Post on 14-Jan-2022
Neuroendokrine Tumorerkrankungen
Immuntherapie
Ulrich Keilholz
Charité Comprehensive Cancer Center
effector cell
Tumor cell Antigen presenting
cell
TCR TCR
Antigen
Antigen
Apoptosis
Chemotherapy
Radiotherapy
Necrosis
effector cell
Tumor cell Antigen presenting
cell
TCR TCR
Antigen
Antigen
Apoptosis
Chemotherapy
Radiotherapy
Necrosis
In all cancer patients, immune-surveillance has failed
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
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
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
TCR TCR
Antigen
Antigen
Stimulation
(e.g. Interleukin-2) effector cell
Tumor cell Antigen presenting
cell
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
(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
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
Antigen
TCR
TCR TCR
Antigen
Antigen
Vaccine
effector cell
Tumor cell Antigen presenting
cell
I Mellman et al. Nature 480, 480-489 (2011)
T-cell-Targets
for immunoregulatory antibodies
B7 B7
CTLA4
CD28 PD1
PD-L1
effector cell
Tumor cell Antigen presenting
cell
CTLA4 und PD1: Die zentralen Immune Checkpoints
B7 B7
CTLA4
CD28 PD1
PD-L1
Anti
CTLA4
effector cell
Tumor cell Antigen presenting
cell
anti-CTLA4 erlaubt Entwicklung von AUTOIMMUNITÄT
B7 B7
CTLA4
CD28 PD1
PD-L1
Anti
PD1/PDL1
effector cell
Tumor cell Antigen presenting
cell
anti-PD1 erlaubt EXECUTION der IMMUNITÄT
Melanom
Melanom
RCC
NSCLC
Weber JS, et al. J Clin Oncol. 2012.
CTLA-4 Blockade With Ipilimumab Kinetics of irAEs in Melanoma
Toxi
city
Gra
de
Time (weeks)
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
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
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
PD-1 Blockade in Tumors with Mismatch Repair Deficiency
Presented By Dung Le at 2015 ASCO Annual Meeting
Mutations per tumor
Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 12
Presented By Dung Le at 2015 ASCO Annual Meeting
Pembrolizumab (anti-PD1) 10 mg/kg alle 2 Wochen
Slide 13
Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 15
Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 17
Presented By Dung Le at 2015 ASCO Annual Meeting
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)
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