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

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Melanoma1 (N=411)KEYNOTE-001

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NSCLC2 (N=262)KEYNOTE-001

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Gastric5 (N=39)KEYNOTE-012

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Urothelial4 (N=33)KEYNOTE-012

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H&N3 (N=61)KEYNOTE-012

Series1

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TNBC6 (N=32)KEYNOTE-012

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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.

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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

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25

50

-25

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ORR = 56% (9/16)

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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: