BADO meeting. Immunotherapy. in Metastatic Melanoma

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1 BADO meeting Immunotherapy in Metastatic Melanoma UCL Université catholique de Louvain Prof J-Fr. BAURAIN Medical Oncology Department BADO Meeting Inaugural Lecture 07 december 2013

2 Melanoma Treatment - Surgery - Radiotherapy - Chemotherapy Baurain

3 Poor Prognosis of Metastatic Melanoma Patients One Year Overall Survival = 25% Six months PFS = 15% Response rate around 5% Standard : DTIC iv 1g/m 2 q3w E.L. Korn et al. J Clin Oncol 2008, 26: Baurain

4 Treatment of Metastatic Melanoma - Surgery - Radiotherapy - Chemotherapy - Targeted therapy - Immunotherapy Baurain

5 Two Major Transduction Signal Pathways and Frequency of Mutations in Melanoma Baurain

6 Melanoma : No more one disease - Genetic Classification Adapted from Curtin JCO 2006

7 BRAF Mutations in Melanoma Type BRAF Mutation V600E V600K V600R V600D Relative Frequency 92,5 % 5,6 % 1,6 % 0,4 % Sala et al. Mol Cancer Res 2008;6:

8 Vemurafenib is a Treatment for BRAF mutated melanoma Response Rate : 48% Vemurafenib efficacy overall RR median PFS median OS median FUP BRIM-2 53% 6.8 mos 15.9 mos 12.9 mos BRIM-3 48% 5.3 mos OS 6m : 84% 3.8 mos Flaherty NEJM 2010 Sosman NEJM 2012

9 Differences in kinetics and outcome between Treatments Baurain

10 Differences in kinetics and outcome between Treatments Baurain

11 Can we cure Metastatic Melanoma?

12 Higher incidences of cancers without known infectious cause in immunosuppressed patients Grulich et al. Lancet 2007

13 Tumour Antigens

14 Human Tumours Antigens recognized by T cells Tumor-specific shared antigens (T-Sp) cancer-germline genes MAGE-A, B, C, NY-ESO1 LAGE-2, BAGE, GAGE, LAGE, SSX2...

15 Human Tumours Antigens recognised by T cells Tumor-specific shared antigens (T-Sp) cancer-germline genes MAGE-A, B, C, NY-ESO1 LAGE-2, BAGE, GAGE, LAGE, SSX2... Viral antigens (Vir) HBV, HPV, EBV... Antigens resulting from mutations (Mut) usually individual, sometimes involved in oncogenesis (CDK4, ß-catenin...) - melanoma cell line COLO-829 complete sequencing of the DNA of - autologous EBV-transformed B cell line - 33,345 somatic base substitutions in protein-coding sequences caused amino acid changes Pleasance et al Nature

16 Human Tumours Antigens recognised by T cells Tumor-specific shared antigens (T-Sp) cancer-germline genes MAGE-A, B, C, NY-ESO1 LAGE-2, BAGE, GAGE, LAGE, SSX2... Viral antigens (Vir) HBV, HPV, EBV... Antigens resulting from mutations (Mut) usually individual, sometimes involved in oncogenesis (CDK4, ß-catenin...) Differentiation antigens (Dif) tyrosinase, Melan-A MART1, gp100 PMEL17, gp75 TRP1,TRP2... PSA, PAP (prostatic acid phosphatase)... Overexpressed antigens (OvEx) p53, PRAME, MC1R, telomerase...

17 Multiplicity of Antigens Recognized by CTL on Melanoma A B C D E F G H A B C D E F G H antigens discovered antigens discovered MZ2-MEL MZ7-MEL A B C D E F A B C D E F antigens discovered antigens discovered LB33-MEL EB81-MEL T-Sp : Tumor-specific shared antigens Diff : Differentiation antigens Mut : Antigens resulting from mutations OvEx : Overexpressed antigens

18 Basis of Immunotherapy Human tumors are antigenic They bear antigens that can be recognized by autologous T lymphocytes. immunogenic They induce spontaneous antitumor T cell responses in vivo. --> = Scientific foundations of cancer immunotherapy through T cells

19 Pros and cons of tumour antigens for immunotherapy Antigen class Advantages Drawbacks cancer-germline (MAGE,...) tumor-specific shared virus tumor-specific shared only a few tumor types mutations tumor-specific individual differentiation shared only a few tumor types on normal cells (> autoimmunity) overexpression shared on normal cells (> autoimmunity)

20 Cancer Immunotherapy : Therapeutic Cancer Vaccines Specific immunotherapy of cancer surgery biopsy Immunisation blood lymphocytes HLA typing PCR analysis: HLA-A1? MAGE-3? probability : 25% 76% peptides recombinant (± adjuvant) viruses specific proteins (± adjuvant) immune response? clinical benefit? both : 19%

21 Clinical Efficacy with Other Antigens Vaccine Peptide Patients treated Patients responding Cancer type Vaccine Dendritic cells Patients treated Patients responding Tumor cells Virus Heat-shock protein Total Rosenberg et al, Nat Med 2004, 10, 909 Objective response rate: 3.8%

22 Passive Immunotherapy : Transferring in vitro amplified CTL Gattinoni et al Nat Rev Immunol

23 Passive Immunotherapy : Transferring in vitro amplified CTL - transfer of T lymphocytes recognizing a melanocyte differentiation antigen (Melan-A) - followed by disappearance of melanoma metastases - and by destruction of melanocytes (vitiligo, poliosis, bilateral panuveitis, hearing loss) Yeh et al Ophtalmology

24 Recombinant TCR: the ultimate adoptive cell therapy

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26 CTLA-4 Dampens T-cell Activation Baurain

27 CTLA-4 Dampens T-cell Activation Baurain

28 Phase III study : gp100 peptide vaccine +/- Ipilimumab patients with metastatic melanoma progressing after first-line chemotherapy - Primary endpoint : Overall survival R

29 Some patients are still alive 3-4 years after Ipilimumab gp100 + placebo lpilimumab + gp100 Ipilimumab + placebo

30 Toxicities of Ipilimumab : Immune Mediated Gastro-Intestinal disorders - diarrhea (38% - 4%) - nausea (35% - 2%) - vomiting (20% - 2%) - abdominal pain (17% - 2%) Dermatologic - pruritus (20% -1%) - rash (20% -1%) Liver - hepatitis (1%) - increase in transaminase (2%) Endocrine - hypophysitis / hypopituarism (3% - 1%) - adrenal insufficiency (1%) - hypo or hyperthyroidism (2% -1%) Neurological - muscal weakness (1%) - sensitive-motor neuropathy (1%)

31 Ipilimumab in First Line : Metastatic Melanoma Robert

32 Phase III study : DTIC +/- Ipilimumab Robert... Baurain et al NEJM 2011

33 Update Results with Longer Follow-up Be carefull of cross over Robert

34 Overall Survival of Melanoma Patients treated with Ipilimumab

35 About 20% are still alive with Ipilimumab

36 About 20% are still alive with Ipilimumab

37 Type of curve is changing! Targeted Therapies Immunotherapies Baurain

38 How to Improve Baurain

39 How to Improve Focus on rapid progressors - Targeted therapies - Combination with Ipilimumab Baurain

40 Combination trials in melanoma

41 How to Improve Raising the BAR Baurain

42 Anti-PD-1 and anti-pd-l1 antibodies Baurain

43 Anti-PD-1 and anti-pd-l1 antibodies Baurain

44 Anti-PD-1 and anti-pd-l1 antibodies Baurain

45 Clinical Trials with anti-pd-1 or PD-L1 Antibodies MDX-1105 BMS Medarex / BMS Fully human IgG4 ANTI-PD-L1 NIVOLUMAB BMS Medarex / BMS Fully human IgG4 ANTI-PD-1 LAMBROLIZUMAB MSD-3475 MSD Fully human IgG4 ANTI-PD-1

46 Nivolumab (3mg/kg q2w) in 27 melanoma patients Topalian et al NEJM

47 Metastatic Melanoma Patient treated with Nivolumab Baseline Week 30 Baurain

48 Lambrolizumab (anti-pd-l1) in Metastatic Melanoma Hamid O NEJM 2013;369:

49 Lambrolizumab (anti-pd-l1) in Metastatic Melanoma Baseline Day 90 Hamid O NEJM 2013;369:

50 Combination of anti-ctla-4 and anti-pd1 Wolchok NEJM 2013

51 On your way to cure Metastatic Cancer Patients Baurain

52 Other mechanisms of immune resistance Coulie

53 Other mechanisms of immune resistance Baurain

54 Other mechanisms of immune resistance Baurain

55 The Clinical Trial based on that Concept DAVANAT - galactomannan derived from guar gum - binds to galectin-1 & -3 - increased the anti-tumor activity of chemotherapy drug 5-fluorouracil in mice Baurain

56 Treatment of Metastatic Melanoma Patients Baurain

57 Treatment of Metastatic Melanoma Patients Baurain

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