Immunotherapies for cancer and infectious diseases

MVA TECHNOLOGY IN THE DEVELOPMENT OF

HIGHLY COMPLEXED TB VACCINE CANDIDATES

Journée infections nosocomiales

15 décembre 2016

Lyon

Aurélie Ray

Infectious Diseases Department, Lyon

- CONFIDENTIAL - 2

Different outcomes of M. tuberculosis infection and underlying

immune mechanisms

Kaufmann and McMichael, Nat Medecine, 2005

- CONFIDENTIAL - 3

TB in the world

In 2015,

- One-third of the world's population has latent TB

- 10.4 million new TB cases

- 1.8 million died from TB (including 0.4 million among people with HIV)

- 580 000 new cases of MDR-TB (including 100 000 cases of rifampicin resistant TB)

- 60% of TB cases worlwide occured in just 6 countries : China, India, Indonesia, Nigeria, Pakistan and South Africa

Global Tuberculosis Report WHO, 2015.

sel16

Diapositive 3

sel16 Il faut citer ta source : "WHO, Global TB report 2016"SeL; 13/12/2016

- CONFIDENTIAL - 4

TB in the world

Global Tuberculosis Report WHO, 2015.

- CONFIDENTIAL - 5

TB current treatments

An estimated 49 million lives were saved through TB diagnosis and treatment between

2000 and 2015.

Drug-sensitive TB

~10 M new cases in 2015

MDR-TB

Multidrug-resistant TB

~580,000 new cases in 2015

• Definition

Mtb strain susceptible to the

first-line drugs

• Treatment: First-line drugs

• Isoniazid

• Rifampicin

• Pyrazinamide

• Ethambutol

• Duration: 6m

• Efficacy: 85%-95%

• Definition

Mtb strain resistant to both

isoniazid and rifampicin

• Treatment: Second-line drugs

• Fluoroquinolones

• Bedaquiline

• ρ-Aminosalicylic acid

• Amikacin/Kanamycin

• Moxifloxacin

• …

• Duration: 24m

• Efficacy: 45%-65%

6- CONFIDENTIAL -

2: Adult vaccines prophylactic and post-exposure

1: Pediatric vaccineprophylactic

INFECTION PHASES AND DISEASE OCCURRENCE

3: Immunotherapeutic (P3) (combination with antibiotics)

3: Therapeutic vaccinesin combination with antibiotics: Increase/acceleration of cure and/or

prevention of rebound or re-infection

Vaccine approaches in the fight against tuberculosis

7- CONFIDENTIAL -

Therapeutic vaccines

• Definition : Manipulation of the immune system in an antigen specific

fashion to treat disease

� enhancement of immunity: cancers, infectious diseases

� attenuation of an immune response: autoimmune diseases

• Aims of therapeutic vaccines targeting chronic infectious diseases :

� Add a mechanism of action poorly used by current therapies (enroll the host’s

immune system to participate in viral/bacterial clearance)

� Mimic major immune features found in resolvers/controllers

� Avoid exacerbation of diseases

- CONFIDENTIAL - 8

Global pipepline of TB vaccine candidates

Vaccine

candidate

Partners Description Current

phase

Attenuated,

Inactivated or

fragmented

mycobacteria

VPM 1002 Serum Institute of India (India) Recombinant BCG Phase Iib/III

MTBVAC Biofabri (Spain) Live attenuated M.TB Phase I/IIb

Vaccae Anhui Zhifei Longcom (China) Heat-inactivated M. vaccae Phase III

RUTI Archivel Farma (Spain) Fragmented M.TB Phase II

Adjuvanted

recombinant

proteins

ID93+GLA-SE Infectious Disease Research

Institute (United States)

Rv3619, Rv3620, Rv1813 and

Rv2608

Phase IIb

H56:IC31 Statens Serum Institut (Denmark), Ag85B, ESAT-6, Rv2660c [H56] Phase II

M72/ASO1E GSK Vaccines (UK° MTB 32A and 39A Phase IIb

H4:IC31 Sanofi Pasteur (France) Ag85B and TB10.4 Phase II

Viral vectors

based vaccine

Ad5 Ag85A McMaster University (Canada) human ad5 - Ag85A Phase II

ChAdOx1-85A/

MVA85A

University of Oxford (UK) Chimp adenovirus/MVA

heterologous prime–boost

expressing M. TB Ag85A

Phase I

MVA85A/

MVA85A

University of Oxford (UK) MVA intradermal followed by

aerosol; prime–boost vaccine

Phase I

- CONFIDENTIAL - 9

TB vaccine candidates positioned as post-exposure vaccine

Vaccine

candidate

Partners Description Current

phase

Attenuated,

Inactivated or

fragmented

mycobacteria

VPM 1002 Serum Institute of India (India) Recombinant BCG Phase Iib/III

MTBVAC Biofabri (Spain) Live attenuated M.TB Phase I/IIb

Vaccae Anhui Zhifei Longcom (China) Heat-inactivated M. vaccae Phase III

RUTI Archivel Farma (Spain) Fragmented M.TB Phase II

Adjuvanted

recombinant

proteins

ID93+GLA-SE Infectious Disease Research

Institute (United States)

Rv3619, Rv3620, Rv1813 and

Rv2608

Phase IIb

H56:IC31 Statens Serum Institut (Denmark), Ag85B, ESAT-6, Rv2660c [H56] Phase II

M72/ASO1E GSK Vaccines (UK° MTB 32A and 39A Phase IIb

H4:IC31 Sanofi Pasteur (France) Ag85B and TB10.4 Phase II

Viral vectors

based vaccine

Ad5 Ag85A McMaster University (Canada) human ad5 - Ag85A Phase II

ChAdOx1-85A/

MVA85A

University of Oxford (UK) Chimp adenovirus/MVA

heterologous prime–boost

expressing M. TB Ag85A

Phase I

MVA85A/

MVA85A

University of Oxford (UK) MVA intradermal followed by

aerosol; prime–boost vaccine

Phase I

10- CONFIDENTIAL -

ActiveActive

LatentLatent

Resuscitation

High plasticity of the MVA has allowed to generate highly complexed candidates

MVA / ACT-LAT-RES

Modified Vaccinia

Ankara virus

(MVA)- Very high safety

profile (150 000

vaccinations

agains small pox)

- High inducer of

innate immune

response

- In clin.trials

malaria, HIV, ..

Multi-phase

antigens covering

all phases of

infection (active,

resuscitation,

latent)

Phases of infection

17 Mtb antigens

evaluated

TB-therapeutic vaccine developed at Transgene

11- CONFIDENTIAL -

MVA-TB lead candidates

� Six genetically stable MVA-TB candidates with at least 5 antigens belonging to the 3 phases of

disease generated.

� All shown to be immunogenic in naïve mouse strains

Vaccines Antigens # cassettes # Ag

MVATG18639 Rv2626/Ag85B - CFP10/ESAT6 - TB10.4/Rv0287 - RpfB/D – Rv3407/Rv1813 5 10

MVATG18598 Rv2626/2A/Ag85B - CFP10/ESAT6 - TB10.4/Rv0287 - RpfB/D – Rv3407/2A/Rv1813 5 10

MVATG18633 Ag85B - ESAT6 - RpfB/D - Rv2626 - Rv1813 5 6

MVATG18690 RpfB/D/Ag85B/TB10.4/ESAT6 - Rv2626/Rv3407 2 7

MVATG18692 RpfB/D/Ag85B/TB10.4/ESAT6 - Rv3478/2A/Rv1733 2 7

MVATG18827 SS-Rv2029/TB10.4/ESAT6/Rv0111 - SS-RpfB/D 2 6

Active – Resuscitation – Latent

Heterodimeric partners

SS: signal sequence

2A: auto-cleavage peptide

RpfB-D= fusion of RpfB (30-284) and RpfD (54-154)

12- CONFIDENTIAL -

�Model typically used to evaluate efficacy of novel antimicrobials (antibiotics)

� Endpoints : 1. Primary: Reduction of bacterial load in relapsing animals;

2. Secondary: Prevention of Relapse/ Reactivation of Mtb infection;

Vaccine candidates move to therapeutic efficacy testing in TB Post-exposure

mouse model (E Nuermberger, JHU)

2

4

6

8

CF

U p

er

lun

g(l

og

10)

Time

Control group Sub-optimal

antibiotic

regimen

Mtb

(H37Rv)

Novel treatment

modality

Bacterial load

Relapse/Reactivation

A typical experiment will last 7-8 months

13- CONFIDENTIAL -

Kruskal-Wallis: p=0.011

Mann-Whitney test:

• §: p<0.05; §§: p<0.01 as comp. with RHZ group

• *: p<0.05; **: p<0.01

Bacterial load Protection[CFU log10 – Mean CFU log10 (RHZ)]

Testing of the 6 MVA-vaccines: measure of primary end-point ie bacterial load in

Relapser mice (Lung CFU counts)

� 3:6 MVA display significant efficacy

� Highest efficacy with MVATG18633 (1.5 log mean

CFU reduction, p=0.004)

CF

U (

log 1

0)(m

ean

±S

EM

)

0

1

2

3

4

5

LLoD

+ RHZ

p=0.061 **§ § §§

** p=0.061

Pro

tect

ion

(∆∆ ∆∆lo

g 10)

(mea

n±

SE

M)

0.0

0.5

1.0

1.5

2.0

+ RHZ

p=0.061 **

§

§ §§** p=0.061

14- CONFIDENTIAL -

Other lead players Vaccines Preclinical models

Main results

Relapse (%)

Vaccine vs. Control

CFU (log10)

Vaccine vs. Control

Serum Statens Institut

(SSI)

H56 / CAF01

(3 Ags)

(Aagaard, Nat Med, 2011)

• Bacterial load post-

antibiotherapy arrest

100% vs 100%

(5/73 vaccinated mice

did not relapse)

1.5-3 vs 2-4

(p<0.05)

Protection: ~1 log10

Vakzine Projekt Management

(VPM)

VPM1002

(Modified BCG)

(Gengenbacher, Microb

Infect, 2016 )

• Bacterial load post-

antibiotherapy arrest

100% vs 100% 4.4 vs 5.5

(p<0.05)

Protection: ~1 log10

Infectious Disease Research

Institute

(IDRI)

ID93-GLA-SE

(4 Ags)

(Coler, JID, 2013)

• Bacterial load post-

antibiotherapy arrest

• Survival

100% vs 100%

+ Vaccination

improved survival

4.3 vs 5.0

(p<0.05)

Protection: ~0.5 log10

Examples of therapeutic efficacy with adjuvanted recombinant protein

and live-based vaccines

H56 VPM1002 ID93

- CONFIDENTIAL - 15

Ongoing efficacy study to test Transgene candidates

● TB post-exposure mouse model, comparison head to head with partner’s candidates.

● TBVAC2020 consortium program

● Mouse model of latent infection

● Supported by Aeras

● Prophylactic heterologous prime-boost in non-human primates including a multi-antigen

MVA-TB vaccine

● Collaboration with GSK

● Supported by Aeras

- CONFIDENTIAL - 16

Host Directed Therapies (HDT): other Immune Players to improve TB

treatment

Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging

due to :

� the virulence of the etiologic strains

� the aberrant host immune responses

� the diminishing treatment options with TB drugs.

To improve the clinical management outcomes, new treatment regimens is

needed that incorporate therapeutics targeting of both :

� M. tuberculosis : therapeutic vaccine

� Host factors : Host directed therapy

In TB, HDTs may neutralize excessive inflammation in organs and decrease M. tb

proliferation while facilitating tissue repair.

17- CONFIDENTIAL -

Host Directed Therapies (HDT): other Immune Players to improve TB

treatment

Lancet, Volume 16, Issue 4, 2016, e47–e63

Host-targeted therapies focus on ameliorating the severity of disease

and improving treatment outcomes

- CONFIDENTIAL - 18

CD4+

T cells

Host directed therapy (HDT) in TB

1 Augmenting cellular anti-microbial mechanisms :

- Promote phagolysosome fusion (Metformin) and

phagosome maturation (Imatinib)

- Induce antimicrobial peptides (Vit D, HDAC inhibitors)

- Induce autophagy (Gefitinib, VitD, mTOR inhibitors)

Inflammatory

pathways activation

2 Reducing inflammation and

preventing lung damage :

- Corticosteroids

- TNF blocker

- Statins

- COX and leukotriene inhibitors

- MMP inhibitors

Adapted from Wallis and Hafner, 2015

- CONFIDENTIAL - 19

Host directed therapy (HDT) in TB

1. Augmenting cellular anti-microbial

mechanisms

Inflammatory

pathways activation

2. Reducing

inflammation and

preventing lung

damage

TB patient

Intranasal administration of

the HDT-MVA

Migration to the lung

Lung epithelial cells

HDT-MVA

Adapted from Wallis and Hafner, 2015

3. Modulating anti-M-tuberculosis protective innate and adaptative

Administration of specific immune mediators (cytokines, chemokines)

• can enhance survival of mice after Mtb infection and decrease bacterial

load

• Induce antimicrobial peptides

• decrease lung pathology

NK

NK cell homeostasis, B

cell immunoglobulin

class switch

DC

Increase CPA

function of DC

Development, proliferation and

activation of NK cells, mature

and memory T cells.

CD8+

T cells

- CONFIDENTIAL - 20

Positioning of MVA-HDT in the treatment of tuberculosis

Active TB

Pre-exposure vaccine

- BCG, M72, MTBVAC, H4

Therapeutic treatment

- Antibiotics

- Therapeutic vaccine

(M. Vaccae, MVA-TB)

Post-exposure vaccine

- M72, H56, ID93

Weakness

- Resistance (MDR, XDR)

- duration

- relapse

- Lung damage

HDT

- Enhance the quality of

the memory response

and prevent risk of

reinfection

- Enhance efficacy of

existing therapy

- Prevent tissue damages

Weakness

- Poor efficacy of BCG

- Selected on their

ability to induce a

CD4 Th1 response.

Weakness

- Selected on their

ability to induce a CD4

Th1 response

Adapted from Kaufmann et al, 2015

21- CONFIDENTIAL -

MVA technology, a comprehensive toolbox

● In the last century vaccination has dramatically reduced death and morbidity caused by

infectious diseases (smallpox, polio, rabies, diphtheria, tetanus, HAV, HBV mumps,

measles …)

● There is still major unmet medical needs HIV, malaria, TB, cancer

● MVA is an interesting technology to develop the next generation of vaccine

● Safe with a high plasticity that allow large transgene

● Strong inducer of innate immunity

● Mimic a live infection by expressing antigen in situ after immunization, thereby

facilitating the induction of a strong T-cell responses

● MVA technology can be adapted to different pathologies

● To induce an immunity specific of a pathogen

● To target host factor and improve the clinical management outcomes

22- CONFIDENTIAL -

Acknowledgements

TRANSGENE

Lyon, France

• Marie Gouanvic

• Charles-Antoine Coupet

• Aurélie Ray

• Clément Levin

• Audrey Glaize

• Cécile Bény

• Emmanuel Tupin

• Stéphane Leung-Theung-Long

• Geneviève Inchauspé

• Romain Micol

• Valentina Ivanova-Segura

• Ludovic Dendane

Strasbourg, France

• Martine Marigliano

• Jean-Baptiste Marchand

• Nathalie Silvestre

• Thierry Menguy

• Joan Foloppe

• Doris Schmitt

• Chantal Hoffmann

• Murielle Klein

• Véronique Koerper

• Sophie Steinbach

• Fabrice Le Pogam

• Patricia Kleinpeter

• Dominique Villeval

• Sophie Jallat

• Annick Hoh

NIH support through grant awarded to

Emergent BioSolutions/Transgene

subcontractor

• Eric Nuermberger

• Paul Converse

• Sandeep Tyagi

• Tom Evans

• Barry Walker

• Nathalie Cadieux