Neuroendokrine Tumorerkrankungen Immuntherapie

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


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

TCR TCR

Antigen

Antigen

Stimulation

(e.g. Interleukin-2) effector cell


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


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


cell

CTLA4 und PD1: Die zentralen Immune Checkpoints

B7 B7

CTLA4

CD28 PD1

PD-L1

Anti

CTLA4

effector cell


cell

anti-CTLA4 erlaubt Entwicklung von AUTOIMMUNITÄT

B7 B7

CTLA4

CD28 PD1

PD-L1

Anti

PD1/PDL1

effector cell


cell

anti-PD1 erlaubt EXECUTION der IMMUNITÄT

Melanom

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



Pembrolizumab (anti-PD1) 10 mg/kg alle 2 Wochen

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

Neuroendokrine Tumorerkrankungen Immuntherapie

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