immunothérapie des cancers, nouveaux concepts - aurélien marabelle
TRANSCRIPT
![Page 1: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/1.jpg)
Programme d’Actions Intégrées de Recherche en cancérologie pédiatrique
(PAIR Pédiatrie)
Maison de la Chimie - 13 avril 2016
![Page 2: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/2.jpg)
Immunothérapie des cancers, nouveaux concepts
Aurélien Marabelle, MD, PhDDirecteur Clinique du Programme d’Immunothérapie
DITEP, Pr JC SoriaINSERM 1015, Pr L Zitvogel
GUSTAVE ROUSSY
![Page 3: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/3.jpg)
Qu’est ce que l’immunothérapie ?Cytokines
Sang
Inné AdaptatifMoelle
![Page 4: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/4.jpg)
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
![Page 5: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/5.jpg)
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
![Page 6: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/6.jpg)
Cancer immunotherapy: “the beginning of the end”
or “the end of the beginning” ?
Durant JR. N Engl J Med 1987; 316:939-41.
![Page 7: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/7.jpg)
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
![Page 8: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/8.jpg)
![Page 9: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/9.jpg)
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 !
![Page 10: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/10.jpg)
Changement de Paradigme
Cellule Tumorale
Paradigme Historique:Cibler les Cellules Tumorales
Lymphocyte
Nouveau Paradigme:Cibler les Cellules Immunitaires
![Page 11: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/11.jpg)
Activation / Inhibition du Lymphocyte
![Page 12: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/12.jpg)
Anticorps Immunomodulateurs dirigés contre des “checkpoints” immunitaires
![Page 13: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/13.jpg)
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
![Page 14: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/14.jpg)
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
![Page 15: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/15.jpg)
Nouveaux Types de Réponses en Oncologie
Immune-Related Response Criteria
![Page 16: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/16.jpg)
Bompaire et al Invest New drugs 2012
Nouvelles Toxicités en Oncologie
![Page 17: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/17.jpg)
Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16.
anti-PD-1 / anti-PD-L1 immunotherapy
![Page 18: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/18.jpg)
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
![Page 19: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/19.jpg)
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
![Page 20: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/20.jpg)
Mais les réponses tumorales aux immunothérapies sont durables
JCO, April 20, 2015.
Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)
![Page 21: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/21.jpg)
Immune-Targeted mAbs provide Survival Benefits
Motzer RJ, et al. NEJM 2015.
nivolumab
docetaxel
Non Sq NSCLC
Borghaei H, et al. NEJM 2015.
![Page 22: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/22.jpg)
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
![Page 23: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/23.jpg)
What is the Future of Oncology ?
![Page 24: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/24.jpg)
Chemotherapy + PD-1/PD-L1 Blockade in 1st line NSCLC
Giaccone et al, ESMO 2015
![Page 25: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/25.jpg)
The Future of Oncology ?
![Page 26: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/26.jpg)
Larkin J, et al. N Engl J Med 2015.
Anti-CTLA4
Anti-PD-1
Anti-PD-1 + Anti-CTLA4
![Page 27: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/27.jpg)
AGONISTIC ANTAGONISTIC
This is just the beginning
![Page 28: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/28.jpg)
But also Target Innate Immune Cells!
DCs
αCD40
TAMs
αCSF1RαCD47
NK Cells
αKIRαCD137αNKG2A
![Page 29: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/29.jpg)
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
Oral Immuno Modulator
![Page 30: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/30.jpg)
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)
![Page 31: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/31.jpg)
Lenalidomide + aPD-1 in Multiple Myeloma
ORR = 76% (13/17)
San Miguel et al, ASH 2015
![Page 32: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/32.jpg)
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
T-VEC EMA approvalQ4 2015
![Page 33: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/33.jpg)
in situ immunization
![Page 34: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/34.jpg)
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
![Page 35: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/35.jpg)
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
![Page 36: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/36.jpg)
T-CELL CAR T-CELL
Nature Reviews Cancer, 13, 525–541 (2013)
Adoptive T-cell Therapy
![Page 37: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/37.jpg)
N Engl J Med. 2014 Oct 16;371(16):1507-17
![Page 38: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/38.jpg)
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
Blinatumomab EMA approvalQ4 2015
![Page 39: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/39.jpg)
Bispecific T-cell Engaging mAbs
![Page 40: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/40.jpg)
Blinatumomab on Chemotherapy-Refractory MRD in B-ALL
Blinatumomab in ALL & NHL
![Page 41: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/41.jpg)
The Future is Bright
BiSpe
OncolyticVirus
Cancer Vaccines
CAR T-cells
IDO inhibitors
T-VEC EMA approvalQ4 2015
Blinatumomab EMA approvalQ4 2015
![Page 42: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/42.jpg)
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
![Page 43: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/43.jpg)
![Page 44: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/44.jpg)
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
![Page 45: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/45.jpg)
![Page 46: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/46.jpg)
![Page 47: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/47.jpg)
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
![Page 48: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/48.jpg)
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.
![Page 49: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/49.jpg)
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.
![Page 50: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/50.jpg)
Challenge #1: How do we overcome resistance to immunotherapy?
Ott et al. Pembrolizumab in SCLC. WCLC 2015
![Page 51: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/51.jpg)
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.
![Page 52: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/52.jpg)
Challenge #3: Financial Toxicity
Nature. 2013 May 30;497(7451)Immunotherapy's cancer remit widens. Ledford H.
ipilimumab
![Page 53: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/53.jpg)
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.
![Page 54: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/54.jpg)
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
![Page 55: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/55.jpg)
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
![Page 56: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/56.jpg)
in situ immunization
![Page 57: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/57.jpg)
William Coley
Streptococcus pyogenes
“…on May 2, 1891, I inoculated a case of sarcoma”
“At the end of two weeks, the tumor had disappeared”
![Page 58: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/58.jpg)
![Page 59: Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle](https://reader036.vdocuments.mx/reader036/viewer/2022062316/588271dd1a28ab470c8b709d/html5/thumbnails/59.jpg)
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: