Programme d’Actions Intégrées de Recherche en cancérologie pédiatrique
(PAIR Pédiatrie)
Maison de la Chimie - 13 avril 2016
Immunothérapie des cancers, nouveaux concepts
Aurélien Marabelle, MD, PhDDirecteur Clinique du Programme d’Immunothérapie
DITEP, Pr JC SoriaINSERM 1015, Pr L Zitvogel
GUSTAVE ROUSSY
Qu’est ce que l’immunothérapie ?Cytokines
Sang
Inné AdaptatifMoelle
HISTOIRE DE L’IMMUNOTHERAPIE DES CANCERS
Chemotherapy - 1930s Paul Ehrlich - alkylating agents 1943 nitrogen mustard - lymphoma
Surgery – 1890 Halsted performs first radical mastectomy
Radiotherapy – late 19th - Becquerel and Rontgen, Marie Curie 1898 radium identified, 1903 first successful cancer tx
Immunothérapies du Cancer
Shekarian T, Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune system rather than cancer cells. Mutagenesis 2014
Cancer immunotherapy: “the beginning of the end”
or “the end of the beginning” ?
Durant JR. N Engl J Med 1987; 316:939-41.
April 19, 2015
April 20, 2015April 19, 2015
June 2, 2013June 2, 2013
Nov 19, 2014
June 30, 2011
Nov 16, 2014
Aug 19, 2010
June 2, 2012June 28, 2012
FOXP3
FOXP3
FOXP3
IMMUNO-TOLERANCE
IMMUNO-SURVEILLANCE
TregsCancer Cells
DCs
TAMs
MDSCs
NKs
CD8+ T-cells
CD4+ T-cells
DCs-
Adapté de Colombo MP, et al Nat Rev Cancer. 2007 Nov;7(11):880-7.
Le Système Immunitaire peut aussi promouvoir le cancer !
Changement de Paradigme
Cellule Tumorale
Paradigme Historique:Cibler les Cellules Tumorales
Lymphocyte
Nouveau Paradigme:Cibler les Cellules Immunitaires
Activation / Inhibition du Lymphocyte
Anticorps Immunomodulateurs dirigés contre des “checkpoints” immunitaires
THERAPIES CIBLANT L’IMMUNITE
Hodi et al. Abstract #3008 ASCO 2008
Screening Week 12 Week 14 Week 72
Schadendorf D, J Clin Oncol 2015.
Anti-CTLA4
Before BRAFi After 15 weeks of BRAFi
After 23 weeks of BRAFi
Wagle N, et al. JCO. 2011 Aug 1;29(22):3085-96
Chapman PB et al. N Engl J Med 2011;364:2507–16.
THERAPIES CIBLANT LA TUMEUR
Nouveaux Types de Réponses en Oncologie
Immune-Related Response Criteria
Bompaire et al Invest New drugs 2012
Nouvelles Toxicités en Oncologie
Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16.
anti-PD-1 / anti-PD-L1 immunotherapy
Spectre d’Activité des Anti-PD-1/PD-L1
Marabelle A, Routy B, Michels J, Kroemer G, Zitvogel L. Prime time for Immune-Checkpoint Targeted Therapy at ASCO 2015. Oncoimmunology 2016. in press.
AMM
AMM
Pembrolizumab Antitumor Activity
Series1
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
Melanoma1 (N=411)KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
NSCLC2 (N=262)KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
Gastric5 (N=39)KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
Urothelial4 (N=33)KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
H&N3 (N=61)KEYNOTE-012
Series1
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
TNBC6 (N=32)KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
cHL7 (N=29)KEYNOTE-013
1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium; 5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR.
-100
-80
-60
-40
-20
0
20
40
60
80
100
Cha
nge
From
Bas
elin
e in
Tu
mor
Siz
e, %
Mesothelioma7 (N=25)KEYNOTE-028
Mais les réponses tumorales aux immunothérapies sont durables
JCO, April 20, 2015.
Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)
Immune-Targeted mAbs provide Survival Benefits
Motzer RJ, et al. NEJM 2015.
nivolumab
docetaxel
Non Sq NSCLC
Borghaei H, et al. NEJM 2015.
Nivolumab(BMS)
Pembrolizumab(MSD)
Atezolizumab (Roche/Genentech)
Durvalumab (AZ/Medimmune)
Avelumab (Pfizer)
Anti-PD-1 Anti-PD-L1
Approved
Ipilimumab(BMS)
Tremelimumab(AZ)
Anti-CTLA-4
Approved
Know your Immune Checkpoint Antibodies
What is the Future of Oncology ?
Chemotherapy + PD-1/PD-L1 Blockade in 1st line NSCLC
Giaccone et al, ESMO 2015
The Future of Oncology ?
Larkin J, et al. N Engl J Med 2015.
Anti-CTLA4
Anti-PD-1
Anti-PD-1 + Anti-CTLA4
AGONISTIC ANTAGONISTIC
This is just the beginning
But also Target Innate Immune Cells!
DCs
αCD40
TAMs
αCSF1RαCD47
NK Cells
αKIRαCD137αNKG2A
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
Oral Immuno Modulator
30
25 mg BID
50 mg BID
100 mg BID
300 mg BID
Off study treatment
Epacadostat + pembrolizumab in Metastatic Melanoma(Incyte, NCT02178722)
Gangadhar et al. SITC 2015. Abstract #07
ORR = 58% (11/19)
Lenalidomide + aPD-1 in Multiple Myeloma
ORR = 76% (13/17)
San Miguel et al, ASH 2015
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
T-VEC EMA approvalQ4 2015
in situ immunization
T-VEC + anti-PD-1 in Melanoma
-100
-75
-50
25
50
-25
0
75
100
ORR = 56% (9/16)
Per
cent
age
Cha
nge
from
Bas
elin
e
Stage IV M1c (N=7)Stage IV M1b (N=2)Stage IV M1a (N=1)Stage IIIc (N=5)Stage IIIb (N=1)
All 16 patients were followed at least 12 weeks from the first dose of pembrolizumab and must have had an evaluable response. Stable disease must be > 77 days to be considered evaluable.
34Long G V et al, SMR congress 2015, San Franisco, USA
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
T-CELL CAR T-CELL
Nature Reviews Cancer, 13, 525–541 (2013)
Adoptive T-cell Therapy
N Engl J Med. 2014 Oct 16;371(16):1507-17
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
Blinatumomab EMA approvalQ4 2015
Bispecific T-cell Engaging mAbs
Blinatumomab on Chemotherapy-Refractory MRD in B-ALL
Blinatumomab in ALL & NHL
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
T-VEC EMA approvalQ4 2015
Blinatumomab EMA approvalQ4 2015
aPD-1/aPD-L1
aOX40
aCD137
aGITR
aKIR
IDOi
Oncolytic Virus
Vaccines
TLR ago
RIG agoSTING ago
CHEMOTHERAPY
RADIOTHERAPY
TKI
TCE BiSpe mAbs
2016 : Combinaisons!
aCTLA4
Asgharzadeh., et al. Journal of Clinical Oncology. 2012
Tumor Associated Macrophages in High-Risk Neuroblastoma
CD16
3+ IH
C st
aini
ng
Macrophages
Good Prognosis Neuroblastoma
Bad Prognosis Neuroblastoma
Stage IV, MYCN NA, >18months
Yu, A. L. et al. (2010). Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for Neuroblastoma. The New England Journal of Medicine, 363(14), 1324–34.
Rationnel pour l’Immunotherapie des Neuroblastomes
Impact Pronostic des Isoformes NKp30 dans les NB de Haut Risque
Semeraro M, et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med 2015;7:283ra55.
Niveaux d’Expression Variables du CMH I dans les Cancers Pédiatriques
Haworth KB, et al. Characterization of MHC Class I and β-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials. Pediatr Blood Cancer 2016;63:618–26.
Challenge #1: How do we overcome resistance to immunotherapy?
Ott et al. Pembrolizumab in SCLC. WCLC 2015
Challenge #2: Immune Toxicity
nivolumab ipilimumab nivo+ipi0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
7.7%
18.6%
39.6%
Grade 3-4 Adverse Events with anti-CTLA4 + anti-PD-1
Grade 3-4
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015.
Challenge #3: Financial Toxicity
Nature. 2013 May 30;497(7451)Immunotherapy's cancer remit widens. Ledford H.
ipilimumab
On treatmentOff treatmentFirst responseOngoing response
0 8 16 24 32 40 48 64 72 8056
Time (weeks)
NIV
OLU
MAB
+ IP
ILIM
UM
AB
Time to and Durability of Response in Patients Who Discontinued Due to Toxicity
The Good News: We Might Not Need To Treat for Long
Larkin et al. Abstract Number 3303. ESMO 2015.
Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr
plus d’informations sure-cancer.fr
Kluger HM. Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases. J Clin Oncol 2015;33:abstr 9009.
Goldberg SB. Activity and safety of pembrolizumab in patients with metastatic NSCLC with untreated brain metastases. J Clin Oncol 2015;33:abstr 8035.
Activity of anti-PD-1 against Brain Mets
in situ immunization
William Coley
Streptococcus pyogenes
“…on May 2, 1891, I inoculated a case of sarcoma”
“At the end of two weeks, the tumor had disappeared”
Copyright © 2012 American Medical Association. All rights reserved.
Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy: A Prospective Multi-institutional TrialArch Otolaryngol Head Neck Surg. 2002;128(10):1137-1144. doi:10.1001/archotol.128.10.1137
Patient 3 with a stage I lymphangioma of the left side of the neck. Photographs taken before (A) and after (B) a single injection demonstrate a complete response to OK-432 treatment.
Figure Legend: