PROGRAMME SIRIC 2018-2022 - INTEGRATED RESEARCH PROGRAM 1 UNDERSTANDING CELL PLASTICITY TO IDENTIFY
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PROGRAMME SIRIC 2018-2022
INTEGRATED RESEARCH PROGRAM 1
• UNDERSTANDING CELL PLASTICITY TO IDENTIFY
INNOVATIVE CANCER CELL AND IMMUNE TARGETS
Leaders : A Traverse-Glehen - C Caux – Young Faculty : N Bendriss-Vermare
PARTICIPANTS IRP1
• Research teams:
• CRCL/INSERM U1052 : A Puisieux, JJ Diaz, P Mehlen, C Caux, L Genestier/G Salles,
M Gabut, J Marie
• IARC : Z Herceg
• CIRI/INSERM U111 : T Walzer
• Translational departments (CLB, HCL)
• M Billaud, I Ray Coquard, Q Wang, P Saintigny, F Tirode, A Viari, S Lantuejoul/A
Traverse-Glehen
• Clinical departments (CLB, HCL)
• Medical Oncology
• Haematology
• Pathology Research
• Platform (drug development): C3D
• Teams n=15 + C3D
INTEGRATED RESEARCH PROGRAM 1
General Objective
Identify innovative targets involved in cell
plasticity at the level of both tumor cells
and/or immune microenvironment in
order to prevent tumor adaptation and
therapeutic resistance
UNDERSTANDING CELL PLASTICITY TO IDENTIFY
INNOVATIVE TARGETS ON CANCER AND IMMUNE CELLS
Nascent Established
tumor tumor
Genetic drivers
1
and epigenetic reprogramming
One molecular High tumor
driver Molecular heterogeneity molecular
heterogeneity
Immuno-
Immunosurveillance Escape
surveillance
2 EMT targeting
Tumor cell plasticity
3
Immune cell
plasticity/adaptability
Cell plasticity and Immune responses
Hétérogénité de l’infiltrat immunitaire des
lymphomes Hodgkiniens traités par anti-PD1
Alexandra Traverse-Glehen, Hervé Ghesquières
Guillaume Aussedat, Laurent Genestier, Gilles Salles
Team "Clinical and Experimental models of lymphomagenesis"
INSERM U1052 – CNRS UMR5286
Faculté de Médecine Lyon-Sud
Mechanism of action of checkpoint inhibitors
Structure
Composition
Organisation spatiale
• 2018 Nobel Prize in Physiology or
Medicine
• James P. Allison, PhD, of The
University of Texas MD Anderson
Cancer Center,
• Dr. Tasuku Honjo of Kyoto
University in Japan
CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; MHC, major histocompatibility complex; TCR, T-cell receptor. Ribas A. N Engl J Med. 2012;366:2517-9.
Le lymphome de Hodgkin: une physiopathologie unique
CD68 CD3
CD163 CD20
Réponse immunitaire inefficace
Lymhome de Hodgkin
• 1840 nouveaux cas diagnostiqués en France en 2011
• 0,5% des cancers, 30% des lymphomes
• Pic adultes jeunes (20-30 ans) et sujets plus âgés (> 60 ans)
• Cancer le plus fréquent chez l’adulte de moins de 40 ans
• Peut se voir chez l’enfant et l’adolescent exceptionnel avant 5 ans
• variations géographique, Sex Ratio: 1,4 : 1
• Cancer de bon pronostic (survie relative à 5 ans de 84%): 0,2% des
décès par cancer
• Efficacité des thérapeutiques actuelles en première ligne
• 10 à 20 % de rechute: RC de 12 à 30 %, mediane de progr 12 mois
• Problème de la toxicité des thérapeutiques à long terme
• Nécessité de tt ciblé: Immunothérapie anti-PDL1 2016-17 première
et deuxième ligne
Échappement au contrôle immunitaire
Cellules de Hodgkin Reed Sternberg orchestre son ME pour
échapper à la réponse immunitaireMicroenvironement tolérant
Expansion TH2 et Treg
PDL1
T cell exhaustion
Inhibition directe des cellules T cytotoxiques et NK
SURVIE-EXPANSION-RESISTANCE THERAPEUTIQUEMechanisms of PD-L1 expression in CHL
9p24.1 alteration EBV
(97% of cases)
Direct amplification Induction via JAK2 Induction via LMP1
PD-L1 expression
CEP9, chromosome enumeration probe 9; EBV, Epstein-Barr virus;
JAK2, Janus kinase 2; LMP1, latent membrane protein 1; Green AS, et al. Blood. 2010;116:3268-77. Hao Y, et al. Clin Cancer Res. 2014;20:2674-83.
STAT, signal transducer and activator of transcription. Green MR, et al. Clin Cancer Res. 2012;18:1611-8. Roemer MG, et al. J Clin Oncol. 2016;34:2690-7.TAM: Impact Pronostique
Profil expression génique chez patients réfractaires au traitement
CD68
Steidl NEJM 2010, Blood 2012FDA-approved checkpoint inhibitors
for the treatment of cancer
Indication (date of approval)
MSI-H
dMM
Isoty Compa Melanom Bladder HNSC
Target Antibody NSCLC RCC HL MCC R
pe ny a cancer C
cance
r
CTLA-4 Ipilimumab IgG1 BMS 2011a – – – – – – –
Pembrolizum
IgG4 Merck 2014 2015 – 2017 2017 2016 – 2017
PD-1 ab
Nivolumab IgG4 BMS 2014a 2015 2015 2016 2017 2016 – –
Atezolizumab IgG1 Roche – 2016 – – 2016 – – –
Merck
Avelumab IgG1 – – – – 2017 – 2017 –
PD-L1 Pfizer
aIpilimumab Astra
and nivolumab approved in monotherapy and in combination.
Durvalumab IgG1 – – – – 2017 – – –
Zeneca
dMMR, mismatch repair deficient; HNSCC, head and neck squamous cell carcinoma; IgG, immunoglobulin G; FDA approval information available at:
MCC, Merkel cell carcinoma; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung cancer; RCC, renal cell cancer. https://www.fda.gov/default.htm. Accessed May 2017.Single agent activity of PD1/PD-L1 blockade in R/R cancer
100
90 ◼ Atezolizumab
HL ◼ Pembrolizumab
80
◼ Nivolumab
70
60
ORR (%)
50 → PD-L1+ in > 90%
40
30
20
10
0
Number of patients 87 66 28 27 120 556 655 35 129 117 183 292 394 83 144 40 16 27 21 20 26 34 168 39 28 46 38 33 10 18 39 39 23 99 39
High PD-L1
Low PD-L1
B-cell NHL
T-cell NHL
Esophageal
MMR-proficient
MMR-deficient
Gastric
HNSCC
HCC
HL Melanoma NSCLC SCLC TNBC Ovary RCC
Urothelial Colorectal
HCC, hepatocellular carcinoma; MMR, DNA mismatch repair; ORR, overall response rate; R/R, relapsed/refractory;
SCLC, small cell lung cancer; TNBC, triple-negative breast cancer; T-NHL, T-cell non-Hodgkin lymphoma. Adapted from Matsuki E, Younes A. Curr Treat Options Oncol. 2016;17:31.Analyse topologique du microenvironnement du LH
Source cellulaire de PD-L1
Importance de l’organisation spatiale des effecteurs immunologiques
TAM expr fortement PDL1 créent une niche immunologique protectrice
au contact des LyT CD’ exp PD1 et des cell HTS
Efficacité des anti-PDL1 doit être influencée par cette niche Carey et al. Blood 2018Objectifs • Caractérisation de l’hétérogénéité de l’infiltrat tumoral et immunitaire • Caractérisation de l’organisation spatiale • Technologie nouvelle d’analyse du transcriptome: Digital Space Profiling
Plateforme Nanostring aux Hospices Civils de Lyon
Dr Jonathan Lopez, Centre de Biologie Sud
• Plateforme nCounter FLEX: Juin 2017
• Génétique somatique des Cancers
– ProSigna, Panels Elements à façon +++, panel fusion (
poumon, thyroide, LA) , Copy number alterations
(Myélome, LLC, Interféronopathies)
22Digital Spacial Profiling (DSP)
GeoMx Digital Space Profiler
GeoMx™ Digital Spatial Profiler
Your GPS for Spatially-Resolved Biology
Illumina NGS --or-- NanoString nCounter
24Highly-multiplexed molecular detection imaging on FFPE
sections
Nanostring’s Digital Space Profiling (DSP) approach
OBECTIVE: validate a custom
RNA/protein panel with 800 targets.
This will allow us to deeply
characterize cellular pathways (MAPK,
PIK3, STAT, Wnt…) and progression
programs (EMT, angiogenesis, ECM,
metastasis…) activated in tumors
together with tumor
A single FFPE section microenvironment with a special
focus on immune contexture (ICP,
immune sub-populations, IFN
pathway…).
Hospices Civils de Lyon Genomics facility will be one of the 3 first sites to access this
cutting-edge technology (first site in Europe) in November 2018.Immuno-oncologie panel
Drug Target Activation/Inhibit Cell Typing
Core Cell Profiling Module ion Module Module
4-1BB ARG1 CD127 PD-L2 CD45RO Gamma
Beta-2-microglobulin FOXP3 Delta TCR
B7-H4 B7-H3 CD25 CD40
CD11c CD34 CD14
LAG3 GITR CD80 CD40L
CD20 CD66b FAPalpha
OX40L IDO1 CD86 HLA-DR
CD3
Tim-3 STING ICOS CD27
CD4
VISTA
CD45
CD56 Trafficking
Tumor Module Cytokine Module
CD68 Module
CD8 MART1 EpCAM CXCR3 CXCL9 Interferon gamma
CTLA4 NY-ESO-1 Her2/Erb CD31 E selectin IL-17
GZMB S100B B2 CXCL10 L-selectin IL-6
Histone H3 Bcl-2 CXCL11 P-selectin TGF beta
Ki-67 TNFalpha
PD1
PD-L1
Pan-Cytokeratin ◼ Human IO Proteins panel
26
S6Master 2: Guillaume Aussedat Plasteforme DSP: Jonathan Lopez
Cohortes du LYSA
• Prolonged remissions after anti-PD-1 discontinuation in patients with
Hodgkin lymphoma.
Manson G,…,Houot R. Blood 2018 Jun 21;131(25):2856-2859.
Patients sous NIVOLUMAB dans le cadre de ATU
Biopsies sequentielles
• Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed
anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: A series
from Lysa centers.
Rossi C,…, Ghesquières H. Am J Hematol. 2018 Jun 8.
3O patients traités et progressifs sous anti-PD1
Biopies sequentielles
Persitance PDL1 et PD1 sous traitement efficacité partielleCoiffier B Salles G Sarkozy C Ghesquières H Bachy E Sujobert P Gazzo S Callet-Bauchu E Baseggio L Jallade L Genestier L
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