Download What is new regarding the immunotherapy of TB Keertan Dheda

What is new regarding the
immunotherapy of TB
Keertan Dheda, MB.BCh, FCP(SA), FCCP, FRCP (UK), PhD (Lond)
Associate Professor and Head:
Lung Infection and Immunity Unit
Division of Pulmonology & UCT Lung Institute,
Department of Medicine, University of Cape Town, South Africa
email: [email protected]
Conflict of interest: none
Overview
Why bother about immunotherapy?
Brief overview of TB immunology
Rationale for immunotherapy
Immunothreapeutic agents under study
Summary
Comprehensive reviews
on this subject
Churchyard CJ, Clinics in Chest Medicine,
2009
WHO. Report of the expert consultation on
immunotherapeutic interventions for TB. 2007
Dheda K, Respirology, 2010
Why bother about immunotherapy?
Shorten standard 6 month anti-TB treatment
In those cured from TB to prevent relapse or
re-infection
Treatment for XDR and TDR-TB
M and XDR-TB: What is the size of the
problem globally?
Worldwide 440 000 cases of MDR-TB in 2008
(3·6% of the total incident TB episodes)
(360 000 new cases)
Only 7% reported and 1-2% actually treated to
WHO standards
XDR-TB: globally~ 25000 XDR-TB cases annually
Size of the problem in SA
2004: 3278 MDR cases
2005: 4305 MDR cases
2006: 6716 MDR cases
2007: 7369 MDR cases
(16000 to 18000 estimated cases for 2007/8)
About 5 to 10% thought to be XDR-TB
1.
2.
3.
Anti-Tuberculosis Drug Resistance in the World Report 2008:Fourth
Global Report, WHO, 2008
South African National Department of Health Report, 2008
WHO. Global TB Control. A short update to the 2009 report.
Why is XDR-TB a threat?
Mortality rates are substantially higher (annual mortality
in patients with XDR TB approaches 40%)
Dheda K, Lancet, 2010
O’Donnell M, IJTLD, 2010
Gandhi N, Lancet, 2006
Drastically increases the costs of running a TB program
(despite annually treating 500 000 cases of drugsusceptible TB and < 10 000 MDR/XDR-TB, the latter
eats up > 50% of the annual TB drug budget).
Cost of treating TB with different DST patterns:
MDR-TB= 110 to 180 fold more expensive
XDR-TB= ~400x more expensive
Can destabilize well or modestly functioning National TB Programs
(NTPs).
Initial optimism of encouraging outcomes in XDR-TB
Mitnick C, NEJM, 2008; Keshavjee S, Lancet, 2008; Sotgiu G, ERJ, 2009
replaced disappointing data
Review of 199 patients with XDR-TB
Dheda K, Shean K, Warren R, Willcox P; Lancet; 2010
Become apparent that outcomes in high burden settings like
South Africa are poorer than in intermediate to low burden
settings
Gandhi N, Lancet, 2006
O’Donnell M, IJTLD, 2009
Kaplan-Meier probabilities of XDR-TB culture-conversion (n= 174)
The overall culture-conversion rate was
19% (33/174)
Sondalo (1938)- 3500 beds
St Helliere
Surgical techniques promoting partial or complete lung
collapse were also used.
With the advent of effective anti-TB therapy, the need for
sanatoria dwindled.
What is happening to these many culture
non-converters?
Given the poor conversion rates, there are large
numbers of treatment failures (defined as failure to cultureconvert after twelve months of intensive in-patient XDR treatment with
regimens including an injectable drug like capreomycin).
While some patients die within weeks or months, a
significant proportion of patients do survive for months
or years.
How should these living treatment failures be dealt with?
These are therapeutically destitute cases!!
The life cycle and immunolgy of TB
Alveolar
pneumocytes
Innate immunity
No detectable T cell priming (IGRA neg., TST neg.)
NK-cells
Neutrophils
Clearance of
Infection
1.Close contacts
inhale M.tb
NK-T cells
Macrophages
βdefensin
γδ T-cells
2. ~50% or more of exposed
persons have no immuno
diagnostic evidence of M.tb
sensitisation and may
remain uninfected through
sterilizing immunity#
Cathelicidin
Adaptive immunity
Evidence of T cell priming (IGRA pos., TST pos.)$
Cytokines
Th1,Th2 &
Th17
CD4+ T cells
T cell
CD4+ T cells
Macrophage
CD4Naive
T cell
CD1
lipid
TLR2
TLR4
TLR9
3. The remainder of exposed persons have
conversion of TST or IGRA and a
proportion have presumed infection**
MHC-II
M.tb
Treg
MHC-I
CD8
Naive
T cell
CD8+ T cells
6. Reversion of TST or
IGRA (Acute or chronic
resolving infection)
7. Reinfection
Schwander and Dheda, AJRCCM, 2011
In ~ 95 %
containment
~5%
~ 2 to 5 %
4. LTBI**
5. Clinically detectable
active or subclinical
disease
NK
cell
M. tuberculosis
IFN -γ
TLR-2/4/9
MMR
TLR
DC-SIGN
T cell
NOD2
MyD88
CR3
MHC/
CD1
γδ T
cell
25D3
1, 25D3
NF-κB
IL-1β; IL-18/12/23;
Autophagy
1,25D3/VDR
TNF-α; Il-8, Chemokines;
NOS-2/NO
Lysosome
Cathelicidin
Macrophage/DC
PMN
Pathology ?
Other antimicrobial
peptide
Dheda K, Respirology, 2010
Schwander and Dheda, AJRCCM,
2011
Killing CD8
+
Alveolar Space
CTL
Perforin
Granzymes
Granulysin
Activation of
macrophages
Apoptosis
Th17
IL-17
IL-21
IL-22
Th1
IFN- ILγ
4
Cytokines
T
cell
γδ T cell
IL-4
IL-5
IL-13
CD4
CD1
lipid
Phosphoantigen
M.t
b
TLR2
TLR4
TLR9
MHC-II
+
T
cell
MHC-I
Macrophage
IFN-γγ
TNF-α
α
IL-2
GMCSF
Th2
IL-4
IL-5
IL-13
IL-25
Inflammation
CD8
+ T
cell
Tre
g
TGF-β
β
IL-10
TGF-β
β
IL-10
Surfactant Proteins
Antimicrobial peptides
Alveolar Type I and II
Epithelial Cells
Why does TB progress to active disease in some?
Failure of CD4 cells e.g. HIV
Failure of multiple innate mechanisms (macrophages, TLR,
cathelicidin etc)
Failure of other protective mechanisms (apoptosis, lymphocytekilling mechanisms, CD8 T cells)
Suboptimal Th1 response (not enough IFN-g, IL-2 etc)
too much Th2 may subvert Th1 and CD8 T cells
Failure to regulate or inappropriate regulation by Treg
Skewing of the immnune response towards an
inappropriate phenotype
Why does TB progress to active disease in some?
Bacteriostatic immune response and immunopathology in the
lung, cavitation and bacterial multiplication
Poor drug penetration and poor response
Rationale for immunotherapy
More effective treatment may require modulation of
the immune system and a switch away from an
immunopathologic phenotype to a protective one.
Restoring this immunoregulatory balance may take
several months
Immuno-regulatory (turn off Th2, TGF-b but turn on
Th1 and favorable Tregs)
Immuno-suppressive
Immuno-supplementary
An approach to immunotherapy for TB
Immuno-regulatory
(turn
off
components of the immune system)
(i)
•
•
•
•
(ii)
•
•
•
•
and/or
on
certain
For which GMP manufacturing capacity exists
High-dose intravenous immunoglobulin (IVIg)
HE2000 (16a-bromoepiandrosterone)
Multi-dose heat-killed Mycobacterium vaccae
Anti-IL-4
For which GMP
established
DNA vaccine (HSP65)
Dzherelo
SCV-07 SciCLone
RUTI
manufacturing
capacity
can
be
Why does TB progress to active
disease in some?
Immuno-suppressive (increases access to and susceptibility to
drugs)
• Thalidomide analogs (lower TNF-a levels)
• Etanercept (blocks TNF-a)
• Prednisolone (reduces TNF-a levels)
Immuno-supplementary (augment deficient cytokines/
biomarkers)
• rh- IFN-g and rh-IFN-a
• rh-IL-2
• rh-GM-CSF
• IL-12
Immunology of XDR-TB- TH1 and Th17
Immunology of XDR-TB- Treg (n= 48)
High-dose intravenous immunoglobulin (IVIg)
High-dose IVIg (treatment of human inflammatory disorders).
Because anti-TNF-a shown to cause reactivation of TB, highdose IVIg was tested in a mouse model of TB to check its safety.
Rather than activating TB, it was found to exert a marked
therapeutic effect
Roy E, Infect Immun, 2005
Mechanism of action is unknown but may involve pathways
implicating sialic acid residues on IgG
Could be worthwhile to test this material in patients with XDRTB, who fail to respond to conventional drug treatment
Multi-dose M.vaccae
Drives Th1 and CD8+ CTL but down regulates Th2 through
CD4+CD45+Rblow regulatory cells
Zuany-Amorim C, Nat Med 2002
Single dose M. vaccae not effective in clinical trials
Johnson JL, J Infect Dis, 2000
Mwinga A, Lancet 2002
One non-GCP multiple dose study showed improved culture
outcomes
Dlugovitzky D, Respir Med, 2006
Multi-dose M.vaccae
RCT (n= 2000) in Tanzania using 5 injections showed that
M.vaccae protected against acquiring definite TB in those with a
CD4 count> 200.
Von Reyn CF, AIDS, 2010
Multiple dose M.vaccae already used in China to treat MDR-TB.
Luo Y. Zhonghua Jie He He Hu Xi Za Zhi, 2001
Fan M, Chinese Journal of Evidence-Based Medicine, 2007 (metaanalysis)
Dzherelo (Immunoxel; Ekomed)
Dzherelo uses plant extracts & marketed by Ekomed LLC (a
Ukrainian company) as a nonregulated health supplement.
Widely used in the Ukraine, and seem to be safe.
Recent studies describe their use as adjunct immunotherapy
against MDR-TB (small case-controlled studies)
Nikolaeva LG, Cytokine 2008
Nikolaeva LG, Int Immunopharmacol, 2008
Prihoda ND, Int J Biomed Pharmaceut Sci, 2008
‘The claims are striking and cannot be ignored. There is a need
for definitive GCP studies’.
RUTI
RUTI is a liposomal preparation of M.tb cell wall skeleton.
Designed as adjunctive treatment of latent TB infection, and is
intended to accelerate treatment after drugs have killed the bulk
of the M tuberculosis (not intended for MDR-TB)
In a mouse model, RUTI accelerates bacterial clearance when
given late in treatment as an adjunct to conventional
chemotherapy.
Cardona PJ, Vaccine 2005
Cardona PJ. Tuberculosis (Edinb), 2006
Further study results are awaited.
Other immunoregulatory agents
Dheda K, Resprology, 2010
Immunosupressive agents
Dheda K, Resprology, 2010
Supplementing effecter cytokines
Summary
Now come a full circle with untreatable forms of TB
increasing in numbers
The TB drug pipeline will take decades to deliver
Thus immunothreapy needs to be given serious
thought
Urgently need funding committed to carry out large
GCP-standard
studies
that
will
resolve
many
outstanding questions
Acknowledgements
Division of Pulmonology and The Lung Infection and Immunity
Unit – Greg Symons, Caroline Whale, Elize Pietersen, Lititia
Pool, Karen Shean, Samuel Murray, Lwazi Mhlanti, Vonnita
Louw, Malika Davids, Motasim Badri, Paul Willcox
Division of Cardiothoracic Surgery - Luven Moodley, Mark de
Groot
Brooklyn Chest Hospital (Cape Town) - Erma Mostert, Richard
Burzelmann, Pieter Roussouw, Avril Burns
Gordonia Hospital (Northern Cape) - Barbara Mastrapa
UKZN Staff/Collaborators - Nesri Padayachee
University of Stellenbosch - Robin Warren, Thomas Victor, Paul
D. Van Helden
WHO Collaborating Centre for Tuberculosis and Lung Diseases
- Giovanni B. Migliori, Giovanni Sotgiu
Albert Einstein College of Medicine - Max R. O’Donnell
University of Florida- Kevin Fennelley
University of Calgary- Julie Jarand
Funding Agencies:
EUFP7
South African
National Research
Foundation
Discovery
EDCTP
NIH Fogerty
South African
MRC