Introduction_sur_l_i..

Introduction sur
l’Immunothérapie des Cancers
Sylvie Rusakiewicz
Gustave Roussy Institute
Villejuif
France
Cancer: modélisation initiale de l’Oncogénèse
Prolifération dérégulée
Echappement aux
facteurs suppresseurs de
croissance illimitée
Résistance à la mort
cellulaire
Induction de
l’angiogénèse
Invasion et métastase
Immortalité réplicative
(Hanahan D, Weinberg RA, Cell 2001)
Evolution du concept initial
Dérégulation
de la
prolifération
Echappement
aux suppresseurs
Echappement au
système
immunitaire
Dérégulation du
métabolisme
Résistance
à la mort
Réplication
immortelle
Instabilité
génomique
et mutation
Inflammation
Dérégulation de
l’angiogénèse
Invasion et
métastases
Tumor formation:
The 3 « E » of Cancer ImmunoEdition
Vesely, Ann Rev Immunol 2004
Immunosurveillance and Immunoedition
(inspiré de R. Schreiber, St Louis, USA)
Vesely, Ann Rev Immunol 2004
Immunosurveillance and Immunoedition
(inspiré de R. Schreiber, St Louis, USA)
Immunothérapie
Vesely, Ann Rev Immunol 2004
Le père de l’immunothérapie antitumorale:
William B. Coley (1862-1936)
Extraits de Streptococcus pyogenes et Serratia Marcescens
Bacille de Calmette-Guérin: Mycobacterium bovis atténué,
Agoniste des Récepteurs Toll-like 2, 4 et 9: Traitement du carcinome vésical in situ.
Albert Calmette
1863-1933
Zbar B and Tanaka T. Science 1971; 172: 271-3.
Efficacité depuis 1970, approuvé par la FDA pour
l’indication thérapeutique en 1990.
Camille Guérin
1872-1961
Albert M and coll. J. Urol. 2010
Prix Nobel 2011: Immunité innée
Jules A. Hoffmann
Bruce Beutler
Ralph M. Steinman
Exemples de Pathogens Recognition Receptors
Les Toll-Like Receptors (TLR)
McInturff, J Invest Dermatol 2005
Activation et maturation des cellules dendritiques:
Récepteurs Toll-like
Maturation des cellules dendritiques:
Augmentation de la Costimulation
Intensification de l’apprêtement antigénique
Cytokines inflammatoires
Production de Chimiokines
Activation complète du lymphocyte T
La cellule dendritique:
Lien entre immunité innée et Immunité acquise
3 – Migration vers les ganglions
4 – Induction de réponses lymphocytaires T
cytotoxiques (réponse cellulaire)
et/ou B (réponse humorale avec
production d’anticoprs)
2 – Production de Cytokines +
Chimiokines
1- Detection et Phagocytose
5 – Retour au site inflammatoire
des lymphocytes T cytotoxiques
et/ou des Anticorps
From Mellman, Coukos and Dranoff, Nature 2011
Plasticité fonctionnelle des cellules dendritiques
Et polarisation des réponses lymphocytaires T.
Immunogenic DC
maturation
Tolerogenic DC
maturation
Inflammatory DC
maturation
Kapsenberger, Nat Rev Med 2003
Contrecarrer l’immunosuppression du cancer:
Activation et maturation des cellules dendritiques via les Récepteurs Toll-like
Maturation des cellules dendritiques:
Augmentation de la Costimulation
Intensification de l’apprêtement antigénique
Cytokines inflammatoires
Production de Chimiokines
Activation complète du lymphocyte T
Agonistes des Récepteurs Toll-like
approuvés par la FDA et EMEA
Imiquimod: Agoniste des Récepteurs Toll-like 7
Approuvé pour le traitement du carcinome basocellulaire,
la kératose actinique, les condylomes acuminata en 1997.
Drobits, J Clin Invest. 2012;122(2):575–585
Stimulation des Récepteurs Toll-like
au niveau tumoral: arme à double tranchant…
Preuves de concept 1: Valeur pronostique
des infiltrats lymphocytaires intratumoraux.
CD8+T
Th1
GzB+T-bet+
CD45RO+
CD3+T
mémoires
Dendritiques
DC-Lamp+
CD1a+
Mélanome
Cancer du Sein
Distribution:
Intratumoral
Cancer du Colon
Front d’ invasion
Lymphome Folliculaire
Cancer Ovarien
Cancer ORL
Lymphocytes B
Cancer vésical
Organes
lymphoides
tertiaires
Foxp3+/Th17+/MDSC+/pSTAT3+/-
M1 CD68+
Macrophages
CX3CL1+
CXCL9, CXCL10+
Galon J, Pagès F, Fridman: NEJM 2006 , Science 2007, JCO 2010
Infiltrats immunitaires: Score supérieur prédit la survie
sans rechute des patients atteints de cancer du colon
Galon J, Pagès F, Fridman: NEJM 2006 , Science 2007, JCO 2010
Infiltrats immunitaires localisation et progression de
la maladie (cancer du colon)
Bindea G, Galon J Immunity, 2013
Preuves de concept 2: Phases II/III randomisées
montrant l’efficacité de l’immunothérapie.
Anti-GD2
+GM-CSF
+IL-2
Short peptides
+IL-2
Anti-CTLA4 Ab
Long peptides
Basedvaccines
Dendritic cellbasedvaccines
Mélanome
Cancers HPV16+
Neuroblastome
Follicular Lymphoma
Prostate cancer
Sarcoma
CLL
Anti-PD1/PDL1?
Defucosylated
ADCC
Antibodies?
Idiotype-based
vaccines
ACT
CAR
Phases III: courts peptides Gp100 dans le MM
Phase II: longs peptides HPV16-E6/E7 dans VIN.
Kenter GG et al. New Engl. J. Med. 2009
VIN: Vulvar Intraepithelial Neoplasia
Schwartzentruber D et al. New Engl. J. Med. 2011
Phases II/III randomisées
montrant l’efficacité des vaccins dendritiques
Vaccins
Longs peptides
Vaccins
Courts peptides
+IL-2
Anti-GD2
+GM-CSF
+IL-2
Vaccins
dendritiques
Mélanome
Lymphome Folliculaire
Cancer Prostatique
Cancer du sein
Anticorps
Anti-CTLA4
Vaccins
idiotypiques
Transfert
adoptif de
Lympho. activés
Anti-PD1/PDL1?
Anticorps
Défucosylés
ADCC
?
Comment générer un
Vaccin Dendritique Thérapeutique anticancéreux efficace?
Modulateurs de l’
IMMUNOSUPPRESSION
ADJUVANT
Agonistes TLR et
CD40L
FORMULATION
(antigène pulsé sur la CD)
Le choix du SOUS
TYPE de CD
Immunité cellulaire effectrice et mémoire antitumorale
Formulations antigéniques testées sur les
Cellules dendritiques.
Longs peptides
Courts peptides
Protéines
Produits de
fusion
Corps
apoptotiques
Formulation
Lipidique
Virus
recombinants
Mélanome
Cancers du sein
Cancer du rein
Cancer Prostatique
Cancers bronchiques
LAM
Vides
(CD
intratumorales)
Corps opsonisés
ADCC
?
ARNm
Exosomes
tumoraux
Unité de Thérapie cellulaire homologuée AFFSSAPS:
Bonnes pratiques de laboratoire.
Culture ex vivo sur 4-6 jours des
Cellules dendritiques.
Deux Phases III randomisées
montrant l’efficacité des cellules dendritiques.
Cancer prostatique
Métastatique osseux
Vaccin sipuleucel-T: Provenge (Dendreon°)
HR 0.77 (0.61-0.98), p=0.04
Kantoff et al., New Engl. J. Med. 2010
Palucka, Banchereau, Ueno (BIIR, Dallas)
Vaccination par exosomes
de cellules dendritiques
Why using Dex as cell free vaccine?
• Dex can be consider as an Antigen Presenting
Unit since
– Highly enriched with MHC-I and –II molecules
– Highly enriched with co-stimulatory molecules (CD86, CD40 in
humans)
– Enriched with adhesion molecules that allow uptake by DCs and
synapse formation with T cells (ICAM-1)
– Enriched with molecules that favor NK cell functions (IL-15Ra, NKG2D
ligands  NK cell proliferation, IFNg secretion and restoration of
NKG2D dependent cytotoxic functions)
Dendritic cell
MVB
Purified Dex
MHC II
1 µm
Phases II IGR/Curie: Génération des exosomes
de cellules dendritiques autologues.
Lymphocytes
DC matures
cryoconservées
iDC (QC)
Dex QC
GM-CSF
IL-4
Surnageant de
culture
Chargement
des peptides
Leukapheresis
D0
Elutriation
Monocytes
iDC
D4
mDC
D6
IFNγ & IL-4
Expression frequency
In NSCLC
Peptide
sequence
MHC I
MAGE-1
MAGE-3
NY-ESO-1
MART-1
KVLEYVIKV
KVAELVHFL
SLLMWITQV
ELAGIGILTV
HLA-A2
42%
39%
28%
N/A*
MHC II
MAGE-3
Human herpesvirus 4
KKLLTQHFVQENYLEY
PRSPTVFYNIPPMPLPPSQL
HLA-DP04
DR5, DR7, DQ2, DQ7, DR1 et DR16
39%
N/A*
Chaput N., Zitvogel L
HLA
Diafiltration 1
Ultracentrifugation
(D20 sucrose cushion)
Diafiltration 2
Conditionnement et stockage
à-80°C
Expression frequency NSCLC : 68% for at least one of these antigen
Phases II IGR/Curie: 11 premiers patients stade
IIIBIV: survie, réponses vaccinales T CD4+ et CD8+.
T0
T2
T3
% of TET PE in CD8
0.015
BOU FA
0.010
*
0.005
0.000
w/o TT
MAGE-1
MAGE-3
MART-1
*
% of TET PE in CD8
0.03
LAR MA
*
0.02
NYESO-1
*
0.01
0.00
w/o TT
Chaput N., Zitvogel L
MAGE-1
MAGE-3
MART-1
NYESO-1
T0
T2
Lessons apprises de la thérapie dendritique:
Immunogénicité des Cellules dendritiques.
Activité
clinique
sur l’OS
Moins de
Foxp3 Treg
Infiltrations
Tumorales par
des CD8
antitumoraux
Pas de toxicité
Réponses
CD4 et CD8
antitumorales
Suivi immunologique
et clinique
Infiltrations
Tumorales par
des CD8
antivaccins
Réponses
D’HSR type III
Activation des
NK
Immunosélection
Tumorale
Perte CMH et Ag
Cellules dendritiques: NOUVELLES PERSPECTIVES
D’après Banchereau et al.
Phases II/III randomisées
montrant l’efficacité des vaccins immunomodulateurs.
Vaccins
Longs peptides
Vaccins
Courts peptides
+IL-2
Anti-GD2
+GM-CSF
+IL-2
Vaccins
dendritiques
Mélanome
Lymphome Folliculaire
Cancer Prostatique
Cancer du sein
Anticorps
Anti-CTLA4
Anti-PD1/PDL1?
Anticorps
Défucosylés
ADCC
?
Vaccins
idiotypiques
Transfert
adoptif de
Lympho. activés
T CARs
Preuves de concept: Transfert adoptif passif de
lymphocytes T CD8+ activés: mélanome, sarcome, LLC
Rosenberg and Dudley, Curr Opin Immunol 2009
T-Cars
Robbins PF et al. J. Clin. Oncol. March 2011
Genération des T-CARs, Carl June
T-CAR therapy for B-cell Lymphoma
Addition of Suicidal gene: T cell targetted by Ganciclovir
Phases II/III randomisées
montrant l’efficacité des vaccins immunomodulateurs.
Vaccins
Longs peptides
Vaccins
Courts peptides
+IL-2
Anti-GD2
+GM-CSF
+IL-2
Vaccins
dendritiques
Mélanome
Lymphome Folliculaire
Cancer Prostatique
Cancer du sein
Anticorps
Anti-CTLA4
Anti-PD1/PDL1?
Anticorps
Défucosylés
ADCC
?
Vaccins
idiotypiques
Transfert
adoptif de
Lympho.
activés
.
Phases III: Effet cytotoxique
d’un Ac (anti-GD2)
combiné au
GM-CSF+IL-2 dans le neuroblastome.
Yu AL, N. Engl. J. Med.. 2010
Effets de polymorphismes génétiques (FCGR2A, FCGR3A SNPs)
gênant l’ADCC dans l’efficacité des anticorps monoclonaux
(Rituximab, Trastuzumab, Cetuximab, anti-GD2).
CD19
HER2
EGFR+
TopoIso I
EGFR
GD2
Phases II/III randomisées
montrant l’efficacité des vaccins immunomodulateurs.
Vaccins
Longs peptides
Vaccins
Courts peptides
+IL-2
Anti-GD2
+GM-CSF
+IL-2
Vaccins
dendritiques
Mélanome
Lymphome Folliculaire
Cancer Prostatique
Cancer du sein
Vaccins
idiotypiques
Transfert
adoptif des
Lympho activés
Anticorps
Anti-CTLA4
Anti-PD1/PDL1?
Anticorps
Défucosylés
ADCC
?
The recent history of cancer immunotherapy
IFN-α as
adjuvant therapy for
melanoma
Discovery of the
dendritic cell
Tumour specific
mAbs
BCG approved for
bladder cancer
Discovery of
checkpoint inhibitor
Adoptive T-cell
immunotherapy
1970s
Immune component to
spontaneous
regressions in
melanoma
1980s
1990s
2000s
First tumourassociated antigen
cloned (MAGE-1)
First immunotherapy
approved for prostate
cancer (sipuleucel-T;
DC vaccine)
2011
First checkpoint inhibitor
(ipilimumab) approved for
advanced melanoma
IL-2 approved for RCC and
melanoma (US)
Adapted from Kirkwood JM Ca J Clin 2012;62:309-35; George S et al. JNCCN 2011;9:1011-18; Garbe C et al. The Oncologist 2011;16:2-24; Rosenberg SA. Sci Transl Med
2012;4:127ps8; Cheeve et al. Clin Cancer Res 2011;17:3520-3526; Kantoff PW, et al. N Engl J Med 2010;363; Mansh M. Yale J Biol Med 2011;84:381-89; Hodi FS, et45
al.
N Engl J Med 2010;363:711–23.
Tumor microenvironment and
immunosuppressive cells
Treg express
CTLA4
OX40
PD1
46
Tumor microenvironment and
immunosuppressive molecules
IDO
47
Adapted from Tartour E, et al. Lancet Respir Med 2013;1: 551–63.
Nouveau concept efficace (mais toxique):
Blocage des circuits d’extinction d’activation.
Mellman, et al. Nature 2011:480;481-9.
PD-L1 expression is induced on cancer cells and
promote T cell suppression/anergy
Two general mechanisms of expression of immune-checkpoint ligands
on tumour cells
49
Adapted from Pardoll DM. Nat Rev Cancer 2012;12(4):252-64.
Distinct roles for CTLA-4 and PD-1 T cell receptors
From Topalian et al. Curr Opin Immunol 2012
50
Anti-PD-1 and PDL-1 antibodies: distinct targets.
From Topalian et al. Curr Opin Immunol 2012
51
Mobilising T cells: creating a new repertoire
or re-activating TILs?
Immune checkpoint blockers
Activate all TILs
Not just TAA nor TRA specific T cells
Vaccines
Expand or generate
TAA or TRA specific T cells
TAA: tumour associated antigens; TRA: tumour rejection antigens; TILs: tumour infiltrating lymphocytes
52
Immuno-Oncology (I-O) earns its spot in the
ranks of cancer therapy
Clinical development of agents that target immune-checkpoint pathways
Target
CTLA-4
PD-1
PD-L1
Biological function
Antibody or Ig fusion
protein
State of clinical development
Ipilimumab
FDA approved for melanoma, phase 2 and 3 trials
ongoing for multiple cancers
Tremelimumab
Previously tested in a phase 3 trial in melanoma;
phase 1 and 2 trials ongoing for multiple cancers
Nivolumab (MDX-1106)
Phase 3 trials in melanoma, renal, and lung cancers
Lambrolizumab (MK3475)
Phase 3 trials in melanoma and lung cancers
Pidilizumab (CT-011)
Phase 2 trials in multiple cancers
AMP-224a
Phase 1 in multiple cancers
MDX-1105
Phase 1 in multiple cancers
Multiple antibodies
Phase 1 and 2 trials in multiple cancers
IMP321b
Phase 1 and 2 in melanoma, breast, and renal cancers
Multiple antibodies
Preclinical development
MGA271
Phase 1 trials in multiple cancers
Inhibitory receptor
Inhibitory receptor
Ligand for PD-1
LAG-3
Inhibitory receptor
B7-H3
Inhibitory ligand
B7-H4
Inhibitory ligand
Preclinical development
TIM3
Inhibitory receptor
Preclinical development
Pardoll DM. Nat Rev Cancer 2012;12(4):252-64; www.clinicaltrials.gov accessed 16 September 2013
aPD-L2
fusion protein; bLAG-3 Ig fusion protein
n
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54
Differences between I-O and other treatment
modalities
Activity
Safety
Responses with I-O therapies different from those
of other treatment modalities
Activity of I-O therapies need to be assessed with
IrRC
Different safety profiles of I-O therapies compared
with other treatment modalities: irAE
Adverse events are managed differently: steroids
Use
Courtesy of E. Felipe
Which tumour types are responsive to I-O
therapies?
Is activity affected by tumour histology or mutation
status?
55
Potential for long-term survival with I-O therapies:
anti-CTLA-4 (ipilimumab)
•
Proportion of patients alive (%)
Ipilimumab was the first therapy to improve overall survival in unresectable
or metastatic melanoma in a randomised phase 3 trial1
100
80
60
Median OS,
months
95% CI
HR
P value
Ipilimumab + gp100
10.0
8.5–11.5
0.68
<0.001
Ipilimumab
10.1
8.0–13.8
0.66
0.003
gp100
6.4
5.5–8.7
40
20
0
0
1
2
3
4
Years
• In clinical trials, most adverse events associated with ipilimumab were immune related and
managed using ipilimumab-specific treatment guidelines2
• Most frequently reported adverse events associated with ipilimumab monotherapy (all grades)
in a clinical study were: diarrhoea (27%), rash (26%) and pruritus (26%)2
56
1. Adapted from Hodi FS, et al. N Engl J Med 2010;363:711–723; 2. Data on File, Bristol-Myers-Squibb Company, Princeton, NJ.
Potential for long-term survival with I-O
therapies: anti-CTLA-4 (ipilimumab) example
• Primary analysis of pooled overall survival data for patients
(N=1861) with melanoma across trials of ipilimumab
1.0
0.9
Median overall survival: 11.4 months (95% CI: 10.7–12.1)
Proportion alive
0.8
0.7
0.6
3-year overall survival: 22% (95% CI: 20–24)
0.5
0.4
0.3
0.2
0.1
Ipilimumab
CENSORED
0.0
0
Patients at risk
Ipilimumab 1861
12
24
36
48
60
Months
72
84
96
108
120
839
370
254
192
170
120
26
15
5
0
1. Adapted from Schadendorf D, et al. Oral presentation at ESMO 2013: abstract 24LBA.
Survival observations with PD-1-targeted
therapy: nivolumab.
•
Clinical activity of nivolumab was assessed in a phase 1 trial in patients with
advanced solid tumours
NSCLC
Died/treated: 88/129
Median OS: 9.6 months
80
60
42%
40
14%
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months since treatment initiation
Overall survival (%)
100
80
70%
Renal Cell Carcinoma
Died/treated: 15/34
Median OS: >22 months
60
50%
40
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
100
Overall survival (%)
Overall survival (%)
100
80
62%
60
Melanoma
Died/treated: 60/107
Median OS: 16.8 months
43%
40
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months since treatment initiation
• 17% of patients had grade 3-4 adverse
events; most were manageable using
standard protocols
• Most frequently reported adverse
events (all-grades): rash (15%),
diarrhoea (13%), pruritus (11%)
Months since treatment initiation
Adapted from Topalian SL, et al. Oral presentation at ASCO 2013: J Clin Oncol 2013;31(15 suppl): abstract 3002; Hodi FS, et al. Poster presentation at ESMO
2013:abstract 880.
58
Durability of responses: the true combat
of I-O
Proportion Alive
Immunotherapy responders can experience a dramatic
impact on survival compared with conventional
chemotherapy due to durability of response
Immunotherapy Combination
LT Survival
Immunotherapy Monotherapy
LT Survival
Control
Chemotherapy/TKI
Time from Treatment
Combining I-O therapies that modulate
different pathways: anti-CTLA-4 + anti-PD-1
•
Concurrent treatment with ipilimumab + nivolumab enhanced responses over
rates seen with either agent alone in patients with advanced melanoma1-4
Cohort
Response
evaluable
patients, n
CR, n
Ipilimumab monotherapy
(MDX010-20 trial)1
137
2
Nivolumab monotherapy
(all doses; CA209-003 trial)2,3
107
Sequential (all doses)
ipilimumab followed by
nivolumab4
30
1
Concurrent (all doses)
ipilimumab plus nivolumab4
52
5
•
PR, n
ORR, %
[95% CI]
Aggregate
clinical activity
rate, % [95% CI]
≥80% tumour
reduction at
8 week, n (%)
13
11 [6.3, 17.4]
-
-
31 [22.3, 40.5]
-
-
5
20 [8-39]
43 [26-63]
4 (13)
16
40 [27-55]
65 [51-78]
16 (31)
33
Concurrent safety profile similar to ipilimumab and nivolumab monotherapies4
–
Representing mostly tissue-specific inflammation: Skin, gastrointestinal and hepatic
–
Any treatment-related adverse event occurred in 93% with grade 3/4 events occurring in 53%
–
Rash (55%), pruritus (47%), fatigue (38%) and diarrhoea (34%) were most common
–
Related adverse events were managed using standard protocol algorithms
60
1. Hodi FS, et al. N Engl J Med 2010;363:711–23 ; 2. Sznol M, et al. Oral presentation at ASCO 2013: J Clin Oncol 2013;31(15 Suppl): abstract 9006;
3. Hodi FS, et al. Poster presentation at ESMO 2013:abstract 880; 4. Wolchok JD et al. ASCO 2013 oral presentation. J Clin Oncol 2013;31(15 Suppl):abstract 9012.
Combining I-O therapies that modulate
different pathways: anti-CTLA-4 + anti-PD-1
Change in target lesions from baseline (%)
• Nature of responses appeared different from those seen with either
monotherapy
– Responses were rapid and deep
Pre-treatment
1 mg/kg nivolumab +
3 mg/kg ipilimumab
300
200
100
80
60
40
20
0
12 weeks
−20
−40
−60
−80
−100
0
10 20 30 40 50 60 70 80 90 100 110 120
Weeks since treatment initiation
61
Wolchok JD et al. ASCO 2013 oral presentation. J Clin Oncol 2013;(suppl):abstract 9012.
I-O therapy: optimising outcomes
• Can outcomes of I-O therapies be improved by combining with
– Other I-O therapies?
– Other treatment modalities?
• How can we increase the proportion of patients benefiting
from I-O therapy?
– Predictive markers of response?
– Pharmacological hallmarks?
62
Combining I-O therapies to enhance
antigen-specific responses
a-CTLA-4
a-PD-1
• Dual T-cell checkpoint inhibition: removing the brakes
a-PD-1
Vaccine
a-CTLA-4
Vaccine
• T-cell checkpoint inhibition: removing the brakes
• Enhancing priming of the immune system
a-KIR
Vaccine
IL-21
Vaccine
• Switching on adaptive immunity
• Improving the function of innate immune cells
• Enhancing priming of the immune system • Enhancing priming of the immune system
63
Drake CG Ann Oncol 2012;23 Suppl 8:viii41-6; Sharma P, et al. Nat Rev Cancer 2011;11:805-12.
Immunotherapy in combination
Multiple mechanisms of synergy between the different treatment modalities
Radiation
Adhesion molecules
(CAM-1) and death
receptors (FAS)
Peptide
pools
Chemotherapy
CD8 T-cell
Upregulation of MHC-1
Uploading of
antigen processing
machinery
Targeted therapies
Vascular normalisation
T-cell initiation
Effector immune
infiltrate Release of tumour
Cytokine release
antigens (cascade)
Translocation of
calreticulin
CD8 T-cells
TAA crosspresentation
Dendritic
cell
MDSC
Treg cells
M2 macrophages
TAA
Upregulates MHC-1
Adhesion molecules/
death receptors
APM
CD8 T-cells
(homeostatic peripheral
expansion)
MDSC
CD8 T-cells
T-cell function
Treg cells
Activation of apoptosis
Blockage of cell cycle
Adapted from Hodge JW. Semin Oncol 2012;39(3):323–339; Drake CG Ann Oncol 2012;23 Suppl 8:viii41-6; Ménard C, et al. Cancer Immunol Immunother
2008;57:1579-87; Hannani D, et al. Cancer J 2011;17:351-358; Ribas A at al. Curr Opin Immunol 2013:25:291-296.
64
Selected I-O combination approaches across multiple
tumour types
I-O + chemotherapy
I-O + radiotherapy
I-O + targeted therapies
Ipilimumab + etoposide/platinum
(SCLC)
Poxviral vaccine + radiotherapy
(prostate cancer)
Pidilizumab + rituximab (follicular
lymphoma)
Ipilimumab +
paclitaxel/carboplatin
(lung cancer and melanoma)
LC9018 (vaccine) + radiotherapy
(carcinoma of the uterine cervix)
Ipilimumab + rituximab
(B-cell lymphoma)
Nivolumab + everolimus (RCC)
Ipilimumab + fotemustine
(melanoma)
Adoptive dendritic cell
immunotherapy + radiotherapy
(heptoma)
Nivolumab + chemotherapy
(NSCLC)
CpG + radiotherapy
(B-cell lymphoma)
IMP321 (LAG-3) + paclitaxel
(breast cancer)
Ipilimumab + radiotherapy
(melanoma, NHL, colon, rectal)
Ipilimumab + temozolomide
(melanoma)
Sipuleucel-T + radiation therapy
(CRPC)
Urelumab + rituximab
(B-cell NHL or CLL)
Nivolumab + sunitinib, or
pazopanib (RCC)
Nivolumab + erlotinib (NSCLC)
Ipilimumab + trametinib +
dabrafenib (melanoma)
Ipilimumab then vemurafenib
(melanoma)
Ipilimumab + dasatinib (GIST)
Ipilimumab + bevacizumab
(melanoma)
65
www.clinicaltrials.gov accessed 16 September 2013; Formennti SC, et al. J Natl Cancer Inst 2013;105(4):256-65; Ferrara TA, et al. Curr Opin Mol Ther 2009;11:37-42.
Effet abscopal de la radiothérapie dans un échec à
l’Ipilimumab (Ac anti-CTLA4).
Postow, N. Engl. J. Med. March 2012
Régressions de métastases
ganglionnaires, hépatiques
et spléniques de mélanome
Après la radiothérapie palliative
de 2 Gy sur une épidurite.
Elévation des Ac anti-NY-ESO-1
Post-Rx.
I-O + radiosurgery: ipilimumab example
•
For patients with melanoma brain metastases who underwent radiosurgery (N=77),
ipilimumab was associated with increased survival
•
2-year survival: 47.2% (+ ipilimumab) versus 19.7% (- ipilimumab)
Received ipilimumab
No ipilimumab
Proportion surviving
P=0.044
4.9 months
21.3 months
Months surviving
Adapted from Knisely JP, et al. J Neurosurg 2012;117(2):227-33.
I-O and biomarkers.
Tumour immune
escape: network of
dynamic pathways
Detection of
biomarkers more
challenging
Different approach to
biomarkers?
No exclusionary I-O biomarkers identified
PD-L1, ALC, T cell populations, immune and tumour related
gene expression, seroreactivity and NY-ESO-1?
68
Adapted from www.biolegend.com
I-O therapies may act regardless of mutation
status: anti-CTLA-4 (ipilimumab) example
• Up to 60% of melanoma
patients have tumours
with a BRAF mutation1
• Objective responses,
stable disease, and
durable disease control
with ipilimumab were
similar in patients with
and without the BRAF
V600E mutation2
Best overall response with ipilimumab by
BRAF mutation status in phase 2 CA184-0042
Best overall response
BRAF wild-type,
n (%)
BRAF V600E,
n (%)
Complete response
1 (3)
0
Partial response
3 (9)
3 (9)
Stable disease
7 (20)
6 (18)
Progressive disease
20 (57)
21 (62)
4 (11)
4 (12)
35
34
Unknown
Total
Durable disease control with ipilimumab by
BRAF mutation status in phase 2 CA184-0042
Disease control state
BRAF wild-type,
n (%)
BRAF V600E,
n (%)
Durable disease control
5 (14)
6 (18)
Non-durable disease control
24 (69)
24 (71)
Unknown
6 (17)
4 (12)
35
34
Total
69
1. Chapman PB, et al. N Engl J Med 2011;364:2507–2516; 2. Shahabi V, et al. Cancer Immunol Immunother 2012;61:733–737.
Potential I-O biomarkers of response: PD-L1
–
Objective response rate (%)
•
Responses were observed in PD-L1
negative patients
PD-L1 expression did not correlate with
response for nivolumab + ipilimumab
concurrent regimen2
Nivolumab monotherapy1
% best response in
baseline target lesions
Pretreatment PD-L1 expression suggested
increased likelihood of response to nivolumab
monotherapy in advanced melanoma1
5% PD-L1+
200
180
160
140
120
100
80
60
40
20
0
−20
−40
−60
−80
−100
60
0
6/13
7/17
9/22
40
30
20
3/21
10
1/13
_
+
_
+
_
+
0
Nivolumab
monotherapy1
Combination
nivolumab plus
ipilimumab2
Sequenced
nivolumab after
ipilimumab3
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Weeks since treatment initiation
4/8
50
% best response in
baseline target lesions
•
1. Grosso JF, ASCO 2013 poster presentation. J Clin Oncol 2013;31(15 Suppl):abstract 3016;
2. Adapted from Callahan MK, ASCO 2013 poster presentation. J Clin Oncol 2013;31(15 Suppl):abstract 3003
5% PD-L1−
200
180
160
140
120
100
80
60
40
20
0
−20
−40
−60
−80
−100
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Weeks since treatment initiation
Courtsey of P. Johnson 70
Potential I-O biomarkers of response:
cell populations
• CD4+ ICOShigh cells increased during ipilimumab induction but decreased before
radiotherapy; after radiotherapy, there was a second increase
• Increase in monocyte HLA-DR expression after radiotherapy
• Myeloid-derived suppressor cells declined after radiotherapy
HLA-DR expression on
monocytes
Radiotherapy
8
6
4
2
0
20,000
Radiotherapy
15,000
10,000
5,000
Month
Adapted from Pastow M, et al. N Engl J Med 2012;366(10):925–931.
Myeloid-derived
suppressor cells
40
MDSCs (%)
10
HLA-DR MFI (relative
fluorescence units)
CD4+ ICOShigh T cells (%)
CD4+ ICOShigh cells
0
Radiotherapy
30
20
10
0
Month
Month
Courtsey of P. Johnson
71
Potential biomarkers of response:
cell populations
• Associations between clinical activity in response to ipilimumab and
increase in TILs, high baseline expression of FoxP3 and indoleamine 2,3dioxygenase (IDO) in melanoma
TILs (P=0.005)
FoxP3 (P=0.014)
57.1%
Non-benefit group
IDO (P=0.012)
36.0%
Non-benefit group
10.0%
Benefit group
11.1%
Non-benefit group
75.0%
Benefit group
37.5%
Benefit group
Benefit group: best overall response of CR, PR, of SD ≥24 weeks
Adapted from Hamid O, et al. J Transl Med 2011;9:204.
Courtsey of P. Johnson
72
Balancing T cell activation: playing with T cell
receptors.
Activating
receptors
Inhibitory
receptors
CTLA-4
CD28
•
PD-1 and CTLA4 play distinct
roles in regulating T cell
immunity.
•
CTLA4 modulates early
phases of T cell priming
(naïve and memory T cells)
•
PD-1 is expressed on
antigen-experienced T cells
(TILs and Tregs)
•
PD-1/PDL-1 interaction
downregulates overt
inflammation in lesions.
PD-1
OX40
TIM-3
CD137
Agonistic
antibodies
LAG-3
T-cell stimulation
Blocking
antibodies
Specific response to tumour, regardless of its
characteristics, including mutation status
73
Adapted from Mellman, et al. Nature 2011;480(7378):480–489; Pardoll DM. Nat Rev Cancer 2012;12:252–264.
Balancing T cell activation: playing with T cell
receptors.
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