumour response Chen and Mellman Immunity 2013

13 Not all cell deaths are equal (at priming an immune response)

14 Cells can die in different ways DAMPs Tumour fragments Immunogenic Cell Death (ICD) (Adjuvanticity, Antigenicity) DAMPs Damage associated molecular patterns

15 Differential requirements for the immunogenicity of cell death TLR4 Nat Rev Immunol Feb;17(2): doi: /nri

16 The Cancer-Immunity Cycle Immunity Jul 25;39(1):1-10. doi: /j.immuni

17 Types of professional Antigen Presenting Cells (APCs) Nat Rev Immunol Nov;14(11): doi: /nri3754.

18 Activation of tumour-specific T cells by APCs TCR with the right specificity

19 Tumor-specific and tumor-associated antigens (Neoantigens) QIMR Berghofer Medical Research Institute 19

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21 TAA therapeutic targets?

22 Cell-mediated and humoral immune responses to tumour

23 Requirements for effective priming of T cells Front. Oncol., 10 April

24 The many flavours of CD4 + T cells Th22

25 Cell-mediated and humoral immune responses to tumour

26 T cell-independent and T cell-dependent B cell activation

27 Antibody mechanism of action IgG1 FcgRIIIa -activating receptor NK cells

28 Antibody mechanism of action Activate cellular effector function Antibody-Dependent Cell-Mediated Cytotoxicity Antibody-Dependent Cellular Phagocytosis Biolegend

29 ADCC - the underlying mechanism for the clinical efficacy of therapeutic anti-cancer antibodies. Biolegend

30 Effector responses of NK cells are regulated by inhibitory and activatory receptors Release of Cytokines Cytolysis Trends in Immunology , DOI: ( /j.it )

31 Major inhibitory and activating receptors on NK cells and their cognate ligands on targets NKp30 isoforms predict clinical outcome of GIST, neuroblastoma Chan et al., 2014 Cell Death Differentiation

32 The Cancer-Immunity Cycle Immunity Jul 25;39(1):1-10. doi: /j.immuni

33 When the Cancer Immunity Cycle is successfully completed

34 Cancer Immunology (pre 2000) Reason for failures Cancer Immunology ( ) - What went right...

35 Conceptual Developments in Cancer Immunology 2 Tumour Neoantigen 1 Cancer immunoediting 3 Immune Reaction 4 Combination mab-based therapy 5 Tumour induced Immune suppression

36 1 3Es KILL BATTLE LOSE Smyth et al. JEM 2000, Shankaran et al. Nature 2001 Swann et al. J. Clin. Invest. 2007, Koebel et al. Nature 2007 Teng et al., JLB 2008; Schreiber..Smyth. Science 2011 Teng et al., Cancer Res QIMR 2012, Berghofer Teng Medical et al., Research JCI 2015 Institute 36

37 2 Mutational load correlates with frequency of tumour neoantigens... & response Estimate of the neoantigen repertoire in human cancer Synder A et al., NEJM 2014 van Allen et al., Science, 2015, Hugo W et al., Cell 2016 Ton N. Schumacher, and Robert D. Schreiber Science 2015;348:69-74 MHC Quality

38 3 Immune contexture correlates with clinical outcome NKT Stroma Immune contexture associated with good prognosis in CRC Chemokine CXCL9 CX3CL1 CXCL10 CCL2 CCL5 CXCL13 Adhesion MADCAM1 ICAM1 VCAM1 Cytotoxic Granzymes Perforin Granulysin Eosinophil Immature DC NK Neutrophil DC Blood vesse l T H 1 Mast cell Tumor core Lymphaic vessel B cells CTL T H 17 MDSC Treg Macrophage Invasive margin Location, density, functional orientation of cells γδt F-DC T FH T H 1 T-bet IRF1 STAT1 T H 1 IL-12 IFN-γ IL-15 T H 1 Epithelial/smooth muscle layer TLS T FH IL21 B cells Tumor margin CD3+, CD8+, CD45RO+ T cells Immunoscore Galon et al., 2006 Science, Pages et al., 2005 NEJM, Fridman et al., 2012 NRC, Bindea el al., 2013 Immunity

39 Mechanism of Treg mediated immunosuppression Worman C et al., Cell Mol Life Sci 2009

40 Mechanism of MDSC mediated immunosuppression Dmitry I. Gabrilovich Cancer Immunol Res 2017;5:3-8

41 4 (trimab) trimab anti-dr5 (immunogenic cell death) anti-cd40 (activate APC) anti-cd137 (enhance effector T cell function and survival) MCA induced fibrosarcoma model MCA WT or KO mouse d Detect sarcoma Measure growth Commence treatment

42 Rejection of carcinogen-induced established tumors by trimab Uno et al. Nature Medicine, 2006

43 4 The four nodes to target for inducing maximal anti-tumour immunity Smyth et al., NRCO 2016

44 5 Engagement of checkpoint receptors represents a major mechanism of tumour-induced immunosuppression Checkpoint receptors: Brakes to limit overzealous T cell activation About 20 interactions regulate T cell immune response APC/Tumour T cell Melero I et al. Nat Rev Cancer 2015

45 Checkpoint blockade can unleash endogenous anti-tumour response ORR 10% 2010 ORR 31% 2012 ORR 53% 2013 ORR 61% 2015

46 Anti-PD-1 to be used as standard of care and in combination immunotherapies ORR 33.7% vs 11.9% 2015 ORR 31.7% vs 10.6% 2015 ORR 20% vs 9% 2015 ORR 44.8% vs 27.8% 2016

47 Cancer immunotherapy-based combination studies underway in 2016 Chen & Mellman Nature 2017

48 Tumour microenvironment can be stratified into 4 types based on TILs and PD-L1 expression in tumours Teng et al., 2015 Cancer Res

49 Summary Anti-PD-1/PD-L1 - will become the immunotherapeutic backbone of future cancer treatments Cancers can be divided into four type absence or presence of TILs and PD-L1 expression Efficient anti-tumour strategies must focus on hitting different targets concurrently Key nodes to target in combination treatment abrogating immune suppression inducing immunogenic cancer-cell death, enhancing antigen presentation/adjuvanticity inducing activation and survival of immune-effector cells

50 Summary Exome-sequencing data can be mined to identify unique neoantigen profile of tumours guide future personalized vaccine design for use in combination treatments A large proportion of patients have immune ignorant (cold) tumours, predicted to have a poor prognosis regardless of any current intervention novel therapies have to be developed (Oncolytic virus, STING agonist, CAR-T).

51 Moving Forward

52 Key issues in cancer immunotherapy 1) Identifying biomarkers to predict what cancers and pts will respond to anti-pd-1/pd-l1 2) How do we increase the proportion of patients who respond to anti-pd-1/pd-l1? 3) What therapies do we use to treat cancers with microenvironments that are resistant to anti-pd-1/pd- L1 monotherapy? 4) What do we do for patients who develop acquired resistance to anti-pd-1 therapies? 5) What is the optimal scheduling for administration of combination immunotherapy? 6) How to assess the therapeutic index (anti-tumour efficacy/iraes) of combination immunotherapies?

53 Overall Survival Improving the tail of the curve... Time

54 Thank You

55 Identifying biomarkers to predict patients who will respond to anti-pd-1/pd-l1

56 Tumour microenvironment can be stratified into 4 types based on TILs and PD-L1 expression in tumours TIL + PD-L1 + (38%) Type I TIL - PD-L1 - (41%) Type II Melanoma Type IV TIL + PD-L1 - (20%) Type III TIL - PD-L1 + (1%) Taube et al. Sci Transl Med 2012, CCR 2014

57 Association of anti-pd-l1 response and tumour-infiltrating immune cell PD-L1 expression Nature, 2014

58 Cancers with type I TME containing CD8 + T cells and PD-L1 most likely to respond to anti-pd-1/pd-l1 Level of PD-1 expression Ngiow et al., Cancer Res 2015 PDL2 expression? Tumeh et al. Nature (2014)

59 QIMR Berghofer Medical Research Institute 59

60 Factors that influence the cancer immune set point

61 Biomarkers of response to PD-1/PDL1 blockade Angiogenesis Density, Location PD-1 expression level Other checkpoint receptors Epigenetics Other immune cells MMR-deficient/MSI-H Somatic vs Driver mutations (e.g Braf V600 ) Genetics Mutational Burden CD8 + T cell PD-L1 expressio n Time Durability of Response Tumor/Immune cells IFN gene signature (early on txt) Tumor load Microbiome Age External factors Prior therapy

62 From bed-side To bed-side Clinical research Ex vivo/ In vitro research To bench Experimental Mouse research From bench QIMR Berghofer Medical Research Institute 62

63 Immunotherapy and GI cancer Melero I et al., Abstract presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA.

64 Atezolizumab (anti-pd-l1) Tecentriq, approved for treatment of bladder cancer

65 Adaptive immune gene signature in early-ontreatment samples best predict responders Checkpoint immunotherapy: picking a winner Teng et al., Cancer Discovery 2016 in press Chen, P, Cancer Discov, 2016 EDT median 1.4 months ( months) Vilain et al EJC 2015; EDT (within 2 months of treatment) increase in intratumoral CD3+, CD8+, CD68+ in responders Non-responders increased VEGFA

66 How do we increase the proportion of patients who respond to anti-pd-1/pd-l1?

67 Can we improve above the 50% ORR induced by anti-ctla-4 & anti-pd-1? * *Without the toxicity

68 Combination of anti-pd-1 or anti-ctla-4 with IDO inhibitors (Indoximod) in melanoma Abstract #3075 ASCO 2016, Yousef Zakharia.. Mhd Milhem

69 IDO - Indoleamine 2,3-dioxygenase, an immune suppressor Abstract #3075 ASCO 2016, Yousef Zakharia.. Mhd Milhem

70 ORR 53% No increase in toxicity Phase II trial ongoing 64 pts Questions 1) PFS? 2) Durability 3) Other cancers?

71 What therapies do we use to treat cancers with TME that are resistant to anti-pd-1/pd-l1 monotherapy?

72 T-VEC + anti-ctla-4 Chemotherapy or targeted therapy + anti-pd-1 Radiotherapy + anti-ctla-4 + anti- PD-1(Twyman-Saint Victor et al., Nature 2015) Type I IFN (poly-ic) + anti-pd-1 (Bald et al. Cancer Discovery 2014) Microbiota (Zitvogel L et al, Gajewski T el, Science 2015) Engineering FcR engaging variants of IgG (Ravetch Cancer Cell 2016) Scheduling (Neoadjuvant/adjuvant) CAR-T + anti-pd-1 anti-cd40 + anti-il-23 anti-cd40 + anti-csfr1

73 What other cancers should we treat with anti-pd-1/pd-l1?

74 PD-1 & PD-L1 expression in various types of solid tumours

75 PD-1 + TILs expression correlates with increasing mutational load Le et al., NEJM, 2015; Maby et al., Cancer Res, 2015

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77 Gut bacteria affect immunotherapy effectiveness Sivan A et al., Science 2015 Vétizou M et al., Science 2015 The composition of intestinal microbiota affects checkpoint blockade efficacy and can be manipulated to improve responses. Alexandra Snyder et al. Science 2015;350:

78 Neoantigen presentation in the tumour microenvironment Khalil, D. N. et al. (2016) Nat. Rev. Clin. Oncol.

79 T-cell inflamed phenotype gene expression signatures to predict clinical benefit from pembrolizumab across 5 cancer types

80 Biomarkers and response to pembrolizumab (pembro) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)

81 What do we do for patients who develop acquired resistance to anti-pd-1 therapies?

82 Jesse Zaretsky.. Antoni Ribas NEJM 2016 Mean time to relapse 624 days (range, 419 to 888)

83 Mechanisms of resistance Whole-exome sequencing of biopsy samples fomr paired baseline and relapsing lesions in 4 pts 2 pts; IFNgR associated JAK1/JAK2 mutations loss of ability to respond to IFNg 1 pt; b2m mutation loss of surface MHC I expression 1 pt; - no defined genetic alterations to explain acquired resistance (no PDL1 on tumors pre/post txt)

84 Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma Hugo W,.. Ribas A, Lo R Cell 2016

85 Association of PD-L2 expression in human tumors with atezolizumab activity. QIMR Berghofer Medical Research Institute 85

86 QIMR Berghofer Medical Research Institute 86

87 QIMR Berghofer Medical Research Institute 87

88 QIMR Berghofer Medical Research Institute 88

89 Evidence for immunoediting in human tumours Analysis of 18 TCGA tumour types shows genomic correlates of immune cytolytic activity Multiple tumour types demonstrate strong link between mutation load and local immunity Number of predicted MHC Class I- associated neoantigens correlated with cytolytic activity. Lower than expected in colorectal and other tumours, suggesting immune-mediated elimination Rooney et al., Cell 2015 Infiltrated tumours are enriched for probable escape lesions affecting CASP8, HLA, B2M

90 Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability MSI and a subgroup of MSS patients have high intratumoral adaptive immune gene expression Functional effector anti-frameshift mutation CTLs kill tumor cells in MSI patients Genetic evidence of immunoediting in human CRC, in particular for MSI patients Mlecnik et al., Immunity 2016 Immunoscore gives an indicator of tumor recurrence and survival beyond MSI staging

91 QIMR Berghofer Medical Research Institute 91

92 Tumor associated antigens and tumor specific antigens

93 ecancer /

94 Activation of tumor specific T cells by Antigen Presenting Cells (APCs)

95 Antibody mechanism of action QIMR Berghofer Medical Research Institute 95

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98 Targeting CTLA-4 and PD-1 to release the brakes on T cells Lymph Node "inflammatory site (tumor) Ribas A NEJM 2012

99 The Immune System Delves P and Roitt I, NEJM 2000

100 Targeting NK cells in cancer immunotherapy Guillerey C et al., Nat Immunol 2016