Neuroendokrine Tumorerkrankungen Immuntherapie
Transcript of Neuroendokrine Tumorerkrankungen Immuntherapie
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Neuroendokrine Tumorerkrankungen
Immuntherapie
Ulrich Keilholz
Charité Comprehensive Cancer Center
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effector cell
Tumor cell Antigen presenting
cell
TCR TCR
Antigen
Antigen
Apoptosis
Chemotherapy
Radiotherapy
Necrosis
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effector cell
Tumor cell Antigen presenting
cell
TCR TCR
Antigen
Antigen
Apoptosis
Chemotherapy
Radiotherapy
Necrosis
In all cancer patients, immune-surveillance has failed
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Failure of Immunesurveillance
no Antigen no AG-specific blockade of Immunoevasisve
T cell response AG-specific Microenvironment
T cells
Tumor Tumor Tumor Tumor
T-cell
T-
cell
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Failure of Immunesurveillance
no Antigen no AG-specific blockade of Immunoevasisve
T cell response AG-specific Microenvironment
T cells
Tumor Tumor Tumor Tumor
T-cell
T-
cell
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Failure of Immunesurveillance
no Antigen no AG-specific blockade of Immunoevasisve
T cell response AG-specific Microenvironment
T cells
Tumor Tumor Tumor Tumor
T-cell
T-
cell
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TCR TCR
Antigen
Antigen
Stimulation
(e.g. Interleukin-2) effector cell
Tumor cell Antigen presenting
cell
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DTIC, Cisplatin, IFNa
with or without intravenous Interleukin-2
in advanced melanoma
Study Coordinator: Ulrich Keilholz, Berlin
Co-Coordinator: Alexander Eggermont, Rotterdam
EORTC trial 18951
J Clin Oncol 2005
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(years)
0 1 2 3 4 5 6 7
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
169 180 65 23 11 4 2 0
159 183 60 31 15 6 4 2
Arm A
Arm B
Overall Survival
Logrank test: p=0.3142
J Clin Oncol 2005
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Failure of Immunesurveillance
no Antigen no AG-specific blockade of Immunoevasisve
T cell response AG-specific Microenvironment
T cells
Tumor Tumor Tumor Tumor
T-cell
T-
cell
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Antigen
TCR
TCR TCR
Antigen
Antigen
Vaccine
effector cell
Tumor cell Antigen presenting
cell
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I Mellman et al. Nature 480, 480-489 (2011)
T-cell-Targets
for immunoregulatory antibodies
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B7 B7
CTLA4
CD28 PD1
PD-L1
effector cell
Tumor cell Antigen presenting
cell
CTLA4 und PD1: Die zentralen Immune Checkpoints
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B7 B7
CTLA4
CD28 PD1
PD-L1
Anti
CTLA4
effector cell
Tumor cell Antigen presenting
cell
anti-CTLA4 erlaubt Entwicklung von AUTOIMMUNITÄT
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B7 B7
CTLA4
CD28 PD1
PD-L1
Anti
PD1/PDL1
effector cell
Tumor cell Antigen presenting
cell
anti-PD1 erlaubt EXECUTION der IMMUNITÄT
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Melanom
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Melanom
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RCC
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NSCLC
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Weber JS, et al. J Clin Oncol. 2012.
CTLA-4 Blockade With Ipilimumab Kinetics of irAEs in Melanoma
Toxi
city
Gra
de
Time (weeks)
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Weber JS, et al. ASCO. 2015.
PD-1 Blockade: Kinetics of irAEs in Melanoma
Skin
0
5
10
15
20
25
30
35
0 10 20 30 40
Ap
pro
xim
ate
pro
po
rtio
n o
f p
atie
nts
(%
)
Time (weeks)
Gastrointestinal
Endocrine
Hepatic
Pulmonary
Renal
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Example: Pembrolizumab Antitumor Activity
cHL = classical Hodgkin’s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer.
1. Daud A et al. 2015 ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. 2015 ASCO; 4. Plimack E et al. 2015 ASCO; 5. Bang YJ et al. 2015 ASCO; 6. Nanda R et al.
SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR; 9. Varga A et al. 2015 ASCO; 10. Ott PA et al. 2015 ASCO; 11. Doi T et al. 2015 ASCO.
Melanoma1 (N=655)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100NSCLC2 (N=262)
KEYNOTE-001
Gastric5 (N=39)
KEYNOTE-012
H&N3 (N=132)
KEYNOTE-012
TNBC6 (N=32)
KEYNOTE-012
cHL7 (N=29)
KEYNOTE-013 Mesothelioma8 (N=25)
KEYNOTE-028
Urothelial4 (N=33)
KEYNOTE-012
Ch
ange
Fro
m B
ase
line
in
Tum
or
Size
, %
Ovarian9 (N=26)
KEYNOTE-028
SCLC10 (N=20)
KEYNOTE-028
Esophageal11 (N=23)
KEYNOTE-028
26
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Example: Pembrolizumab Antitumor Activity
cHL = classical Hodgkin’s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer.
1. Daud A et al. 2015 ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. 2015 ASCO; 4. Plimack E et al. 2015 ASCO; 5. Bang YJ et al. 2015 ASCO; 6. Nanda R et al.
SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR; 9. Varga A et al. 2015 ASCO; 10. Ott PA et al. 2015 ASCO; 11. Doi T et al. 2015 ASCO.
Melanoma1 (N=655)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100NSCLC2 (N=262)
KEYNOTE-001
Gastric5 (N=39)
KEYNOTE-012
H&N3 (N=132)
KEYNOTE-012
TNBC6 (N=32)
KEYNOTE-012
cHL7 (N=29)
KEYNOTE-013 Mesothelioma8 (N=25)
KEYNOTE-028
Urothelial4 (N=33)
KEYNOTE-012
Ch
ange
Fro
m B
ase
line
in
Tum
or
Size
, %
Ovarian9 (N=26)
KEYNOTE-028
SCLC10 (N=20)
KEYNOTE-028
Esophageal11 (N=23)
KEYNOTE-028
27
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PD-1 Blockade in Tumors with Mismatch Repair Deficiency
Presented By Dung Le at 2015 ASCO Annual Meeting
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Mutations per tumor
Presented By Dung Le at 2015 ASCO Annual Meeting
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Slide 12
Presented By Dung Le at 2015 ASCO Annual Meeting
Pembrolizumab (anti-PD1) 10 mg/kg alle 2 Wochen
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Slide 13
Presented By Dung Le at 2015 ASCO Annual Meeting
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Slide 15
Presented By Dung Le at 2015 ASCO Annual Meeting
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Slide 17
Presented By Dung Le at 2015 ASCO Annual Meeting
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2WUY1M (BER-04) – NET
Hypermutation
7987 nonsilent SNVs, viele nicht in RNA oder mit sehr geringer AF
Tyrosine Kinases
snv: ERBB3 exp+: RET, ERBB4 exp-: STK11
Cell Cycle
RAF-MEK-ERK
snv: NRAS
PI3K-AKT-mTOR
Developmental Pathways
snv: 2 in NOTCH2, 3 in FBXW7 exp-: NOTCH1, HOXC11
Other
snv: CDC73 exp+: PDCD1LG2, CD274, CTLA4, viele B- und T-Zell-Gene => Infiltration
10 100
snv = single nucleotide variant, in = insertion, del = deletion, amp = amplification, exp+ = increased expression
exp- = decreased expression, fus = fusion
DNA Damage Response
snv: POLE germline rar + zweimal somatic, exp-, MSH2/6, FANCL, ERCC3 exp+: ERCC4/6 exp-: BAP1
Single Nucleotide Variants (SNVs)
7987
Insertions/Deletions (Indels) 5
Mutationslast des Tumors
Signatur entspricht: C11 alkylating
agents (nicht POL eta, da dominant C>T)
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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