Immunotherapie in oncologie

Immunotherapie in oncologie
Lore Decoster
Medische oncologie
Oncologisch Centrum, UZ Brussel
Immuuntherapie
• Definitie:
– Gebruik vh immuunsysteem vd patiënt om kanker
te behandelen
• De ‘ideale’ kankerbehandeling
– Zeer uitgebreid wapenarsenaal
• T cellen, antilichamen, natural killers, etc
– Precies en doelgericht
– Recall effect: na priming levenslange immuniteit
Immuunsysteem
Immuunsysteem in evenwicht
Immuun activatie
Te weinig
(infecties, kanker)
Te veel
(autoimmuniteit,weefselschade)
Immuunsysteem vs kanker
• Spontane regressie vb in melanoom en RCC
• Immunosuppressie verhoogt kanker risico
– Lymfoom x90; huidkanker x29
• Lymfocyten in bloed en in de tumor (TILs)
• Tumoren zijn immunogeen door tumor Ag
– HER2, RAS, MAGE
Stimulatory and inhibitory factors in the cancer
immunity cycle
3
Trafficking of T cells to
tumours
4
Priming and Activation
CX3CL1, CXCL9, CXCL10
CCL5
CD28/B7.1, CD137/CD137L
OX40/OX40L, CD27/CD70
HVEM, GITR, IL-2, IL-12
Infiltration of T cells into
tumours
CTLA4/B7.1
PD-L1/PD-1
PD-L1/B7.1 Prostaglandins
Blood
vessel
Lymph
node
2
5
LFA1/ICAM1
Selectins
VEGF
Endothelin-B receptor
Cancer antigen presentation
TNF-, IL-1
IFN-, CD40L/CD40
CDN, ATP
HMGB1, TLR
Tumour
Recognition of cancer
cells by T cells
T cell receptor
Reduced pMHC on cancer cells
IL-10, IL-4, IL-13
Killing of cancer cells
1
IFN- , T-cell granule content
Release of cancer cell antigens
Immunogenic cell death
Tolergenic cell death
6
 Stimulatory factors
 Inhibitors
Chen DS and Mellman I. Immunity. 2013 Jul 25;39(1):1-10.
PD-L1/PD-1
VISTA
PD-L1/B7.1
LAG-3
IDO
Arginase
MICA/MICB
TGF-
BTLA
B7-H4
TIM-3/phospholipids
7
Tumor microenvironment:
Immune escape mechanisms
A. Ineffective tumor antigen
presentation (gp100, MART-1,
decreased MHC expression)
CD8*
T cell
TCR
VEGF
APC
B. Recruitment of
immunosuppressing cells
(regulatory T cells =Tregs,
MDSCs, other)
MHC
CTLA-4
MDSC
Treg
PD-L1
Tumor cells
PD-1
P-DL1
PD-1
TGF-β
IDO
IL-10
D. T cell checkpoints
TGF-β
ARG1
iNOS
TGF-β
IL-10
CD4+
T cell
CD8*
T cell
C. Secretion of
immunosuppressive signals
(e.g. PD-L1, TGF-β, IL-10,
and indolamine 2,3dioxygenase [IDO])
Vesely MD, et al, Ann Rev Immunol 2011, 29: 235
13
Immuuntherapie
•
•
•
•
Immuun stimulerende cytokines
Monoclonale antilichamen
Kanker vaccins
Checkpoint inhibitoren
– Anti-cTLA4
– Anti PD1
– Anti PDL1
Immuun checkpoints
• T cel respons geregeld door een evenwicht
tussen co-stimulatie en inhibitie signalen
(imuun checkpoints)
• ‘normale omstandigheden’:
– Bescherming normaal weefsel tegen schade
tijdens immuunrespons op infecties
– Preventie autoimmuniteit
Ways to keeping the T cells “active”
Presented By Michael Postow at 2015 ASCO Annual Meeting
T-cell checkpoint inhibition
AntiPD1/
PDL1
AntiCTLA4
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
Immuun therapie en mutaties in
tumor
The prevalence of somatic mutations across human cancer types.
LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477
T-cell checkpoint inhibition
AntiPD1/
PDL1
AntiCTLA4
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
Anti-cTLA4
Anti-cTLA4
• Ipilimumab (Yervoy)
– Geregistreerd en terugbetaald in melanoma
• Tremelimumab
– In studie in verschillende tumoren
Hodi et al. N Eng J Med 2010
Robert et al N Eng J Med 2011
Ipilimumab in melanoom
Ipilimumab in melanoom
• 2e lijn na chemo:
– DCR 20-28% vs 11%
– Mediane OS 10 vs 6,4 m
– 1 jaar S: 25% vs 15%
– 2jaar S: 22% vs 14%
Hodi et al. N Eng J Med 2010
Na 3j 20% in leven!
Kaplan–Meier Curves for Overall Survival, Progression-free Survival, and Duration of Response.
• 1e lijn vs chemo:
– Mediane OS 11 vs 9 m
– 1j OS 47 vs 36%
– 3j OS 21 vs 12%
Robert C et al. N Engl J Med 2011;364:2517-2526.
T-cell checkpoint inhibition
AntiPD1/
PDL1
AntiCTLA4
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
Anti-PD1
Anti-PD1
• Nivolumab (Opdivo)
–
–
–
–
Geregistreerd en terugbetaald in melanoom
Geregistreerd en terugbetaald tweede lijn in NSCLC
Geregistreerd en terugbetaald in niercelcarcinoom
Geregistreerd en terugbetaald in Hodgkin lymfoom
• Pembrolizumab (Keytruda)
– Geregistreerd en terugbetaald in melanoom
– Geregistreerd in PDL1 positief NSCLC (1e en 2e lijn)
– Evidentie in Merkelcelcarcinoom, Head and neck,…
Anti-PDL1
• Atezolizumab
– FDA blaasCA
– FDA NSCLC
• Durvalumab
– FDA PDL1+ blaasCA
• Avelumab
– FDA Merkel cel CA
Anti-PD1 in melanoom
• Pembrolizumab fase 1 na ipilimumab
Robert Lancet 2014
Survival End Points.
• Nivolumab 1e lijn bij BRAF wild type
Robert C et al. N Engl J Med 2015;372:320-330.
Anti-PD1 vs anti-cTLA4
Robert N Eng J Med 2015
Anti-PD1 in long
2e lijn NSCLC:
4 fase 3 studies in 2e lijn
Key patient inclusion
criteria
• Previously treated
with a first line
platinum-based
regimen
Differences between
studies:
• PD-L1 status
• PD-L1 cut off
Primary endpoint: OS
Secondary endpoint: PFS, RR, QOL
Docetaxel
PD or
toxicity
PD-(L)1 inhibitor
PD or
toxicity
R
Geen vergelijking met:
- Docetaxel + nintedanib in adenoca
- Docetaxel + ramucirumab
Checkmate 017: Nivo in sqNSCLC
Brahmer et al
N Eng J Med 2015
Keynote 010: Pembro in NSCLC (PDL1≥ 1%)
Herbst RS et al
Lancet 2016;387:1540-50
Checkmate 057: Nivo in nonsqNSCLC
Borghaei H et al
N Eng J Med 2015
OAK: atezolizumab in NSCLC
Impact op QoL Checkmate 017
Tumor PD-L1 expressie?
Prevalentie
RR
40%
10.7%
35%
16.5%
25%
45.2%
Garon et al.
N Eng J Med 2015
PD-L1 expressie: beperkingen
Verschillende technieken: Ab als IHC platform
Verschillende cut off
PD-L1 expressie is heterogeen
PD-L1 expressie is dynamisch
CONCLUSIE: PDL1 IH lijkt een ‘enrichment biomarker’
Pembrolizumab 1e lijn vs
chemotherapie in PDL1>50% NSCLC
CHECKMATE 026:
Nivolumab PDL1≥5% NSCLC
Median PFS, months
(95% CI)
1-year PFS rate, %
Nivolumab
n = 211
Chemotherapy
n = 212
4.2
(3.0, 5.6)
5.9
(5.4, 6.9)
23.6
23.2
HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511
Median OS,
months
(95% CI)
Nivolumab
n = 211
Chemotherapy
n = 212
14.4
(11.7, 17.4)
13.2
(10.7, 17.1)
56.3
53.6
100
1-year OS rate, %
OS (%)
80
HR = 1.02 (95% CI: 0.80, 1.30)
60
40
Chemotherapy
20
Nivolumab
0
No benefit for subgroup PDL1≥50%
0
3
6
9
12
15
18
21
24
27
30
Months
Socinski et al ESMO 2016
AntiPD1 (Nivolumab) in
niercelcarcinoom
Response rate:
25 vs 5%
Median OS:
25 vs 19,6 maand
Motzer RJ et al. N Eng J Med 2015;373
Anti (PD1)
Nivolumab in Hodgkin lymfoom
Response 87%
Ansell SM et al. N Engl J Med 2015;372:311319
Pembrolizumab in Merkel cel
carcinoom
Phase 2, treatment naive
Response 56%
6 maand PFS 67%
Nghiem PT et al. N Engl J Med
2016;374:2542-2552.
Avelumab in Merkel cel carcinoom
Phase 2 previously treated
Kaufman HL et al. Lancet Oncol 2016;17:1374-1385
Anti PD(L)1 in plaveiselcelcarcinoom
van hoofd en hals
Nivolumab in SCHNC
Ferris et al. N Eng J Med 2016
Atezolizumab in transitioneel cel
carcinoom
Rosenberg et al. Lancet 2016;387:1909-20
Combinatie anti-cTLA4 en anti-PD1
Slide 9
Presented By Michael Postow at 2015 ASCO Annual Meeting
Immune related toxiciteit
Toxiciteit
Frequency of irAE
All % (G3/4 %)
Ipilimumab
Pembrolizumab
Nivolumab
Diarrhoea
37 (6.9)
18 (2)
13 (1)
Colitis
8 (4.9)
1 (0.2)
2 (1)
Rash
33.2 (2.5)
<1
15 (0)
Hepatotoxicity
0.7 (0.7)
0.5 (0.2)
1 (<1)
Hypophysitis
2.7 (2.1)
0.5 (0.2)
<1 (<1)
Pneumonitis
<2
2.9 (0.2)
3 (1)
Hypo 1.8 (0.1)
Hyper 1.2 (0.2)
Hypo 8.3 (0.2)
Hyper 1 (<1)
Hypo 4 (<1)
Nephritis
<2
0.7 (0.5)
1 (0)
Neuropathies
<1
<1
<1
Thyroid dysfunction
Ibrahim JCO 2011
Pembrolizumab PI, 2014
Nivolumab, safety management BMS, 2014
Data obtained from different studies and not directly comparable
J.M. Michot, et al
European Journal of Cancer, Volume 54, 2016, 139–148
Toxiciteit
Diarrhea and Colitis
Presented By Michael Postow at 2015 ASCO Annual Meeting
Ipilimumab Rashes
Presented By Michael Postow at 2015 ASCO Annual Meeting
PD-1 Rashes
Presented By Michael Postow at 2015 ASCO Annual Meeting
Hypophysitis Endocrinopathy
Presented By Michael Postow at 2015 ASCO Annual Meeting
Pneumonitis
Presented By Michael Postow at 2015 ASCO Annual Meeting
• Uveitis and episcleritis
– Evaluatie door oogarts
– Oogdruppels met corticoïden
Tarhini et al
Toxiciteit
• Efficiënte behandeling van bijwerkingen igv:
– Informeren van de patiënt
– Monitoring
– Vroegtijdig herkennen
– Tijdig opstarten immuunsuppressieve behandeling
– Behandelingsalgoritmen
Future prospects
Where do we want to go?
Survival
Survival
Where are we now?
Time
?
Time
Control
Targeted therapies
Immune checkpoint blockade
Combinations
Adapted from Ribas A, presented at WCM, 2013; Ribas et al, Clin Cancer Res. 2012; 18: 336; Drake CG, Ann
Oncol. 2012; 23(suppl 8): viii41.
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