L'Institut national du cancer, la Fondation Arc et la Ligue contre le cancer ont organisé le séminaire de préparation à l'appel à projet "Programme d'Actions Intégrées de Recherche (PAIR) sur les cancers de l'enfant" qui s'est tenu le 13 avril 2016 à Paris.

1. Programme d’Actions Intégrées de
Recherche en cancérologie pédiatrique
(PAIR Pédiatrie)
Maison de la Chimie - 13 avril 2016

2. Immunothérapie des cancers,
nouveaux concepts
Aurélien Marabelle, MD, PhD
Directeur Clinique du Programme d’Immunothérapie
DITEP, Pr JC Soria
INSERM 1015, Pr L Zitvogel
GUSTAVE ROUSSY

3. Qu’est ce que l’immunothérapie ?
Cytokines
Sang
Inné AdaptatifMoelle

4. 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

5. 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

6. Cancer immunotherapy:
“the beginning of the end”
or “the end of the beginning” ?
Durant JR. N Engl J Med 1987; 316:939-41.

7. April 19, 2015
April 20, 2015
April 19, 2015
June 2, 2013
June 2, 2013
Nov 19, 2014
June 30, 2011
Nov 16, 2014
Aug 19, 2010
June 2, 2012
June 28, 2012

9. FOXP3
FOXP3
FOXP3
IMMUNO-
TOLERANCE
IMMUNO-
SURVEILLANCE
Tregs
Cancer 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 !

10. Changement de Paradigme
Cellule
Tumorale
Paradigme Historique:
Cibler les Cellules Tumorales
Lymphocyte
Nouveau Paradigme:
Cibler les Cellules Immunitaires

11. Activation / Inhibition du Lymphocyte

12. Anticorps Immunomodulateurs
dirigés contre des “checkpoints” immunitaires

13. 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

14. 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

15. Nouveaux Types de Réponses en Oncologie
Immune-Related Response Criteria

16. Bompaire et al Invest New drugs 2012
Nouvelles Toxicités en Oncologie

17. Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16.
anti-PD-1 / anti-PD-L1 immunotherapy

18. 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

19. Pembrolizumab Antitumor Activity
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Melanoma1 (N=411)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
NSCLC2 (N=262)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Gastric5 (N=39)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Urothelial4 (N=33)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
H&N3 (N=61)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
TNBC6 (N=32)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
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
ChangeFromBaselinein
TumorSize,%
Mesothelioma7 (N=25)
KEYNOTE-028

20. Mais les réponses tumorales aux
immunothérapies sont durables
JCO, April 20, 2015.
Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)

21. Immune-Targeted mAbs provide Survival Benefits
Motzer RJ, et al. NEJM 2015.
nivolumab
docetaxel
Non Sq NSCLC
Borghaei H, et al. NEJM 2015.

22. 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

23. What is the Future of Oncology ?

24. Chemotherapy + PD-1/PD-L1 Blockade in 1st
line NSCLC
Giaccone et al, ESMO 2015

25. The Future of Oncology ?

26. Larkin J, et al. N Engl J Med 2015.
Anti-CTLA4
Anti-PD-1
Anti-PD-1 + Anti-CTLA4

27. AGONISTIC ANTAGONISTIC
This is just the beginning

28. But also Target Innate Immune Cells!
DCs
αCD40
TAMs
αCSF1R
αCD47
NK Cells
αKIR
αCD137
αNKG2A

29. The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
Oral Immuno
Modulator

30. 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)

31. Lenalidomide + aPD-1 in Multiple Myeloma
ORR = 76%
(13/17)
San Miguel et al, ASH 2015

32. The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
T-VEC EMA approval
Q4 2015

33. in situ immunization

34. T-VEC + anti-PD-1 in Melanoma
-100
-75
-50
25
50
-25
0
75
100
ORR = 56% (9/16)
PercentageChangefromBaseline
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

35. The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors

36. T-CELL CAR T-CELL
Nature Reviews Cancer, 13, 525–541 (2013)
Adoptive T-cell Therapy

37. N Engl J Med. 2014 Oct 16;371(16):1507-17

38. The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
Blinatumomab EMA approval
Q4 2015

39. Bispecific T-cell Engaging mAbs

40. Blinatumomab on Chemotherapy-Refractory MRD in B-
ALL
Blinatumomab in ALL & NHL

41. The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
T-VEC EMA approval
Q4 2015
Blinatumomab EMA approval
Q4 2015

42. aPD-1/aPD-L1
aOX40
aCD137
aGITR
aKIR
IDOi
Oncolytic
Virus
Vaccines
TLR ago
RIG ago
STING ago
CHEMOTHERAPY
RADIOTHERAPY
TKI
TCE
BiSpe
mAbs
2016 : Combinaisons!
aCTLA4

44. Asgharzadeh., et al. Journal of Clinical Oncology. 2012
Tumor Associated Macrophages
in High-Risk Neuroblastoma
CD163+IHCstaining
Macrophages
Good Prognosis
Neuroblastoma
Bad Prognosis
Neuroblastoma
Stage IV, MYCN NA, >18months

47. 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

48. 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.

49. 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.

50. Challenge #1: How do we overcome resistance to
immunotherapy?
Ott et al. Pembrolizumab in SCLC. WCLC 2015

51. Challenge #2: Immune Toxicity
7.7%
18.6%
39.6%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
nivolumab ipilimumab nivo+ipi
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.

52. Challenge #3: Financial Toxicity
Nature. 2013 May 30;497(7451)
Immunotherapy's cancer remit widens. Ledford H.
ipilimumab

53. On treatment
Off treatment
First response
Ongoing
response
0 8 16 24 32 40 48 64 72 8056
Time (weeks)
NIVOLUMAB+IPILIMUMAB
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.

54. 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 sur
e-cancer.fr

55. 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

56. in situ immunization

57. William Coley
Streptococcus pyogenes
“…on May 2, 1891,
I inoculated a case of sarcoma”
“At the end of two
weeks, the tumor had
disappeared”

59. Copyright © 2012 American Medical Association. All
rights reserved.
Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy: A Prospective
Multi-institutional Trial
Arch 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: