Neuroendokrine Tumorerkrankungen Immuntherapie. Ulrich Keilholz Charité Comprehensive Cancer Center

Transcription

1 Neuroendokrine Tumorerkrankungen Immuntherapie Ulrich Keilholz Charité Comprehensive Cancer Center

2 effector cell Antigen TCR TCR Antigen Antigen presenting cell Tumor cell Apoptosis Chemotherapy Radiotherapy Necrosis

3 In all cancer patients, immune-surveillance has failed effector cell Antigen TCR TCR Antigen Antigen presenting cell Tumor cell Apoptosis Chemotherapy Radiotherapy Necrosis

4 Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells

5 Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells

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8 Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells

9 effector cell Stimulation (e.g. Interleukin-2) Antigen TCR TCR Antigen Antigen presenting cell Tumor cell

10 DTIC, Cisplatin, IFNa with or without intravenous Interleukin-2 in advanced melanoma Study Coordinator: Ulrich Keilholz, Berlin Co-Coordinator: Alexander Eggermont, Rotterdam EORTC trial J Clin Oncol 2005

11 Overall Survival Logrank test: p= (years) O N Number of patients at risk : Arm A Arm B J Clin Oncol 2005

12 Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells

13 Vaccine effector cell TCR Antigen Antigen TCR TCR Antigen Antigen presenting cell Tumor cell

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15 T-cell-Targets for immunoregulatory antibodies I Mellman et al. Nature 480, (2011)

16 effector cell CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell CTLA4 und PD1: Die zentralen Immune Checkpoints

17 Anti CTLA4 effector cell CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell anti-ctla4 erlaubt Entwicklung von AUTOIMMUNITÄT

18 effector cell Anti PD1/PDL1 CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell anti-pd1 erlaubt EXECUTION der IMMUNITÄT

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20 Melanom

21 Melanom

22 RCC

23 NSCLC

24 Toxicity Grade CTLA-4 Blockade With Ipilimumab Kinetics of iraes in Melanoma Weber JS, et al. J Clin Oncol Time (weeks)

25 Approximate proportion of patients (%) PD-1 Blockade: Kinetics of iraes in Melanoma Time (weeks) Skin Gastrointestinal Endocrine Hepatic Pulmonary Renal Weber JS, et al. ASCO

26 Change From Baseline in Tumor Size, % Example: Pembrolizumab Antitumor Activity Melanoma 1 (N=655) KEYNOTE NSCLC 2 (N=262) KEYNOTE-001 H&N 3 (N=132) KEYNOTE-012 Urothelial 4 (N=33) KEYNOTE-012 Gastric 5 (N=39) KEYNOTE TNBC 6 (N=32) KEYNOTE-012 chl 7 (N=29) KEYNOTE-013 Mesothelioma 8 (N=25) KEYNOTE-028 Ovarian 9 (N=26) KEYNOTE-028 SCLC 10 (N=20) KEYNOTE-028 Esophageal 11 (N=23) KEYNOTE-028 chl = classical Hodgkin s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer. 1. Daud A 26 et al ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al ASCO; 4. Plimack E et al ASCO; 5. Bang YJ et al ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al ASH Annual Meeting; 8. Alley EA et al AACR; 9. Varga A et al ASCO; 10. Ott PA et al ASCO; 11. Doi T et al ASCO.

27 Change From Baseline in Tumor Size, % Example: Pembrolizumab Antitumor Activity Melanoma 1 (N=655) KEYNOTE NSCLC 2 (N=262) KEYNOTE-001 H&N 3 (N=132) KEYNOTE-012 Urothelial 4 (N=33) KEYNOTE-012 Gastric 5 (N=39) KEYNOTE TNBC 6 (N=32) KEYNOTE-012 chl 7 (N=29) KEYNOTE-013 Mesothelioma 8 (N=25) KEYNOTE-028 Ovarian 9 (N=26) KEYNOTE-028 SCLC 10 (N=20) KEYNOTE-028 Esophageal 11 (N=23) KEYNOTE-028 chl = classical Hodgkin s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer. 1. Daud A 27 et al ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al ASCO; 4. Plimack E et al ASCO; 5. Bang YJ et al ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al ASH Annual Meeting; 8. Alley EA et al AACR; 9. Varga A et al ASCO; 10. Ott PA et al ASCO; 11. Doi T et al ASCO.

28 PD-1 Blockade in Tumors with Mismatch Repair Deficiency Presented By Dung Le at 2015 ASCO Annual Meeting

29 Mutations per tumor Presented By Dung Le at 2015 ASCO Annual Meeting

30 Pembrolizumab (anti-pd1) 10 mg/kg alle 2 Wochen Slide 12 Presented By Dung Le at 2015 ASCO Annual Meeting

31 Slide 13 Presented By Dung Le at 2015 ASCO Annual Meeting

32 Slide 15 Presented By Dung Le at 2015 ASCO Annual Meeting

33 Slide 17 Presented By Dung Le at 2015 ASCO Annual Meeting

34 2WUY1M (BER-04) NET Single Nucleotide Variants (SNVs) 7987 Insertions/Deletions (Indels) Mutationslast des Tumors Signatur entspricht: C11 alkylating agents (nicht POL eta, da dominant C>T) PI3K-AKT-mTOR Developmental Pathways snv: 2 in NOTCH2, 3 in FBXW7 exp-: NOTCH1, HOXC11 Tyrosine Kinases snv: ERBB3 exp+: RET, ERBB4 exp-: STK11 Hypermutation 7987 nonsilent SNVs, viele nicht in RNA oder mit sehr geringer AF RAF-MEK-ERK snv: NRAS Cell Cycle DNA Damage Response snv: POLE germline rar + zweimal somatic, exp-, MSH2/6, FANCL, ERCC3 exp+: ERCC4/6 exp-: BAP1 Other snv: CDC73 exp+: PDCD1LG2, CD274, CTLA4, viele B- und T-Zell- Gene => Infiltration snv = single nucleotide variant, in = insertion, del = deletion, amp = amplification, exp+ = increased expression exp- = decreased expression, fus = fusion

35 Konsequenzen Immuntherapie mit Checkpoint-Inhibitoren öffnet komplett neue Perspektiven Saubere Diagnostik nötig, um Wirksamkeit einzuschätzen Einfach Dysfunktions-Mutationen Hohe Mutationslast Starke Inflammation Schwierig Treiber-Mutationen Niedrige Mutationslast Keine Inflammation