Moleculair diagnostiek dag 15012016_JHaanen.pptx

Immuuntherapie van kanker:
voor wie en in welke vorm?
John Haanen
Internist-oncoloog
Disclosures
•  Advisory role:
BMS, Novartis, Roche,
MSD, Pfizer, Neon
Therapeutics
•  Research grants: BMS, MSD, GSK
•  Geen persoonlijke neveninkomsten hieruit!
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
Wat is immuuntherapie?
•  Versterken van de immunologische afweer
tegen kanker
–  Versterken van de T-celimmuniteit
–  Versterken van de NK-celimmuniteit
–  Versterken van de B-celimmuniteit
–  Versterken van de ‘innate’ immuniteit
Wat is immuuntherapie?
•  Versterken van de immunologische afweer
tegen kanker
–  Versterken van de T-celimmuniteit
–  Versterken van de NK-celimmuniteit
–  Versterken van de B-celimmuniteit
–  Versterken van de ‘innate’ immuniteit
Versterken van de T-celimmuniteit
•  Toename in aantal tumor-specifieke T
cellen
•  Verbetering van de functie van tumorspecifieke T cellen
•  Toename in diversiteit van de T
celrespons tegen de tumor
Toename in aantal tumor-specifieke T
cellen
•  Adoptieve transfer van T cellen
–  TIL behandeling
–  TCR gentherapie
–  CAR gentherapie
Cellulaire infiltraten in de ‘tumor microenvironment’
Kerkar S P , Restifo N P Cancer Res 2012
Tumor infiltrating lymphocytes (TIL) therapy
From: Restifo et al., Nat Rev Immunol 2012
Tumor-infiltrating lymphocyte (TIL) therapy of melanoma
Clinical data N10TIL003 patient: CR at 20 weeks
PriortoTIL
3wksaNerTIL
8wksaNerTIL
20wksaNerTIL
Days-7to-1:Nonmyeloabla2vechemotherapywithCyclophosphamideandfludarabin
Day0:2x1011TIL(unselected‘young’TIL)
Days0–3:highdosebolusIL-2(4intotal)
Overall survival of metastatic melanoma
patients treated with TIL (ITT analysis)
1-year OS: 46%
2-year OS: 30%
Besser et al., Clin Canc Res 2013
Infusion of gene-modified T cells
Kershaw et al. Nat Rev Cancer 2013
CAR T cell concept
Ramos et al. Ann Rev Immunol 2016
Further development of CARs
Ramos et al. Ann Rev Immunol 2016
Success of CD19 CAR T cell therapy
Srivastava & Riddell Trends in Immunol 2015
Verbeteren van de functionaliteit
•  Blokkeren van immunologische checkpoints
–  Anti-CTLA4
–  Anti-PD1/PDL1
•  Stimuleren van costimulatoire moleculen
–  Agonistische anti-OX40, anti-CD40, anti-CD137
etc
•  Verbeteren van de tumor microenvironment
–  IDO-remmer
Immuunmodulatie door stimulerende en
blokkerende antilichamen
Ott et al., CCR 2014
T cell signaling
CTLA-4 inhibitie
T-cel
activatie
T cell
TCR
MHC
APC
T-cel
inhibitie
T cell
T cell
CTLA4
CD28
B7
T-cel
potentiatie
CTLA4
TCR
CTLA4
TCR
CTLA-4 inhibitor
CD28
MHC
APC
Adapted from Lebbé et al. ESMO 2008
B7
MHC
APC
B7
CTLA4 speelt een rol
tijdens T cel priming
Ribas. N Engl J Med 2012
PD-1 pathway remt T cel respons direct downstream van
de TCR
Freeman PNAS 2008
Blokkeren van PD-1 versus PD-L1
Arlene Sharpe, ASCO 2013
PD1/PD-L1 speelt een rol
in de tumor/effector fase
Ribas. N Engl J Med 2012
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
2010: jaar van eerste doorbraak:
• 
Ipilimumab verbetert de ‘Overall Survival’ van patienten
met een uitgezaaid melanoom (2e lijnstherapie)
Ipilimumab
naive-pts
+ DTIC
10 mg/kg
Maintenance possible
Pre-treated-pts
+/- gp100
HLA-A2
3mg/kg
Re-induction possible
1 Year
Ipi + gp100 N=403
44%
22%
Ipi + pbo N=137
46%
24%
gp100 + pbo
N=136
25%
14%
Hodi et al 2010 NEJM
1 Year
2 Year
3 Year
Ipilimumab+
DTIC
N=250
47.3
28.5
20.8
Placebo+
DTIC
N=252
36.3
17.9
12.2
2 Year
Robert et al NEJM 2011
Subset OS Analysen naar dosis (N=1861)
Median
3-yr OS rate
3 mg/kg
11.4 (10.3, 12.5)
21% (17%, 24%)
10 mg/kg
11.1 (9.9, 13.0)
24% (21%, 28%)
12.4 (10.4, 15.1)
20% (14%, 26%)
Other
Hodi et al ESMO 2013
Gepoolde OS Analyse Inclusief EAP Data: 4846
Patienten
Mediane OS (95% CI): 9.5 (9.0–10.0)
3-jaar OS rate (95% CI): 21% (20–22%)
Hodi et al ESMO 2013
2010: 1ste jaar van doorbraak:
• 
Ipilimumab verbetert OS van uitgezaaide melanoom in 2e
lijn
2011: 2e jaar van doorbraak:
• 
Ipilimumab verbetert OS van uitgezaaide melanoom in 1e
lijn
2012: 3e jaar van doorbraak:
• 
Anti-PD1/PDL1 toont activiteit in fase I studie bij meerdere
tumor types (ASCO presentaties over melanoom, NSCLC
en RCC)
Anti-PDL1 (MDX-1105)
Brahmer et al., NEJM 2012
Anti-PD1 (nivolumab)
Topalian et al., NEJM 2012
2013
2014
2015
Fase I data bij
uitgezaaide
melanoom met
pembrolizumab
Hamid et al., NEJM 2013
Eerste data van 1st lijn nivolumab in BRAF wild type melanoompatienten
Robert et al., NEJM 2015 (presented at ASCO 2013)
Fase I resultaten van de combinatie
immuuntherapie (anti-CTLA4 + anti-PD1)
Wolchok et al., NEJM 2013
2013
2014
2015
2014
•  Beter begrip van waarom immuuntherapie
met checkpoint inhibitors werkt
–  Correlaties met
•  CD8 TIL
•  Mutational load
•  PDL1 expressie
2013
2014
2015
2015
•  Goedkeuring van nivolumab en pembrolizumab
–  mMelanoom: 1ste lijn
–  mNSCLC: 2de lijn
–  mRCC: TKI refractair
•  Goedkeuring van ipilimumab + nivolumab (US)
–  mMelanoom
•  Goedkeuring van ipilimumab als adjuvante
therapie
–  stage III melanoma
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
Dilemmas voor immuuntherapie
(CTLA4 en PD1/PDL1 blokkade)
•  Relatieve lage objectieve responskans,
maar significant OS voordeel
•  Indrukwekkende toxiciteit
–  Ipilimumab
–  (Anti-PD1)
–  Combinatie anti-CTLA4 en anti-PD1
•  Extreem hoge kosten
Effectvancheckpointblokkade(pembrolizumab)over
verschillendetumortypes
Courtesy of Joseph Eid, MSD
Frequente AE
Incidence per 1000 person-months of all grade
and grade 3 to 5 adverse events under
immunotherapy using the SAS System. The
results include data from the following studies:
CA-184-002, KEYNOTE-001, KEYNOTE-002,
KEYNOTE-006, CheckMate-037,
CheckMate-066, CheckMate-067, and
CheckMate-069
Boutros et al Submitted
AE « of special interest »
Boutros et al Submitted
Auto-immuun uveitis na
anti-CTLA-4 behandeling
Na topicale
behandeling
Immune related adverse events
colitis
hypophysitis
Dreigend financieel probleem van
betaalbaarheid van de zorg
1 mg = 90,10 €1
1 mg = 0,03 €2
eind 2015
3 mg/kg x 4 cycli = 86.400 €
86.400 € = 2,76 kg goud
1
http://www.medicijnkosten.nl/
2 https://www.goudmarkt.nl/goudprijs
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
Respons op nivolumab naar PDL1 expressie
Topalian et al., NEJM 2012
MSD (Merck) PD-L1 NSCLC Sample IHC kleuring
PD-L1 = 0% positief
PD-L1 = 2% positief
PD-L1 = 100% positief
Negatief
Zwak Positief
(1%-49%)
Sterk Positief
(50%-100%)
PD-L1 als biomarker bij NSCLCs
Drug/
Sponsor
Nivolumab
BMS
Pembrolizumab
MSD (Merck)
Assay
28-8
22C3
Cells
scored
Tumor cell membrane
Tumor cell (and stroma)
Infiltrating immune cells
Tissue
Archival
Recent
Arch./Recent
Arch./Recent
2L ++
2L ++
MEDI4736
MedImmune
SP263
1st line
Cut-point
5%
1%
5%
1%
1%
50%
1%
5%
10%
ORR in
PD-L1 +
50%
N=10
13%
N=38
15%
N=33
26-47%
N=45
19-23%
N=177
37%
N=41
31%
N=26
46%
N=13
83%
N=6
39%
N=13
ORR in
PD-L1 -
0%
N=7
17%
N=30
14%
N=35
???
9-13%
N=40
11%
N=88
20%
N=20
18%
N=33
18%
N=40
5%
N=19
Daud, AACR 2014
Ghandi, AACR 2014
Rizvi, ASCO 2014,
#8009
Garon, ASCO 2014,
#8020
2L ++
MPDL3280A
Topalian, NEJM 2012
Grosso, ASCO 2013, #3016
Brahmer, ASCO 2014, #8112
Gettinger, ASCO 2014, #8024
PEMBRO
2L ++
Hamid, ASCO 2013, #9010
Herbst, ASCO 2013, #3000
Powderly, ASCO 2013,
#3001
Spigel, ASCO 2013, #8008
MEDI4736
Setting
NIVO
1st line
MPDL3280A
Genentech
Segal, ASCO 2014, #3002
Brahmer, ASCO 2014, #8021
PD-L1 en respons bij Mel en NSCLC
Melanoma
NSCLCs
Pembrolizuma
b
MK-3475
Pembrolizuma
b
MK-3475
ORR –
“PDL1+”
1% cut-off: 49%
10% cut-off: 52%
ORR –
“PDL1+”
1% cut-off: 25%
50% cut-off: 37%
ORR – PDL1-
1% cut-off: 13%
10% cut-off: 23%
ORR – PDL1-
1% cut-off: 7%
50% cut-off: 11%
Daud, AACR 2014
Garon, WCLC 2013, #2416
Ghandi, AACR 2014
Ni
v
(T olu
op
al m
ia
a
Ni n)et)a b*S
v l.)N ol
EJ id
(W olu
M
eb
m
)2 *Tu
er
01
m
)A ab
Ni SCO *M 2) or
v )201 e
s**
l
(G olu
****
3
a
)
ro
no
****
ss m
o)
m
****
et ab
a*
M )al. *M
* ***
****
PD )ASC e
****
(H
O) la
er L3
20 n
****
bs
2
o
1
3)
****
t)e 8
m
**))
a*
M t)al)A 0a*
****
PD SC So
****
O)
(H
20 lid
am L3
****
1
*
2
T
id
3)
****
u
)e 80
m
))
M t)al)A a*
or
PD SC M
s
O)
e
(S
))))
20 la
or L3
))))
13
ia
n
2
l)e
)
om
))))
t)a 80
Pe l)EC a*
))))
a
****
m C)2 NS
))))
(D
01
*
b
))))
C
*
*
au ro
3)
LC
****
d)
*
*
et liz
****
****
Pe )al)AA um
***
****
m CR) ab
*
*
*
****
(G
b 201 *M
an ro
****
4)
dh
el
****
i)e liz
an
M t)al) um
***)
o
PD AAC a
m
(P
R) b*
a*
ow L3
2
N
*)))
el 28 014 S
C
s)e
)
))))
LC
))))
Pe t)al)A 0a*B
*
****
))))
m SCO la
****
(S
d
b
)
2
el
01 d
*** )
w ro
4) e
er
))))
r**
t)e liz
u
)))
*
t
*
Pe )al)A m
))))
a
)
S
m
))))
CO b
))))
(R bro )2014 *He
))))
ib liz ) ad
)))))
as um
*&
)
)e
*
N
t)a ab
e
ck
l)A *M
*
SC ela
O) no
20 m
14 a*
) ****
)
Intra-tumorale PD-L1 expressie en respons
op PD-1/PD-L1 blokkade
n=)
42
44
34
94
30
53
113
129
65
55
411
Response*Rates
Unselected
21%
32%
29%
22%
23%
23%
40%
19%
26%
18%
40%
PDQL1)+
36%
67%
44%
39%
27%
46%
49%
37%
43%
46%
49%
PDQL1)−
0%
19%
17%
13%
20%
15%*
13%
11%
11%
11%
13%
Presented by: Margaret Callahan
Callahan, ASCO 2014
Mogelijke limitaties voor PD-L1
•  PD-L1 expressie is dynamisch
•  PD-L1 is heterogeen in weefsel
•  Onduidelijk welk niveau van expressie belangrijk is
•  Belang van co-localizatie met TILs
•  Betrouwbaarheid en reproduceerbaarheid van de
verschillende assays
•  Gearchiveerd materiaal
•  Variatie in weefsel collectie, timing, cell sampling,
gebruikt mAb voor kleuring, IHC criteria
Overzicht van deze presentatie
• 
• 
• 
• 
• 
Wat is immuuntherapie van kanker?
Successen van immune checkpoint inhibitie
Dilemmas van checkpoint remmers
Biomarker onderzoek: waar staan we?
Hoe selecteer je patienten voor
immuuntherapie van kanker?
Biomarker research
Melero, .., Haanen, Nat Rev Canc 2015
Combination therapy guided by biomarkers
Melero, .., Haanen, Nat Rev Canc 2015
The Cancer – Immunogram
Describing the state of Cancer - Immune interaction
high tumor foreignness
mutational load
Does the extent of DNA damage
correlate with the clinical effects of cancer immunotherapy?
Adjusted from Alexandrov et al, Nature 2013
Mutational load correlates with improved clinical benefit
from CTLA-4 or PD-1 blockade
Melanoma
NSCLC
Durable clinical
benefit
Van Allen et al., Science 2015
Non-durable
benefit
Rizvi et al., Science 2015
high tumor foreignness
mutational load
general immune status
lymphocyte count
General immune status – lymphocyte count
ipilimumab
Martens et al., submitted
pembrolizumab
Weide et al., submitted
high tumor foreignness
mutational load
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
Evolution of CD8+ T-cells, according to treatment outcome
IHC Analysis of CD8+ T-cells in samples obtained before and during anti-PD1 treatment
Tumeh et al. Nature 2014
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
high tumor foreignness
mutational load
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
absence of inhibitory
tumor metabolism
LDH, glucose utilization
high tumor foreignness
mutational load
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
High LDH and poor survival to ipilimumab in melanoma
Kelderman et al., CII 2014
High LDH and poor survival in melanoma treated with
pembrolizumab
response rate
Daud et al., ASCO 2015
overall survival
Weide et al., submitted
ORR in Patient Subgroups
ORR (Patients)
Total population
NIVO + IPI
Unweighted ORR
difference vs IPI (95% CI)
NIVO
57.6% (314)
43.7% (316)
38.6% (31.3–45.2)
24.6% (17.5–31.4)
53.3% (212)
46.8% (218)
66.7% (102)
36.7% (98)
35.6% (26.8–43.6)
29.1% (20.5–37.1)
44.7% (31.5–55.6)
14.7% (2.0–26.8)
51.4% (185)
38.9% (185)
37.1% (27.9–45.4)
24.6% (15.8–33.0)
65.3% (199)
51.5% (196)
44.7% (114)
30.4% (112)
37.8% (37)
21.6% (37)
40.6% (31.1–48.9)
26.8% (17.3–35.6)
35.2% (24.1–45.2)
20.8% (10.5–30.7)
37.8% (20.0–53.9)
21.6% (6.3–37.2)
57.4% (94)
48.1% (79)
54.3% (35)
43.6% (39)
39.5% (25.8–51.0)
30.1% (16.0–42.8)
27.0% (5.3–45.8)
16.3% (-4.1–35.2)
54.8% (210)
41.3% (208)
72.1% (68)
57.5% (80)
36.9% (28.0–45.0)
23.5% (14.8–31.8)
50.7% (35.0–62.8)
36.2% (21.0–49.0)
ORR
ipi
BRAF
Wild-type
Mutant
M Stage
M1c
Baseline LDH
≤ULN
>ULN
>2x ULN
Age (yr)
≥65 and <75
≥75
PD-L1 Expression Level
<5%
≥5%
70
50
30
10
NIVO or NIVO + IPI better
0
-10
IPI better
24.7%
9.7%
0.0%
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
high tumor foreignness
mutational load
absence of inhibitory
tumor metabolism
LDH, glucose utilization
absence of local inhibitory factors:
soluble mediators
IL6->CRP/ESR
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity
CRP
Zelenay et al. Cell 2015
Signature Expanded in Validation Set<br />(While Blinded to Clinical Outcome)
Presented By Antoni Ribas at 2015 ASCO Annual Meeting
high tumor foreignness
mutational load
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
absence of inhibitory
tumor metabolism
LDH, glucose utilization
absence of local inhibitory factors:
soluble mediators
IL6->CRP/ESR
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
high tumor foreignness
mutational load
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
absence of inhibitory
tumor metabolism
LDH, glucose utilization
absence of local inhibitory factors:
soluble mediators
IL6->CRP/ESR
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
high tumor foreignness
mutational load
sensitivity to immune
effector mechanisms
pMHC expression
IFNg sensitivity?
absence of inhibitory
tumor metabolism
LDH, glucose utilization
absence of local inhibitory factors:
soluble mediators
IL6->CRP/ESR
general immune status
lymphocyte count
high immune
infiltration capacity
CD8 intratumoral
absence of local inhibitory factors:
Checkpoints
PD-L1
conclusions
•  The Cancer – Immunogram is a framework to help to
describe the cancer – immune system interaction for
individual patients and predict which aspect to target
•  LDH (< 2x ULN) appears to be a solid biomarker of
response to select melanoma patients for ipilimumab
treatment
•  Many biomarkers of response to CIT are in development.
Linking all this information to create a large database will
rapidly increase our understanding of immune resistance
and escape.