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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 in evenwicht
Te weinig
(infecties, kanker)
Te veel
(autoimmuniteit,weefselschade)
Immuun activatie
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
Trafficking of T cells to tumours
CX3CL1, CXCL9, CXCL10CCL5
Killing of cancer cells
IFN- , T-cell granule content
Priming and Activation
CD28/B7.1, CD137/CD137LOX40/OX40L, CD27/CD70HVEM, GITR, IL-2, IL-12
CTLA4/B7.1PD-L1/PD-1PD-L1/B7.1 Prostaglandins
Chen DS and Mellman I. Immunity. 2013 Jul 25;39(1):1-10.
Stimulatory and inhibitory factors in the cancer
immunity cycle
Cancer antigen presentation
TNF-, IL-1IFN-, CD40L/CD40CDN, ATPHMGB1, TLR
IL-10, IL-4, IL-13
Release of cancer cell antigens
Immunogenic cell death
Tolergenic cell death
PD-L1/PD-1PD-L1/B7.1IDOTGF-BTLA
VISTALAG-3ArginaseMICA/MICBB7-H4
Recognition of cancer cells by T cells
T cell receptor
Reduced pMHC on cancer cells
Infiltration of T cells into tumours
LFA1/ICAM1Selectins
VEGFEndothelin-B receptor
4
Stimulatory factors Inhibitors
Lymphnode
Bloodvessel
Tumour
5
6
71
2
3
TIM-3/phospholipids
13
Tumor microenvironment: Immune escape mechanisms
Tumor cells
CD8* T cell Treg
MDSC
CD8* T cell
CD4+
T cell
TGF-β
IL-10
TGF-β
ARG1
iNOS
VEGFAPC
TGF-β
IDO
IL-10
PD-1
P-DL1PD-1
PD-L1
CTLA-4TCR
MHC
Vesely MD, et al, Ann Rev Immunol 2011, 29: 235
A. Ineffective tumor antigen presentation (gp100, MART-1, decreased MHC expression)
B. Recruitment of immunosuppressing cells (regulatory T cells =Tregs, MDSCs, other)
C. Secretion of immunosuppressive signals (e.g. PD-L1, TGF-β, IL-10, and indolamine 2,3-dioxygenase [IDO])
D. T cell checkpoints
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
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
T-cell checkpoint inhibition
Anti-CTLA4
Anti-PD1/PDL1
LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477
The prevalence of somatic mutations across human cancer types.
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
T-cell checkpoint inhibition
Anti-CTLA4
Anti-PD1/PDL1
Anti-cTLA4
• Ipilimumab (Yervoy)
– Geregistreerd en terugbetaald in melanoma
• Tremelimumab
– In studie in verschillende tumoren
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.
Robert C et al. N Engl J Med 2011;364:2517-2526.
• 1e lijn vs chemo:
– Mediane OS 11 vs 9 m
– 1j OS 47 vs 36%
– 3j OS 21 vs 12%
Ribas A. N Engl J Med 2012. DOI: 10.1056/NEJMe1205943
Ribas A. N Engl J Med 2012
T-cell checkpoint inhibition
Anti-CTLA4
Anti-PD1/PDL1
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
Robert C et al. N Engl J Med 2015;372:320-330.
• Nivolumab 1e lijn bij BRAF wild typeSurvival End Points.
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
R
Docetaxel
PD-(L)1 inhibitor
PD or toxicity
PD or toxicity
Primary endpoint: OSSecondary endpoint: PFS, RR, QOL
Geen vergelijking met:- Docetaxel + nintedanib in adenoca- Docetaxel + ramucirumab
Checkmate 017: Nivo in sqNSCLCBrahmer et al N Eng J Med 2015
Checkmate 057: Nivo in nonsqNSCLCBorghaei H et al N Eng J Med 2015
Keynote 010: Pembro in NSCLC (PDL1≥ 1%)Herbst RS et al Lancet 2016;387:1540-50
OAK: atezolizumab in NSCLC
PD-L1 expressie: beperkingen
Verschillende technieken: Ab als IHC platformVerschillende cut offPD-L1 expressie is heterogeenPD-L1 expressie is dynamisch
CONCLUSIE: PDL1 IH lijkt een ‘enrichment biomarker’
CHECKMATE 026:Nivolumab PDL1≥5% NSCLC
Nivolumab
n = 211
Chemotherapy
n = 212
Median PFS, months
(95% CI)
4.2
(3.0, 5.6)
5.9
(5.4, 6.9)
1-year PFS rate, % 23.6 23.2
HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511
Months
OS
(%)
2421181512963 30
100
80
60
40
0
20
0 27
Nivolumab
Chemotherapy
Nivolumab
n = 211
Chemotherapy
n = 212
Median OS,
months
(95% CI)
14.4
(11.7, 17.4)
13.2
(10.7, 17.1)
1-year OS rate, % 56.3 53.6
HR = 1.02 (95% CI: 0.80, 1.30)
No benefit for subgroup PDL1≥50%
Socinski et al ESMO 2016
AntiPD1 (Nivolumab) in niercelcarcinoom
Motzer RJ et al. N Eng J Med 2015;373
Response rate:25 vs 5%
Median OS:25 vs 19,6 maand
Pembrolizumab in Merkel cel carcinoom
Nghiem PT et al. N Engl J Med 2016;374:2542-2552.
Phase 2, treatment naiveResponse 56%6 maand PFS 67%
Avelumab in Merkel cel carcinoom
Kaufman HL et al. Lancet Oncol 2016;17:1374-1385
Phase 2 previously treated
Toxiciteit
Frequency of irAE
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)
Thyroid dysfunctionHypo 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
All % (G3/4 %)
Ibrahim JCO 2011Pembrolizumab PI, 2014Nivolumab, safety management BMS, 2014
Data obtained from different studies and not directly comparable
Toxiciteit
• Efficiënte behandeling van bijwerkingen igv:
– Informeren van de patiënt
– Monitoring
– Vroegtijdig herkennen
– Tijdig opstarten immuunsuppressieve behandeling
– Behandelingsalgoritmen