International Journal of Infectious Diseases 80 (2019) S62–S67Contents lists available at ScienceDirect
International Journal of Infectious Diseases
journal homepage: www.elsevier .com/ locate / i j id
Improving treatment outcomes for MDR-TB — Novel host-directed
therapies and personalised medicine of the future$
Martin Raoa, Giuseppe Ippolitob, Sayoki Mfinangac, Francine Ntoumid,e,
Dorothy Yeboah-Manuf, Cris Vilaplanag, Alimuddin Zumlah, Markus Maeurera,i,*  
a ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
bNational Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy
cNational Institute of Medical Research Muhimbili, Dar es Salaam, Tanzania
dUniversity Marien NGouabi and Fondation Congolaise pour la Recherche Médicale (FCRM), Brazzaville, Congo
e Institute for Tropical Medicine, University of Tübingen, Germany
fDepartment of Bacteriology, Noguchi Memorial Institute for Medical Research, Accra, Ghana
g Experimental Tuberculosis Unit (UTE), Fundació Institut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Catalonia, Spain
hDivision of Infection and Immunity, University College London and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK
iDepartment of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt am Main, Germany
A R T I C L E I N F O A B S T R A C T
Article history: Multidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients
Received 19 December 2018 with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who
Received in revised form 17 January 2019 recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB
Accepted 19 January 2019 treatment regimens are becoming available, conventional drug therapies need to be complemented with
Corresponding Editor: Eskild Petersen, Aar-
hus, Denmark host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. 
This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and
genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for
Keywords:
Multidrug-resistant tuberculosis cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in 
Clinical studies patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct 
Host-directed therapies MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing 
Personalised medicine standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action 
Immunotherapy of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway
Biomarkers (s) in Mtb-driven immunopathology.
© 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction
The 2018 WHO Global Tuberculosis (TB) Report states that in
2017, the treatment success of multidrug-resistant (MDR) TB
using WHO-recommended TB drug regimens cases was a meagre
55% globally (WHO, 2018). With an estimated half a million cases,
MDR-TB remains a serious global health threat. Furthermore,$ World Tuberculosis Day 2019 Series: a viewpoint for the International Journal of
Infectious Diseases World TB Day TB Theme Series.
* Corresponding author at: Champalimaud Centre for the Unknown, Avenida
Brasília, 1400-038 Lisbon, Portugal.
E-mail addresses: martin.rao@research.fchampalimaud.org (M. Rao),
giuseppe.ippolito@inmi.it (G. Ippolito), gsmfinanga@yahoo.com (S. Mfinanga),
ffntoumi@hotmail.com (F. Ntoumi), dyeboah-manu@noguchi.ug.edu.gh
(D. Yeboah-Manu), cvilaplana@gmail.com (C. Vilaplana), a.zumla@ucl.ac.uk
(A. Zumla), markus.maeurer@fundacaochampalimaud.pt (M. Maeurer).
https://doi.org/10.1016/j.ijid.2019.01.039
1201-9712/© 2019 Published by Elsevier Ltd on behalf of International Society for Infect
creativecommons.org/licenses/by-nc-nd/4.0/).most patients who recover from the lengthy and toxic treatment
course of anti-TB drugs develop lung damage and long-term
functional disability due to aberrant host immune responses to
Mycobacterium tuberculosis (Mtb). Data from clinical trials,
retrospective cohort studies and routine follow-up examinations
can allow for studying the immuno-physiological status of
patients with MDR-TB and designing personalised adjunct host-
directed therapies (HDT) based on clinical experience from cancer
treatment options (Tiberi et al., 2018).
Drug-susceptible vs MDR-TB: immunopathological differences
A noteworthy difference between patients with MDR-TB and
those with drug-susceptible TB is the genetic background of the
infecting Mtb strain. Resistance to standard antibiotic therapy
allows for drug-resistant Mtb to linger longer in the host and
induce immunopathological changes which may differ to thatious Diseases. This is an open access article under the CC BY-NC-ND license (http://
M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S63caused by their drug-susceptible counterparts. Li et al. (2017)
showed that patients with primary MDR-TB tend to exhibit a
greater extent of lung cavitation and lower number of calcified
nodules compared to patients with drug-susceptible pulmonary
TB. A more recent review also shed light on thicker cavity walls in
MDR-TB lung lesions further to extensive tissue loss (Wáng et al.,
2018), collectively suggesting intense inflammatory processes
unleashed by MDR-Mtb infection in the lungs. Interestingly,
patients with MDR-TB have also been shown to have slightly
higher T-cell counts and IgM titres in serum compared to patients
with drug-susceptible TB (Sun et al., 2017). Another study showed
that the baseline levels of IL-6 and IL-8 produced by peripheral
blood mononuclear cells (PBMCs) from patients with MDR-TB are
higher than that of PBMCs from patients with drug-susceptible TB
(Skolimowska et al., 2012).
Recent data on cellular immune responses and applicability to
HDT development
T-cell effector functions are recognised as central to anti-TB
immunity. Emerging evidence shows that the ‘understudied’
natural killer (NK) cells may have an important protective role
in preventing active TB disease (Garand et al., 2018; Roy
Chowdhury et al., 2018). Vaccination-induced T-cell populations
expressing certain surface molecules i.e. CXCR3, CCR7, CD45RA
signify specific subsets which can predict desirable clinical
responses (Mpande et al., 2018; Stylianou et al., 2018). Next-
generation sequencing has revealed differential V-J recombination
patterns (at the gene level) among T-cell receptor gamma-delta
(TCR-gd) Vg9Vd2 cells in patients with pulmonary TB (Cheng et al.,
2018). These translational and clinical studies also capture the
different human leukocyte antigen (HLA) backgrounds of patients,
an essential determinant of conventional TCR alpha-beta (TCR-αβ)
CD4+ and CD8+ T-cell responses. For example, previous studies
have shown a correlative link between polymorphisms in HLA class
I/II genes in various populations globally and susceptibility or
resistance to clinical TB (reviewed by Harishankar et al. (2018)).
Collectively, such findings may advance further deconvolution of
immune biomarkers with direct clinical relevance to MDR-TB.
The pro-inflammatory cytokines released early after Mtb
infection include IL-6, IL-1β, IL-12, IFN-g and TNF-α which,
through nitric oxide (NO) production, can also perpetrate DNA
damage (Landskron et al., 2014). Mtb infection of human macro-
phages has been shown to induce nuclear membrane blebbing and
DNA breakage (Castro-Garza et al., 2018). As such, do patient-
specific private mutations (such as the tumour mutational burden
in cancer) also develop in TB granulomas and would they govern
the course of disease in each individual and influence clinical
outcome? Genetic analysis of lung TB granulomas and blood
samples from patients with MDR-TB may further enrich personal-
ised, precision medicine HDT strategies for patients with MDR-TB,
particularly since Mtb mutant target epitopes may prime and
expand T cells which are unfamiliar to their wild type counterparts,
thereby providing a richer source for potentially protective and
non-exhausted cellular immune responses.
Gut and lung microbiomes
The gut and lung microbiomes are inevitably altered in patients
with TB who undergo standard antibiotic therapy (Wipperman
et al., 2017; Hong et al., 2016). Gut bacterial species producing
butyrate and propionate were found to be enriched in patients
with TB in conjunction with impaired vitamin and amino acid
synthesis compared to healthy controls (Maji et al., 2018). The lung
microbiota in patients with pulmonary TB, based on the meta-
analysis of 5 independent studies, also appears distinct comparedto healthy controls, marked by enrichment of Rothia mucilaginosa,
Actinomyces graevenitzii (opportunistic lung pathogens), Tumeba-
cillus, Propionibacterium (propionate-producing) and Haemophilus
spp. in addition to Mtb itself (Hong et al., 2018). However, these
studies were performed with clinical samples from patients with
drug-susceptible TB and not MDR-TB. As an integral part of all
mammals including humans, incorporating microbiome profiling
(gut and lung) in clinical biomarker studies for MDR-TB would,
therefore, be highly valuable.
The types of clinical studies which can contribute to better
understanding the host/and pathogen factors modulating immune
responses and how this knowledge can help develop new HDTs are
represented in Figure 1.
Standardised therapy for MDR-TB
Establishing HDTs as a standardised treatment method would
be extremely challenging as the mainstay of antitubercular
therapy, including MDR-TB, requires the elimination of Mtb from
the host. As such, standard forms of future treatment to manage
clinical TB would rely on new drug regimens designed based on the
patient population, genetics of the infecting Mtb strain(s) as well as
the host (this affects drug metabolism and bioavailability), Mtb
drug susceptibility profile(s) and presence of co-morbidities in the
patient to name a few (Lange et al., 2018; Gröschel et al., 2018). The
combination of these criteria will deliver specific regimens for
designated patient groups in various geographical regions,
embodying a more personalised and targeted approach compared
to classical antibiotic prescribing. Corticosteroids (prednisolone
and dexamethasone) are a class of HDT candidates which are
already given to patients experiencing severe inflammation during
anti-TB treatment. The drugs themselves do not have targeted
effects but rather a general dampening of the host immune
response to extend survival in the short-term (Critchley et al.,
2016). However, emerging evidence from clinical studies involving
patients with MDR-TB may help identify more targeted HDT
strategies which could be standardised for some patient groups i.e.
cytokine neutralisation, metformin therapy.
Small-molecule and soluble HDTs for MDR-TB
Studies to date have shown that several clinically approved
drugs used in non-TB modalities may have therapeutic value in
managing patients with TB. The adjunctive use of metformin, an
anti-diabetic drug which activates the 50 AMP-activated protein
kinase (AMPK), was shown to complement the antitubercular
properties of rifampicin and reduce the pulmonary load of an
MDR-Mtb strain while potentiating Mtb-directed CD8+ T-cell
responses in mice (Singhal et al., 2014). Clinical studies imple-
mented afterwards showed that patients with diabetes mellitus
who were also taking metformin had shorter hospital stays due to a
diagnosis of active pulmonary TB concomitant with a reduced risk
of relapse and lower rates of mortality (Marupuru et al., 2017;
Degner et al., 2018; Lee et al., 2018a). Metformin may also help
enhance control of the high mycobacterial burden in patients with
cavitary pulmonary TB, based on improved sputum culture
conversion rates and reduce the culture conversion time in
patients with MDR/XDR-TB in the first 2 months following therapy
initiation (Lee et al., 2018b). However, further randomised clinical
trials are necessary to determine whether metformin therapy is
able to extend the lifespan of patients with MDR/XDR-TB while
subduing tissue pathology as previously shown in the first
preclinical study (Singhal et al., 2014).
Similarly, the non-steroidal anti-inflammatory drugs
(NSAIDs) ibuprofen and indomethacin have shown remarkable
anti-TB and pathology-limiting effects in murine models of TB
S64 M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67
Figure 1. Clinical studies in the context of HDT development for MDR-TB.
Shown is a schematic representation of the different types of clinical studies and their contribution to understanding biological pathways and targets in patients with MDR-TB.
The innermost circle (yellow) represents interventional clinical studies which include small-molecule and vaccine clinical trials, routine thoracic surgery (lung resections) as
well as treatment follow-up. These scenarios yield ample patient material i.e. biopsies, resected lung tissue and blood that can be used for extensive immunological and
genetic assessments of the patients. The readouts from these studies will inform of the mutations in the host — both naturally occurring and pathogen-induced, the
modulation of immune cells in blood and tissue and how this is directly affected by the disease process and in combination with therapy i.e. antibiotics and/or surgery, where
applicable. The middle circle (yellowish-green) represents semi-interventional studies, where blood draws and lung biopsies are obtained. Here, similar studies to those
achievable via clinical material from interventional studies can be implemented i.e. lung tissue specimen and blood but the target groups would also include household
contacts of patients with MDR-TB who may have LTBI and could be treated with prophylactic moxifloxacin and/or isoniazid, for example. This measure allows for tracking of
biological pathways that become aberrant upon constant exposure to MDR-TB and how this might affect initially healthy household contacts to eventually contract clinical
disease. Importantly, these data could lead to identification of druggable host targets. Finally yet importantly, the outermost circle (green) represents non-interventional
studies which incorporate the use of faecal material and results from standard laboratory data i.e. sputum and blood, and if possible, bronchoalveolar lavage fluid in some
instances. This circle accounts for the largest collection of biological samples since these studies are usually observational and prospective in nature and can be performed in
large cohorts of participants across various geographical regions, involving patients and clinically healthy individuals alike.(Kroesen et al., 2017). There is currently one clinical trial in the
recruitment phase to test the adjunctive potential of ibuprofen
in patients with XDR-TB in Georgia (ClinicalTrials.gov identifier:
NCT02781909).
Vitamin D has also been tested in many clinical trials involving
large patient cohorts although there still appears to be no decisive
effect on the clinical outcome of TB in treated individuals
(reviewed by Wallis and Zumla, 2016). However, further clinical
trials are warranted due to a clinical benefit observed in some of
the studies described in the review. There is also clinical evidence
of cytokine neutralisation using antibody-based drugs i.e. anti-
TNF-α to reduce mortality and immunopathology during severe
clinical TB (Wallis et al., 2009). Another important biological
mediator, IL-6, can be measured at TB diagnosis and during
antibiotic treatment to guide the selection of patients who are
likely to succumb to severe pulmonary tissue damage despite
achieving microbiological cure (Nagu, 2017), thus making it a
possible HDT target. Further clinical trials are neverthelessrequired to weigh the benefit of pursuing these approaches as
adjunct HDTs catering for large patient groups.
A crucial factor to consider when adding small molecules to
MDR/XDR-TB regimens is the possible drug-drug interactions
which may eliminate the HDT potential. For instance, CYP3A4,
which in addition to the bona fide enzymes CYP2R1 and CYP27A1
can hydrolyse cholecalciferol (vitamin D3) to calcifediol (25-
hydroxy-vitamin D) prior to conversion to its active form calcitriol
(1,25-dihydroxy-vitamin D), is reversibly inhibited by isoniazid
(Robien et al., 2013). Existing pharmacological experience will
guide dosing and timing of the intervention, importantly with
assistance from clinical biomarker studies in patients with TB (as
described in Figure 1).
Cell-based therapeutics as personalised HDTs to treat MDR-TB
Clinical studies provide ample information for patient selection
and stratification to develop immune-based personalised HDTs.
M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S65Much can be learned from personalised cancer immunotherapy,
where clinical guidelines for managing metastatic, chemotherapy-
refractory disease are available and undergo constant renewal.
Routine clinical diagnostics may also incorporate extended
immunological tests to report circulating lymphocytes (including
NK cells), cytokines and antibodies to pre-screen for patients who
may most benefit from personalised HDTs.
Adoptive cell therapies: learning from cancer management
The workflow used in anti-cancer adoptive cell therapy
programmes using tumour-infiltrating lymphocytes (TIL) provides
an excellent template for developing personalised cellular HDTs for
MDR-TB. Whole-exome sequencing of genomic DNA isolated from
MDR-TB lung granulomas would identify all host- and pathogen-
associated mutations, from which mutated protein targets (neo-
antigens) recognised by the host’s circulating and lung-derived
lymphocytes can be screened using in vitro immunoassays. Lung
granuloma tissue specimens from patients with MDR-TB as well as
those with LTBI or healed/calcified lesions (i.e. tissue from
lobectomy procedures), peripheral blood, pleural effusion (PE)
and bronchoalveolar lavage (BALF) represent highly valuable
sources of TB-specific lymphocytes. Flow cytometric analysis can
further characterise specific T-cell populations that may be selected
for targeted therapy based on (i) surface marker expression (i.e.
CXCR3, CCR7, CD45RA) which indicates access to target tissue — a
prerequisite for successful protective immune responses, (ii)
intracellular cytokine expression/production profiles and (iii)
multimer-based recognition of specific epitopes which promote
Mtb eradication without exacerbating existing immunopathology.
These initial screening assays will also reveal specific TCRs – αβ and
gd alike – and B-cell receptors (BCRs and immunoglobulin profile)
correlating with clearance (sterilising immunity) or optimal control
of Mtb infection. The most promising and non-cross-reactive Mtb
target-specific TCRs can also be transfered into appropriate
recipient effector (T or NK cells) either by lentiviral infection or
transient CRISPR-Cas9 technology to develop a genetically modified
therapeutic cellular product. The most promising TB-specific Tcells
– possibly also mutation-directed subpopulations – can be
expanded in vitro with gamma-chain cytokines i.e. IL-2/IL-15/IL-
21 (Rao et al., 2018) and assessed further for biological activity and
re-infusion into patients with MDR-TB.
Mesenchymal stromal cells
Mesenchymal stromal cells (MSC), known for their anti-
inflammatory, immunomodulatory properties and safety in several
clinical modalities (Mizukami and Swiech, 2018), are excellent
candidates for treating patients with MDR-TB. Adjunctive therapy
with a single infusion of bone marrow-derived autologous MSC has
been clinically evaluated in two separate studies involving patients
with MDR/XDR-TB. In the first study, 30 patients were enrolled,
comprising 17 MDR-TB cases and 13 XDR-TB cases. 21 patients
showed radiological improvements in the lungs at 6 months post-
MSC therapy (MDR-TB = 12 patients; XDR-TB = 9 patients) while
stablediseasewasobservedin2 patients withMDR-TBand3 patients
with XDR-TB (Skrahin et al., 2014). This was accompanied by
approximately 80% reductioninviable Mtb load in sputum, with only
20% of patients displaying positive culture conversion. A total of 16
patients who received MSC therapy achieved microbiological cure,
indicated by at least 18 months of Mtb-negative cultures. Only 3
patients with MDR-TB and 1 patient with XDR-TB experienced
disease progression, with grade 3 adverse events recorded in only 2
patients throughout the study period. In comparison, only 5 out of
30 patients with MDR/XDR-TB in the control arm who did not
receive adjunctive MSC therapy experienced microbiological cure,further to 5 other patients who died while receiving second-line
antibiotic treatment. No deaths were reported in the MSC-
treatment arm. Importantly, MSC infusion induced immune re-
focusing of Mtb antigen-directed T-cell responses, resulting in
improved recognition of Ag85B (Rv1886), an immunodominant Mtb
protein, as well as increased sensitivity to IL-2 and IL-7 stimulation.
The second study showed that 81% of 36 patients with MDR/XDR-TB
experienced a successful clinical outcome (radiological improve-
ments) 6 months after MSC infusion as opposed to only 39% of 36
control patients who did not receive adjunctive MSC therapy
(Skrahin et al., 2016). No immunological analysis was performed in
the second study. Further large, controlled cohort studies are
required to confirm the usefulness of adjunct MSC therapy in MDR-/
XDR-TB, and the immunological correlates therein.
Building capacity for HDT evaluation in low-resource and high
TB endemic settings
Patients with MDR-TB, further subdued by HIV-co-infection in
countries where MDR-TB/HIV is a major issue i.e. South Africa,
India, Indonesia, China to name a few (WHO, 2018) (although the
rates of HIV-co-infection differ across the countries) are generally
very weak and frequently anaemic, which poses a major challenge
to obtaining blood, and worse still, bone marrow aspirates. In
addition, allogeneic NK, TCR gd T cells and MSCs cells from
immuno-competent individuals, as opposed to patients with MDR-
TB, may be physiologically fitter, exhibit uncompromised biologi-
cal activity and able to expand more readily with cytokine
conditioning. Similarly, TCRs which can promote disease amelio-
ration in patients with MDR-TB – initially discovered from in vitro
screening of patient material – can be transduced into allogeneic
NK or Vg9Vd2T cells. The use of allogeneic sources of NK cells,
MSCs and Vg9Vd2 T cells for therapy should, therefore, be
encouraged in resource-limited and high TB burden settings since
technological advances must be translated to areas of greatest
clinical need. This approach is feasible and will also reduce the
number of biological samples i.e. blood, tissue as well as the
frequency at which they are obtained from patients with MDR-TB
(Jarry et al., 2016; Veluchamy et al., 2017; Galipeau and Sensébé,
2018). Figure 2 is a schematic representation of how personalised
cellular HDTs, as a future possibility, may be incorporated into the
standard MDR-TB treatment programmes in practice in high-
burden countries. The strategy proposed here is also explained in
detail in the accompanying legend and considers that resource
limitation is a crucial factor governing the provision of cutting-
edge personalised medical care. As previously mentioned,
personalised HDTs are a suggestion to complement more strati-
fied/generalised HDTs for suitable patients in combination with
conventional drugs and not a replacement for standard therapy at
this juncture.
Public-private partnerships (PPPs) are key in fuelling modern
infrastructure for healthcare provision, the Biovac Institute in Cape
Town, South Africa and the African Health Markets for Equity
(AHME) project in Ghana and Kenya (Suchman et al., 2018) serve as
good examples. Cellular therapies may also be developed and
administered at certain centres with suitable infrastructure i.e.
Alberts Cellular Therapy (Gauteng, South Africa), and once the
mechanisms of protection and correlates of beneficial clinical
responses in patients with MDR-TB treated with personalised HDTs
are better defined, the HDT treatment regimen could potentially be
replaced with more generalised biologicals to reach more patients.
Here, timing and dosing of intervention with the appropriate HDTs
is of paramount importance, based on lessons from cancer
(Rothschilds and Wittrup, 2019) and inflammatory diseases i.e.
ankylosing spondylitis, arthritis and IL-17A blockade (Baraliakos
and Braun, 2018). Also, MSCs in GVHD work via reduction of IL-6,
S66 M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67
Figure 2. Possible HDT strategies for inclusion into future anti-MDR-TB therapy programmes.
The schematic diagram represents a possible path to including HDTs in standard-of-care programmes for MDR-TB. The WHO-recommended antibiotics regimens are
mandatory, thus comprising the standardised therapy regimen for patients based on designated criteria, at which point routine laboratory examinations i.e. microbiology,
haematology, chest X-rays (CXR) and drug susceptibility testing (DST) are carried out to form a baseline of the patient’s clinical status and amenability to antibiotics. All
patients who undergo standard treatment are required to appear for routine follow-up sessions with the attending medical team. In addition to lung function and
microbiological examinations, blood draws could be obtained to understand the immunological status of each patient after having undergone at least several weeks of anti-
MDR-TB therapy and in comparison with baseline (prior to treatment initiation) using the same set of laboratory analyses. CXR bears an asterix(*) since not all patients may be
amenable to exposure to radiation during follow-up. This also applies to the treatment continuation phase since clinical follow-ups are regular. Following consultation with
published clinical studies concerning biological mediators and biomarkers in patients with MDR-TB, the individuals who are most likely to respond to HDTs can then be
selected. Of note, it is of paramount importance that the timing of immunomodulatory HDT is best planned for after the intensive phase of therapy so that the necessary anti-
mycobacterial defence system in the host is not compromised in any way. More generalised HDT options may be administered here, possibly differing from one patient group
to another based on their biomarker profile(s) stratification. Herein, HDTs targeting cytokine neutralisation (i.e. anti-IL-6, anti-TNF-α), vitamin supplementation (i.e. vitamin
D, vitamin A), metformin therapy and non-steroidal anti-inflammatory drugs (NSAIDs i.e. ibuprofen, aspirin, indomethacin) would more likely cater for a large number of
patients at the same time as these are readily available (’off-the-shelf’) therapeutics. In contrast, more personalised HDTs such as cellular therapy with T cells, NK cells as well
as mesenchymal stromal cells (MSCs) would require a longer preparation time and very importantly, a sufficient amount of material to start with for cell propagation. This also
requires a suitable facility for cell expansion and quality control processes i.e. a GMP-compliant laboratory. NK cells and MSCs may be of allogeneic origin, thus curtailing the
product generation time compared to isolation, culture and expansion of autologous T-cell products for re-infusion into patients. TCR-transduced T cells could also use
allogeneic sources if the patient’s native, restricting HLA elements matches that of the donor’s. The clinical and laboratory assessment of the data arising from HDTs, further to
the continuation of standard treatment for MDR-TB, will give rise to newer information which can contribute to previously unknown therapeutic HDT targets, thus feeding
into baseline immunological data collection as well as immune-monitoring.TNF-α and inducing tissue regeneration and remodelling by
vascular endothelial growth factor (VEGF) production (Wang
et al., 2016), potentially paving the way for treating more patients
with HDTs targeting the IL-6/TNF-α axis and VEGF supply albeit
with correct timing of intervention. With tantamount funding,
specialised GMP-compliant laboratories within mobile container
units such as the BioGoTM Mobile solution (Germfree, USA) – as an
alternative to permanent facilities – can be deployed in suitable
regions to manufacture advanced cellular therapeutics.
These solutions augment the state-of-the-art under technically
challenging circumstances and can be supported by clinical
research grants as well as investigator-initiated studies and/or(co-)funded by pharmaceutical companies. Assessment of clinical-
ly relevant immune reactivity and general immune-modulation in
the host may identify new, biologically relevant HDT targets and
ultimately revolutionise the clinical management of MDR-TB.
Conclusions
Conventional MDR-TB drug treatment needs to be comple-
mented with HDTs to reduce tissue damage and improve
treatment outcomes. However, the critical question in developing
personalised therapies for TB is whether this strategy is routinely
applicable in resource-limited settings. This viewpoint proposes to
M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S67consider the application of personalised cell-based HDTs to
complement promising small molecule-based and soluble HDT
agents as adjuncts to conventional anti-TB treatment regimens.
Therefore, with the growing number of HDTs, infrastructure for
conducting clinical trials of HDTs should be established in
resource-limited and high TB endemic settings with international
and local support.
Funding
Giuseppe Ippolito, Sayoki Mfinanga, Francine Ntoumi, Dorothy
Yeboah-Manu and Alimuddin Zumla are members of the PANDORA-
ID-NET consortium supported by the European and Developing
Countries Clinical Trials Partnership (EDCTP2) programme (Grant
Agreement RIA2016E-1609). GI received support from the Italian
Ministry of Health (Grant Ricerca Corrente, Research programme n.4:
Tuberculosis). The views and opinions of authors expressed herein do
not necessarilystateorreflect thoseofEDCTP. Markus Maeurerreports
receiving funding from the Champalimaud Foundation.
Conflict of interest
The authors declare no conflicts of interest.
Ethical approval
No ethical approval was required for this work.
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