transgeneL’immunothérapie appliquée

au traitement des cancers

et des maladies infectieuses

Immunotherapy to fight cancer

and infectious diseases

G Inchauspé

Christophe Mérieux Conference, New Trends in tumor Virology, Jan. 2010

WHAT IS NEW WITH HCV VACCINES ?

transgene

Five major cancers(worldwide): liver fith

Lung(1.239.000)

Breast(1.050.000)

Colo-rectum(943.000)

Stomach(875.000)

Liver(566.000)

[Parkin et al., Int J Cancer 2001]

VHB(53%)

VHC(25%)

Autres(22%)

Current medical need

HBV + HCV = 75% ofAll liver cancers

transgene

Spontaneous

Clearance(1% ??)

Primary

Infection

Spontaneous

Clearance(15-30%)

Chronic Carrier

State(70-85%)

Chronic Liver

Inflammation

Fibrosis, Cirrhosis,

Hepatocellular Carcinoma(5- 70%) Healthy Carriers

(30 %) +/- Antiviral TherapiesAcute phase (< 6 months)

Chronic phase (>6 months)

HCV vaccine options

Preventive Therapeutic

Before disease During disease

transgene Name of the speaker Page 4

HCV: Current and Evolution of Standard of Care (SOC)

2011

New SOC(tri-therapy with

antiprotease):

45% cure

70 % cure(clin. trials…real

life ?? )

2009

Pipeline HCV New therapeutic

agents:

> 70 molecules!

2016

New SOCBi or tri-

therapy,

small molecules

only, no more

IFN-a:

≥ 70 %

cure

Therapeutic

vaccines

Very active competition

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Therapeutic vaccines provides a mechanism of action different

than those already exploited by Standard-of-Care (SOC)/ small

molecules

• small molecules = direct effect on virus (or key cell proteins)

effect on viral replication

• therapeutic vaccines = effect on host immune system

effect on infected cells

Therapeutic vaccines versus SOC/antivirals: what

is different

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HCV-specific CD8+ T cell responses (IIFN- g) associated

with clearance

Weeks after infection

HCV

2 4 6 8 10 12 14 16 18

Active

replication

T cell

induction

6-8 weeks

1

10

100Sustained Adaptive

responses

HCV%tet.+

CD8+ T cells

1

10

100

0.4

0.8

Weeks after infection2 4 6 8 10 12 14 16 18 20

% IFNg+/CD8HCV-RNA

Weeks after infection

1

10

100

200

300

100

0

CHIMPANZEE

INFECTIONHUMAN INFECTION

0 8 16 24 32 40

Thimme, R. et al, J Exp Med 2001 Shoukry, N. et al, J Exp Med 2003

NS3 is a key

target

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Goal = priming of multifunctional effector T cells immune responses

in the « already infected host »

• Infected host = impaired immune responses (B and T),

exhaustion, escape, immature, T-regs, ….

• Would therapeutic vaccines:

• be capable directly overcome some of these limitations e.g.

effective priming of novel T cells ? « stand alone vaccination »

early clinical proof-of-concept• Would therapeutic vaccines be most effective as « add-on » therapies ?

ongoing (initiation of clinical trials)

Why HCV (HBV) therapeutic vaccines could work

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CD8+ priming: the «importance of the « where »

An advantage for therapeutic vaccines for HCV/HBV infections ?

The site of viral infection and of antigenic expression plays a

critical role in the quality of induced T cell responses (Bowen et

al., 2004):

In transgenic mice expressing transgenes both in the liver and

periphery:

• Naïve CD8+ T cells activated within liver exhibit defective cytotoxic

function and shortened half-life

•Naïve CD8+ T cells activated within lymph nodes are fully activated

and capable of lytic activity

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The different ways leading to HCV-specific CD8+ CTL

priming according to the site of viral entry (Racanelli 2007)

PREFERED SITE OF

EXPRESSION

FOLLOWING VACCINE

ADMINISTRATION

Activation of T cells in

lymph nodes = effective

LIVER = PREFERED INFECTION AND EXPRESSION SITE

Activation of T cells in the liver = impaired

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HCV therapeutic vaccines: first and second generation

Company Vaccine

Innogenetics INNO10101 (E1) HCV +

Intercell IC41-102 (5 HCV peptides) HCV +

GlobeImmune GI-5005 (Yeast - NS3/Core) HCV +

Novartis/CSL ISCOMATRIX (Core) HCV -

Novartis HCV-MF59 (E1E2) HCV -/+

Kurume Univ. ND (4 peptides) HCV +

Tripep/Inovio ChronVac-C® (NS3) HCV +

Transgene TG4040 (MVA-NS345B) HCV+

Okairos Adenos (NS3-NS5) HCV-

Target populations Preclinical Phase I Phase II Phase III

Safety + Lack of

efficacy. Stopped

Safety + lack of

efficacy

Safety + efficacy ?

Safety

Safety

Safety + efficacy ?

Safety + early efficacy

Safety + early efficacy

Safety

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Poxvirus (MVA)-based therapeutic vaccine TG4040.01

(NS3-NS4-NS5B) – Transgene

8 12 16 20 40 44 4828 32 360

TG4040 TG4040 (cohort 3)

weeks4 24

Viral load

Immunology

Collected samples for:

Transcriptomic■

PHASE I Multicenter (France) Safety Study in treatment naïve pts

(genotype 1; 0< F< 2), dose escalating; Preliminary efficacy

Cohort 1: 3 injections of 106 pfu at D1, D8 and D15 in 3 patients

Cohort 2: 3 injections of 107 pfu at D1, D8 and D15 in 3 patients

Cohort 3: 3 injections of 108 pfu at D1, D8 and D15 in 9 patients + 1 boost injection

at M6

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Interim Clinical results

TG4040 is safe at all dose levels:

- most common AEs related to TG4040 = injection site reactions

7 subjects experienced a viral load reduction ranging from 0.5 to 1.24 log10:

- 3/3 patients from cohort 1 (106 pfu/dose)

- 3/3 patients from cohort 2 (107 pfu/dose)

- 1/9 patients from cohort 3 (108 pfu/dose)

-1.5

-1.0

-0.5

0

0.5

1

Ch

an

ge in

HC

V R

NA

(lo

g10 IU

/ml)

D22 D37 M2 M3Mean +/- SD

D1 D8 D15

TG4040 injections

transgene

Delta-S

po

ts (Sp

ecific –b

kgd

spo

ts)

NS4B NS5/1 NS5/2NS3/1 NS3/2 VL

ELISPOT analysis versus viral load changes (Cohort

1: 106 pfu)

tested only for VL

Vir

al lo

ad F

old

ch

ang

e/b

asel

ine

(lo

g10

)

-2 0

Pt 02

-1

-0,5

0

0,5

1

0

100

200

250

28

BL

D22

M6

D37

0-1

-0,5

0

0,5

1

100

200

250

28ND

Pt 01

BL D22

M6D37

M2n

eg

neg

neg

Pt 031

-1,5

-1

-0,5

0

0,5BL

D22 M6

2850

100

150

200

250

ND ND

transgene NS4B NS5/1 NS5/2NS3/1 NS3/2 VL

-1

-0,5

0

0,5

1

0

100

200

250

BL

M6

D37D22

Pt 05

28

BL

D8D22

D37M2

M6

-1

-0,5

0

0,5

1

0

100

200

Pt 08

Vir

al lo

ad F

old

ch

ang

e/b

asel

ine

(lo

g10

)D

elta-Sp

ots (S

pecific –

bkg

d sp

ots)

28

-1

-0,5

0

0,5

1

100

200

300

28

Pt 04

BL

M6D37

0ND ND

neg

ELISPOT analysis versus viral load changes (Cohort

2: 107 pfu)

tested only for VL

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LUMINEX analysis: Pt 03, “responder”

Cohort 1: 106 pfu

1

-1,5

-1

-0,5

0

0,5BL

D22

M6

50

100

150

200

250

ND ND

Limited Th1/proinflammatory panel of cytokine at M-1,

D22: extension of Th1/proinflammatory panel mostly in response to TG4040-derived

antigens

M6: widening of D22-cytokine panel, emergence of Th2 cytokines (IL-5/IL-13/IL-4)

IL-1

5

IL-1

a

IFN

g

GM

-CS

F

IL-1

b

sC

D40L

IP10

IL-2

M-1

D22

M6

IL-5

IL-1

3

IL-4

IL-1

7

NS3/1 NS3/2 NS4b

NS5/1 NS5/2

Elispot/VL

LuminexPeptide pools for restim.:

transgene

MC

P-1

Fra

cta

lkin

e

IL-1

0

EG

F

IP10

VE

GF

M-1

D1

D22

IL-5

IL-1

2 p

40

IL-2

D37

M2

M6 D8

M6 D22

D8

Limited Th2/anti-inflammatory panel of cytokine at M-1& D1,

Very limited panel of soluble factors at each time point during follow-up

-1,0

-0,5

0

0,5

1,0

BL

D22 M6

M9 M12

LUMINEX Analysis: Pt 17, “non responder” Cohort 3:

108 pfu

NS3/1 NS3/2 NS4b

NS5/1 NS5/2

Elispot/VL

LuminexPeptide pools for restim.:

transgene

Anti- MVA antibodies (preliminary results)

Total anti-MVA Abs

Time

Cohort 1

0

40,000

80,000

120,000

M-1 D22 M2 M6

Cohort 2

M-1 D22 M2 M6

Cohort 3

M-1 D22 M2 M6 M12

Neutralizing anti-MVA Abs

0200400600

80010001200

Tite

r

M-1 D22 M2 M6 M-1 D22 M2 M6 M-1 D22 M2 M6 M12

140,000

Cut-off

2,700

Cut-off

300

Measure of anti-MVA antibodies following TG4040 vaccination at the three different injected doses (3 cohorts)

Neutralizing Abs detected only with highest dose of vaccine

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Conclusion

The preliminary results show that TG4040 is:

1. Well tolerated at all dose levels:

The most commonly AEs are injection site reactions.

2. Immunogenic:

Detection of TG4040-specific IFN-g production in 7/15 treatment

naïve patients

Strongest TG4040-induced immune responses in 2/7 treatment

naïve patients with highest viral load decrease

Moreover, 7 subjects experienced a viral load reduction ranging from 0.5

to 1.24 log10 concordant to TG4040 injections.

Phase II in preparation: TG4040 combined with SOC (Q12010). Further

development with antivirals is planned.

transgeneMatti Sällberg, cot 09 19

ChronVac-C, a DNA vaccine delivered by in vivo

electroporation or the treatment of chronic HCV infection

Phase I/II : Karolinska Institute/Tripep AB/Inovio Biomedical- NS3NS4A

Inclusion criteria: HCV genotype 1, treatment naive, low viral load (<800,000 IU/mL)

Study aims: safety, activation of HCV-specific immune responses, effects on viral load

Site: Karolinska University Hospital, Stockholm (PI: Prof Ola Weiland, MD, PhD)

Blood samples and clinical follow up

Dose No. of patients M/F Age HCV RNA (log10)

167µg 3 1/2 43±13 3,4±3,1

500µg 3 2/1 43±7 5,8±0,1

1500µg 3(+3) 3 41±5 5,42±1

Screening

Vaccinations with DNA and in vivo EP

1 m 2 m 3 m 4 m 5 m 6 m 7 m 8 m 9 m

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Relation between T cell responses and HCV RNA

levels

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HCV Therapeutic vaccines: conclusion

Whether B or T cell inducers, they all show a good safety

profileNo exhacerbation of liver inflamation

A few have shown capacity to induce T-cells in face of

ongoing viral replication

For a couple (MVA/ DNA), have shown capacity to induce

specific T-cells concomittent with viral decrease

But vaccine responses are not long lastingAdditional booster vaccinations needed ?

Viral replication too rapid/ VL yet too high ?• Future combination with antivirals

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Optimization of therapeutic vaccination

C Ferrari Gastroenterology 08

Recovery of HCV T-cell responsivness by inducing decline opf antigen load ?

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ARM C

4 8 12 16 20 24 40 44 48 52 56 60 64 68 7228 32 360

SOC

TG4040 107

PRIMARY ENDPOINT

cEVR (undetectability)

N=49

ARM C

4 8 12 16 20 24 40 44 48 52 56 60 64 68 7228 32 360

SOC

N=49

ARM A

4 8 12 16 20 24 40 44 48 52 56 60 64 68 7228 32 360

SOC

N=25

TG4040 107

If viral load is detectable:

stop treatment

TG4040 in combination with SOC:

Design of the Phase II

Three arms study:

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Acknowledgement

TG. Infectious Diseases Department

Emilie Jacquier

Perrine Martin

Estelle Gérossier

Alexeï Evlachev

Anne Fournillier

Geneviève Inchauspé

TG. Molecular Immunology Department

JM Balloul/Joerg Schneider

Nathalie Silvestre

Doris Schmitt

Renée Brandely

Michel Julien/ JP Lemarchand

Karola Rittner

TG TG4040 Product Team

Delphine Agathon

Christine Bain

Bernard Burtin

Patricia Zerr

Geraldine Honnet

Sophie Jallat

Sandrine Lemius

Clémentine Spring-Giusti

Arend Winter

Lyon Biopôle

Ministary of French

Industry

CliniciansC. Trépo, Lyon

JP. Zarski, Grenoble

F. Habersetzer, Strasbourg

Tripep

M Salbërg