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

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

Ways to keeping the T cells “active”

Presented By Michael Postow at 2015 ASCO Annual Meeting

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

Immuun therapie en mutaties in tumor

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

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.

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

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

Robert C et al. N Engl J Med 2015;372:320-330.

• Nivolumab 1e lijn bij BRAF wild typeSurvival End Points.

Robert N Eng J Med 2015

Anti-PD1 vs anti-cTLA4

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

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

Impact op QoL Checkmate 017

Tumor PD-L1 expressie?

Prevalentie 40% 35% 25% RR 10.7% 16.5% 45.2%

Garon et al.

N Eng J Med 2015

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’

Pembrolizumab 1e lijn vs chemotherapie in PDL1>50% NSCLC

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

Anti (PD1) Nivolumab in Hodgkin lymfoom

Ansell SM et al. N Engl J Med 2015;372:311-319

Response 87%

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

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

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

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

80

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.

Where are we now? Where do we want to go?

Surv

ival

Time

Control

Targeted therapies

Immune checkpoint blockade

Combinations

?

Surv

ival

Time