Vaccins thérapeutiques et VHC - Dr François Habersetzer Hôpitaux universitaire de Strasbourg Inserm 1110
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Vaccins thérapeutiques et VHC Dr François Habersetzer Hôpitaux universitaire de Strasbourg Inserm 1110
HCV: natural course of infection
Spontaneous
Clearance
Spontaneous (1% ??)
Primary Clearance
Infection (15-50%)
Chronic Carrier
State
(50-85%)
Healthy Carriers
(30%)
Acute phase (< 6 months) Chronic phase (>6 months)Components of the adaptative anti-hepatitis
C virus immune responses
Spontaneous Clearance of HCV infection
requires :
•Early and multispecific class 1
restricted CD8+ T cell and class II
restricted CD4+ T cell responses directed
to S and NS HCV proteins
• The quality of HCV clearance and
protection from reinfection is
determined by the functional potency
and cytotoxic potential of HCV-specific
CD8+cells
CD81, SRBI,
•NS3 is a key viral protein for HCV Occludine, Claudine
elimination
NAb responses to epitopes in E1 and E2
are associated with resolution of
infection and protection against
reinfection
.
Adapted from Freeman AJ et al. Immunology and Cell Biology 2001: 79: 515-536
Rehermann et al. JCI, 2009Importance of HCV-Specific Intra-Hepatic CD8+ T Cell
Immune Responses (IFN-γγ) in Control of HCV Replication
Thimme, R. et al, J Exp Med 2001 Shoukry, N. et al, J Exp Med 2003
100 0.8 100 HCV % IFNg+/CD8 300
CD8+ T cells
% HCV tet.+/CD8
Virions 106 / ml
Virions 104 / ml
HCV CHIMPANZEE
HUMAN
IFN-g ELISPOT
%tet.+ 200 INFECTION
INFECTION
10 10
0.4 100
1 0
1 0 8 16 24 32 40
2 4 6 8 10 12 14 16 18 20
Weeks after infection
Weeks after infection
T cell
Active
induction
replication
6-8 weeks
100
Sustained
Virions 106 / ml
HCV NS3 is a key
Adaptive target
10 responses
1
2 4 6 8 10 12 14 16 18 Weeks after infection
●●●●●●●●● 4Mechanism of HCV Clearance and Persistance
Spontaneous Clearance of HCV Persistance of HCV infection
infection
Strong and wide CD8+ and CD4+ T –cell Limited T-cell responses and limited
responses to HCV epitopes reactivity to HCV epitopes;
Viral CD4+ and CD8+ escape mutants
Lack of memory T-cell maturation
Persistence of dysfunctional T-cells
Strong cytotoxic T cell responses Negative costimulators of T cells : PD-
1/PDL1 receptors-ligand;
Immunoregulatory cytokines IL10
Neutralising Ab to E1/E2 Escape Mutants
IL28B gene polymorphisms IL28B gene polymorphisms
C/C genotype T/T genotype
Impairment of DC maturation
Ferrari C. Gastroenterology 2008; 134: 1601-1604; Rehermann B et al. Nat Rev Immunol 2005; 5: 215-229;
Thomas DL et al. Nature 2009; 461: 798-801; Wherry EJ et al. J Virol 2004; 78: 5535-5545Need to develop vaccine strategies For Preventing HCV infection: need of strong cross-reactive neutralising (Ab) responses To reconstitute efficient immune control in chronically infected patients : by restoring functional T-cell responses similar to those patients who resolve the HCV infection spontaneously : le vaccin thérapeutique
Therapeutic Vaccines for chronic hepatitis C
• Different strategies for immunization
Peptides
Proteins
DNA-immunization
Virus-like particules
Tarmogens
Life attenatued carriers : recombinant viruses and bacteria
Recombinant viruses are an efficient way to deliver heterologous DNA that can mediate a
large amount of HCV antigens potentially increasing the immunogenicity of the vaccine in
comparison with peptides and proteinsHCV Treatment: TG4040 Therapeutic Vaccine Based on non-replicative, poxvirus MVA (Modified Viral Ankara strain) was choice because he was successfully administered to immunize high risk patients against smoll pox without any significant side effects in the primary vaccination of over 150 000 humans T cell-based therapeutic vaccine: expressing 3 of the major non- structural HCV proteins (NS3, NS4, NS5B) that are prominant targets of host induced immune responses during clearance / control of infection First viral-based vaccine in the field of HCV therapies having entered clinical development Objective: to prime HCV specific functional CD4+ and CD8+ T lymphocytes capable to produce IFN-γ and lyse infected cells
Mécanisme d’action supposé de TG4040
Induction d’une réponse immunitaire
cellulaire après injection de TG4040
Administration s.c. de TG4040 (Mécanisme
d’induction de la réponse immunitaire) Voie non cytolytique
TG4040 Infection et
capture
Élimination VHC via
les cytokines
Hépatocytes Infectés
+ NK
Migration
DC
LT
Migration
CD8 cytotoxique
Au Foie
www.cancer-info.com Lyse des hépatocytes par les
CD4 cellules CD8 spécifique anti-VHC
●●●●●●●●● 9Etude de phase 1 - TG4040.01 - d’escalade de dose chez
des patients ayant une hépatite chronique C minime
• Dose escalating study
Cohort 1: 106 pfu, 3 patients
Cohort 2: 107 pfu, 3 patients
Cohort 3: 108 pfu, 9 patients + boost at month 6
All patients: Prime injection (3 weekly injections)
TG4040 inj (cohort 5)
TG4040 inj (cohort 6)
TG4040 injection TG4040 inj (cohort 3, 4)
0 4 8 12 16 20 24 28 32 36 40 44 48 weeks
Habersetzer F et coll. Gastroenterology, 2011.
●●●●●●●●● 10Étude de phase 1 d’escalade de dose: Evolution de la
virémie
Change in HCV RNA from baseline
1,0
Change in HCV RNA (log10)
0,5 107 pfu (n=3)
108 pfu (n=6)
0,0
Rappel (108 pfu)
106 pfu (n = 3)
- 0,5
- 1,0
D1 D8 D15 D22 D37 M2 M3 M4 M5 M6 M6+8 M6+22 M9
Pas d’effet sur charge virale 108 pfu
TG4040 injections Nadir après 37 j
Diminution prolongée de la virémie de 37 à 6 mois 106 pfu
Habersetzer F et coll. Gastroenterology, 2011.
11Patient 3 Corrélation réponse T et virémie C
ELISpot : Réponse augmentée contre NS3/1 et NS4B (> moy pré-
thérapeutique + 2SD) et induction de réponse contre NS3/2
1 250
Pt 3
0.5
D1 200
0
D22 M6 150
-0.5 M2
100
-1 M-1 D37
-1.5 50
28
neg
-2 ND ND 0
NS3/1 NS3/2 NS4B NS5/1 NS5/2 VL measurements
Corrélation entre la diminution de la virémie et la réponse immunitaire
spécifique au TG4040
Habersetzer F et coll. Gastroenterology, 2011.Résultats étude de phase 1 : preuve de concept
Chez des patients ayant une hépatite C chronique
Vaccin thérapeutique TG4040 bien toléré
Baisse transitoire de la virémie chez 50% des patients
Permet d’induire une réponse immunitaire chez 33% des patients
Nécessité d’envisager des combinaisons pour permettre une élimination
virale
Habersetzer F et coll. Gastroenterology, 2011.Randomized
Résultats Open
étude de Label
phase 1 :Phase IIde
preuve Trial
concept
Control Arm
(n=31)
1:2:2 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Randomization
2 experimental arms SOC Lead-In Arm
(n=63)
Treatment-naïve 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Non-cirrhotic
Genotype 1
Patients TG4040 Lead-In
Arm (n=59)
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 Weeks
TG4040
monotherapy Second stopping rule
if viral load detectable after 24
Initiation of weeks of SOC (all Arms)
SOC
SOC: PegIFN/ribavirin
(Pegasys®/Copegus®) Primary endpoint:
improvement of cEVR rates Evaluable population: ITT
TG4040, 107 pfu population excluding patients
First stopping rule if viral load decrease is inferior to
(subcutaneous injection) who left study before cEVR
2 log10 IU/mL (Control Arm only)
evaluation
Wedemeyer H et al. EASL 2013 ●●●●●●●●● 14Demographic and baseline characteristics
Stratification by age (>vs≤50 years) and baseline viral load (>vs≤400 000 IU/mL)
Control SOC Lead-In TG4040 Lead-In
(n=31) (n=63) (n=59)
Mean Age in years 41 44 43.6
Gender, n females / n males 15/16 27/36 27/32
Caucasian, n (%) 30 (96.8) 60 (95.2) 59 (100)
Mean Baseline HCV RNA in log10 IU/mL (SD) 5.96 (0.68) 5.74 (0.81) 5.71 (0.81)
HCV genotype, n (%)
1a 6 (19.4) 12 (19) 15 (25.4)
1b 25 (80.6) 50 (79.4) 44 (74.6)
1a/b 0 1 (1.6) 0
IL28B n C-C / n non C-C 7/17 14/33 16/32
(All data are not yet available)
F3 Fibrosis, n (%) (Biopsy or FibroScan®) 1 (3.2) 6 (9.5) 7 (11.8)
High Baseline ALT (≥ 2 ULN), n (%) 5 (16.1) 15 (23.8) 16 (27.1)
Good balance between arms, including IL28B polymorphism and genotype 1a/1b
distribution
Wedemeyer H et al. EASL 2013
●●●●●●●●● 15TG4040 Pre-Vaccination Improves cEVR Rates
Percentage
p=0,003
of patients
70
*
60 64,2%
34/53
50
40 45,9% Control
28/61 SOC Lead-In
*
30 TG4040 Lead-In
30%
20 9/30
Three-outcome one-stage design
based on: Ho < 40 %, HA > 60 %
10 According to final evaluable set of
patients in pre-vaccination arm:
0 Null hypothesis accepted if cEVR ≤
cEVR 25 patients, rejected if cEVR ≥ 29
Primary objective of the study reached: significant improvement of cEVR rates in
TG4040 lead-in arm (64.2 %)
Wedemeyer H et al. EASL 2013
●●●●●●●●● 16SVR24 Response Relapse and Viral Breakthrough
Percent of patients
- ITT: at least one PR
administration
n/N = 15/31 32/63 32/55 6/31 6/63 7/55 - LODTG4040 Induces HCV Specific T-Cell Responses
Baseline TG4040 pre-treatment
Ex: NS3
W12
M-1
W9
D1
Representative ELISpot well
TG4040
Mean SFC/106 PBMC
Pre-Treatment
Arm (n=55) Negative
control
No SFC/106 PBMC
< 50 SFC/106 PBMC
50-100 SFC/106 PBMC
100-150 SFC/106 PBMC
150-200 SFC/106 PBMC
> 200 SFC/106 PBMC
NS3
-SFC: Spot-forming cell
-PBMC: Peripheral
Blood Mononuclear
Cells
Baseline TG4040 Pre- PegIFN/RBV End Of
(M-1; D1) Treatment + Study
(W9; W12) TG4040 (W84)
(W14; W24)
NS3 specific ELISpot IFN-γ responses: 46% of patients
Overall, 71% of patients had TG4040 specific T-cell responses
Wedemeyer H et al. EASL 2013
●●●●●●●●● 18Induction of Anti-MVA Humoral Immune Responses
Neutralizing anti-MVA antibodies
Mean FoldChange from Baseline (D1)
Control Arm
PegIFN/RBV lead-in Arm
TG4040 Pre-Treatment Arm
W12
W14
W24
W8
W9
W2
D1
All TG4040 treated patients developed detectable anti-MVA humoral responses
No significant correlation between neither total nor neutralizing antibodies and
virological response (cEVR and/or SVR24)
Wedemeyer H et al. EASL 2013 ●●●●●●●●● 19Safety
Cut-off: 24 weeks of PegIFN/riba. in each arm Control (n=31) SOC Lead-In (n=63) TG4040 Lead-In (n=59)
Any adverse events n (%) 27 (87.1%) 58 (92.1%) 57 (96.6%)
Adverse events related to PegIFN & ribavirin 25 (80.6%) 56 (88.9%) 51 (86.4%)
Adverse events related to TG4040 NA 21 (33.3%) 35 (59.3%)
Most common adverse events (more than 15%)
(*; significant difference; p ≤ 0,05)
Fatigue 18 (58.1%) 33 (52.4%) 30 (50.8%)
Pyrexia 6 (19.4%) 15 (23.8%) 21 (35.6%)
Injection site erythema* 1 (3.2%) * 11 (17.5%) 18 (30.5%) *
Influenza like illness 8 (25.8%) 11 (17.5%) 8 (13.6%)
Injection site induration 0 4 (6.3%) 9 (15.3%)
Injection site pruritus 0 4 (6.3%) 9 (15.3%)
Neutropenia 9 (29%) 18 (28.6%) 15 (25.4%)
Anaemia 8 (25.8%) 8 (12.7%) 16 (27.1%)
Leukopenia 5 (16.1%) 4 (6.3%) 7 (11.9%)
Headache 7 (22.6%) 13 (20.6%) 17 (28.8%)
Insomnia 7 (22.6%) 8 (12.7%) 5 (8.5%)
Pruritus 6 (19.4%) 9 (14.3%) 9 (15.3%)
Alopecia 2 (6.5%) 4 (6.3%) 12 (20.3%)
Nausea 5 (16.1%) 5 (7.9%) 7 (11.9%)
Decreased appetite 5 (16.1%) 5 (7.9%) 12 (20.3%)
Myalgia 4 (12.9%) 12 (19%) 9 (15.3%)
Grade 3/4 adverse events 7 (22.6%) 15 (23.8%) 13 (23.7%)
●●●●●●●●● 20Safety
As of today, 19 SAEs reported in 13 patients, none related to TG4040 alone
Control SOC Lead-In TG4040 Lead-In Total
Total SAEs (events) 4 11 4 19
Related to PegIFN/ribavirin only 2 5 0 7
Related to TG4040 only 0 0 0 0
Related to TG4040 & PegIFN/ribavirin - 2 3 5
SAEs unrelated to treatments 2 4 1 7
SAEs related to PegIFN/ribavirin & TG4040 in 4 patients
Three patients with severe peripheral thrombocytopenia (2 in SOC lead-in arm, 1 in vaccine lead-in
arm) and one patient with aplastic anemia in vaccine lead-in arm
Recovery of blood parameters in 1 to 4 months, one recent case ongoing
Common feature between the 3 patients with thrombocytopenia: HLA-DRB1*04 allele (statistical
association p=0.001)
Wedemeyer H et al. EASL 2013
●●●●●●●●● 21Summary and Conclusions
Pre-treatment with immunotherapeutic TG4040 followed by
PegIFNα2a/RBV significantly increased cEVR as compared to
PegIFNα2a/RBV alone, in treatment-naive patients with genotype 1
HCV: 64% compared to 30%
In pre-treatment arm, higher SVR24 rate as compared to the
control arm: 58% vs 48%
And lower relapse rate: 12% vs 19%
TG4040 alone was generally well tolerated.
However, TG4040 treatment may be associated with exacerbation
of IFNa-related immune side effects in distinct HLA-backgrounds
●●●●●●●●● 22Summary and Conclusions
TG4040 induced HCV-specific T cell responses:
46% NS3-specific ELISpot IFN-gamma responses, 71% overall
T cell and/or B cell responses against MVA were induced in all
patients
In Conclusion:
This study in chronic hepatitis C illustrates the potential value of
viral vector-based immunotherapy for the treatment of chronic
infections including viral hepatitis which warrants further evaluation
●●●●●●●●● 23Acknowledgements
The patients and their families
The HCVac investigators and their study staff
Poland Romania Israel
•Robert Flisiak, Bialystok •Mircea Calistru, Bucharest •Yaacov Baruch, Haifa
•Mazur Wlodzimierz, Chorzów •Adrian Goldis, Timisoara •Alexander Fich, Soroka
•Maciej Jablkowski, Lodz •Ioan Sporea, Timisoara •Ran Tur Kaspa, Petah Tikva
•Ewa Janczewska-Kazek, Czeladz •Carol Stanciu, Iasi •Yoav Lurie, Tel Aviv
Spain •Coman Tanasescu, Bucharest USA
•Vicente Carreno, Madrid France •Adrian Di Bisceglie, Saint Louis
•Moises Diago, Valencia •Thomas Baumert •Eugene Schiff, Miami
•Manuel Romero Gomez, Sevilla •Cyrille Feray, Nantes
•Ricardo Sola, Barcelona •Véronique Grando, Créteil Transgene
•Maria Trapero, Madrid Geneviève Inchauspé
•François Habersetzer,
Strasbourg Jean Marc Limacher
Germany
•Frank Lammert, Hamburg •Christian Trepo, Lyon
•Ulrich Spengler, Bonn •Jean-Pierre Vinel, Toulouse
•Heiner Wedemeyer, Hannover •Jean-Pierre Zarsky
•Stefan Zeuzem, Frankfurt •Vicent Leroy
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