International Journal of Infectious Diseases 80 (2019) S62–S67 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid 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 b National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy c National Institute of Medical Research Muhimbili, Dar es Salaam, Tanzania d University Marien NGouabi and Fondation Congolaise pour la Recherche Médicale (FCRM), Brazzaville, Congo e Institute for Tropical Medicine, University of Tübingen, Germany f Department 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 h Division of Infection and Immunity, University College London and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK i Department 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 most patients who recover from the lengthy and toxic treatment course of anti-TB drugs develop lung damage and long-term The 2018 WHO Global Tuberculosis (TB) Report states that in functional disability due to aberrant host immune responses to 2017, the treatment success of multidrug-resistant (MDR) TB Mycobacterium tuberculosis (Mtb). Data from clinical trials, using WHO-recommended TB drug regimens cases was a meagre retrospective cohort studies and routine follow-up examinations 55% globally (WHO, 2018). With an estimated half a million cases, can allow for studying the immuno-physiological status of MDR-TB remains a serious global health threat. Furthermore, patients with MDR-TB and designing personalised adjunct host- directed therapies (HDT) based on clinical experience from cancer treatment options (Tiberi et al., 2018). $ World Tuberculosis Day 2019 Series: a viewpoint for the International Journal of Drug-susceptible vs MDR-TB: immunopathological differences Infectious Diseases World TB Day TB Theme Series. * Corresponding author at: Champalimaud Centre for the Unknown, Avenida Brasília, 1400-038 Lisbon, Portugal. A noteworthy difference between patients with MDR-TB and E-mail addresses: martin.rao@research.fchampalimaud.org (M. Rao), those with drug-susceptible TB is the genetic background of the giuseppe.ippolito@inmi.it (G. Ippolito), gsmfinanga@yahoo.com (S. Mfinanga), infecting Mtb strain. Resistance to standard antibiotic therapy ffntoumi@hotmail.com (F. Ntoumi), dyeboah-manu@noguchi.ug.edu.gh (D. Yeboah-Manu), cvilaplana@gmail.com (C. Vilaplana), a.zumla@ucl.ac.uk allows for drug-resistant Mtb to linger longer in the host and (A. Zumla), markus.maeurer@fundacaochampalimaud.pt (M. Maeurer). induce immunopathological changes which may differ to that https://doi.org/10.1016/j.ijid.2019.01.039 1201-9712/© 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/). Descargado para Anonymous User (n/a) en Autonomous University of Barcelona de ClinicalKey.es por Elsevier en marzo 26, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S63 caused by their drug-susceptible counterparts. Li et al. (2017) to healthy controls, marked by enrichment of Rothia mucilaginosa, showed that patients with primary MDR-TB tend to exhibit a Actinomyces graevenitzii (opportunistic lung pathogens), Tumeba- greater extent of lung cavitation and lower number of calcified cillus, Propionibacterium (propionate-producing) and Haemophilus nodules compared to patients with drug-susceptible pulmonary spp. in addition to Mtb itself (Hong et al., 2018). However, these TB. A more recent review also shed light on thicker cavity walls in studies were performed with clinical samples from patients with MDR-TB lung lesions further to extensive tissue loss (Wáng et al., drug-susceptible TB and not MDR-TB. As an integral part of all 2018), collectively suggesting intense inflammatory processes mammals including humans, incorporating microbiome profiling unleashed by MDR-Mtb infection in the lungs. Interestingly, (gut and lung) in clinical biomarker studies for MDR-TB would, patients with MDR-TB have also been shown to have slightly therefore, be highly valuable. higher T-cell counts and IgM titres in serum compared to patients The types of clinical studies which can contribute to better with drug-susceptible TB (Sun et al., 2017). Another study showed understanding the host/and pathogen factors modulating immune that the baseline levels of IL-6 and IL-8 produced by peripheral responses and how this knowledge can help develop new HDTs are blood mononuclear cells (PBMCs) from patients with MDR-TB are represented in Figure 1. higher than that of PBMCs from patients with drug-susceptible TB (Skolimowska et al., 2012). Standardised therapy for MDR-TB Recent data on cellular immune responses and applicability to Establishing HDTs as a standardised treatment method would HDT development be extremely challenging as the mainstay of antitubercular therapy, including MDR-TB, requires the elimination of Mtb from T-cell effector functions are recognised as central to anti-TB the host. As such, standard forms of future treatment to manage immunity. Emerging evidence shows that the ‘understudied’ clinical TB would rely on new drug regimens designed based on the natural killer (NK) cells may have an important protective role patient population, genetics of the infecting Mtb strain(s) as well as in preventing active TB disease (Garand et al., 2018; Roy the host (this affects drug metabolism and bioavailability), Mtb Chowdhury et al., 2018). Vaccination-induced T-cell populations drug susceptibility profile(s) and presence of co-morbidities in the expressing certain surface molecules i.e. CXCR3, CCR7, CD45RA patient to name a few (Lange et al., 2018; Gröschel et al., 2018). The signify specific subsets which can predict desirable clinical combination of these criteria will deliver specific regimens for responses (Mpande et al., 2018; Stylianou et al., 2018). Next- designated patient groups in various geographical regions, generation sequencing has revealed differential V-J recombination embodying a more personalised and targeted approach compared patterns (at the gene level) among T-cell receptor gamma-delta to classical antibiotic prescribing. Corticosteroids (prednisolone (TCR-gd) Vg9Vd2 cells in patients with pulmonary TB (Cheng et al., and dexamethasone) are a class of HDT candidates which are 2018). These translational and clinical studies also capture the already given to patients experiencing severe inflammation during different human leukocyte antigen (HLA) backgrounds of patients, anti-TB treatment. The drugs themselves do not have targeted an essential determinant of conventional TCR alpha-beta (TCR-αβ) effects but rather a general dampening of the host immune CD4+ and CD8+ T-cell responses. For example, previous studies response to extend survival in the short-term (Critchley et al., have shown a correlative link between polymorphisms in HLA class 2016). However, emerging evidence from clinical studies involving I/II genes in various populations globally and susceptibility or patients with MDR-TB may help identify more targeted HDT resistance to clinical TB (reviewed by Harishankar et al. (2018)). strategies which could be standardised for some patient groups i.e. Collectively, such findings may advance further deconvolution of cytokine neutralisation, metformin therapy. immune biomarkers with direct clinical relevance to MDR-TB. The pro-inflammatory cytokines released early after Mtb Small-molecule and soluble HDTs for MDR-TB infection include IL-6, IL-1β, IL-12, IFN-g and TNF-α which, through nitric oxide (NO) production, can also perpetrate DNA Studies to date have shown that several clinically approved damage (Landskron et al., 2014). Mtb infection of human macro- drugs used in non-TB modalities may have therapeutic value in phages has been shown to induce nuclear membrane blebbing and managing patients with TB. The adjunctive use of metformin, an DNA breakage (Castro-Garza et al., 2018). As such, do patient- anti-diabetic drug which activates the 50 AMP-activated protein specific private mutations (such as the tumour mutational burden kinase (AMPK), was shown to complement the antitubercular in cancer) also develop in TB granulomas and would they govern properties of rifampicin and reduce the pulmonary load of an the course of disease in each individual and influence clinical MDR-Mtb strain while potentiating Mtb-directed CD8+ T-cell outcome? Genetic analysis of lung TB granulomas and blood responses in mice (Singhal et al., 2014). Clinical studies imple- samples from patients with MDR-TB may further enrich personal- mented afterwards showed that patients with diabetes mellitus ised, precision medicine HDT strategies for patients with MDR-TB, who were also taking metformin had shorter hospital stays due to a particularly since Mtb mutant target epitopes may prime and diagnosis of active pulmonary TB concomitant with a reduced risk expand T cells which are unfamiliar to their wild type counterparts, of relapse and lower rates of mortality (Marupuru et al., 2017; thereby providing a richer source for potentially protective and Degner et al., 2018; Lee et al., 2018a). Metformin may also help non-exhausted cellular immune responses. enhance control of the high mycobacterial burden in patients with cavitary pulmonary TB, based on improved sputum culture Gut and lung microbiomes conversion rates and reduce the culture conversion time in patients with MDR/XDR-TB in the first 2 months following therapy The gut and lung microbiomes are inevitably altered in patients initiation (Lee et al., 2018b). However, further randomised clinical with TB who undergo standard antibiotic therapy (Wipperman trials are necessary to determine whether metformin therapy is et al., 2017; Hong et al., 2016). Gut bacterial species producing able to extend the lifespan of patients with MDR/XDR-TB while butyrate and propionate were found to be enriched in patients subduing tissue pathology as previously shown in the first with TB in conjunction with impaired vitamin and amino acid preclinical study (Singhal et al., 2014). synthesis compared to healthy controls (Maji et al., 2018). The lung Similarly, the non-steroidal anti-inflammatory drugs microbiota in patients with pulmonary TB, based on the meta- (NSAIDs) ibuprofen and indomethacin have shown remarkable analysis of 5 independent studies, also appears distinct compared anti-TB and pathology-limiting effects in murine models of TB Descargado para Anonymous User (n/a) en Autonomous University of Barcelona de ClinicalKey.es por Elsevier en marzo 26, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. 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 required to weigh the benefit of pursuing these approaches as recruitment phase to test the adjunctive potential of ibuprofen adjunct HDTs catering for large patient groups. in patients with XDR-TB in Georgia (ClinicalTrials.gov identifier: A crucial factor to consider when adding small molecules to NCT02781909). MDR/XDR-TB regimens is the possible drug-drug interactions Vitamin D has also been tested in many clinical trials involving which may eliminate the HDT potential. For instance, CYP3A4, large patient cohorts although there still appears to be no decisive which in addition to the bona fide enzymes CYP2R1 and CYP27A1 effect on the clinical outcome of TB in treated individuals can hydrolyse cholecalciferol (vitamin D3) to calcifediol (25- (reviewed by Wallis and Zumla, 2016). However, further clinical hydroxy-vitamin D) prior to conversion to its active form calcitriol trials are warranted due to a clinical benefit observed in some of (1,25-dihydroxy-vitamin D), is reversibly inhibited by isoniazid the studies described in the review. There is also clinical evidence (Robien et al., 2013). Existing pharmacological experience will of cytokine neutralisation using antibody-based drugs i.e. anti- guide dosing and timing of the intervention, importantly with TNF-α to reduce mortality and immunopathology during severe assistance from clinical biomarker studies in patients with TB (as clinical TB (Wallis et al., 2009). Another important biological described in Figure 1). mediator, IL-6, can be measured at TB diagnosis and during antibiotic treatment to guide the selection of patients who are Cell-based therapeutics as personalised HDTs to treat MDR-TB likely to succumb to severe pulmonary tissue damage despite achieving microbiological cure (Nagu, 2017), thus making it a Clinical studies provide ample information for patient selection possible HDT target. Further clinical trials are nevertheless and stratification to develop immune-based personalised HDTs. Descargado para Anonymous User (n/a) en Autonomous University of Barcelona de ClinicalKey.es por Elsevier en marzo 26, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S65 Much can be learned from personalised cancer immunotherapy, further to 5 other patients who died while receiving second-line where clinical guidelines for managing metastatic, chemotherapy- antibiotic treatment. No deaths were reported in the MSC- refractory disease are available and undergo constant renewal. treatment arm. Importantly, MSC infusion induced immune re- Routine clinical diagnostics may also incorporate extended focusing of Mtb antigen-directed T-cell responses, resulting in immunological tests to report circulating lymphocytes (including improved recognition of Ag85B (Rv1886), an immunodominant Mtb NK cells), cytokines and antibodies to pre-screen for patients who protein, as well as increased sensitivity to IL-2 and IL-7 stimulation. may most benefit from personalised HDTs. The second study showed that 81% of 36 patients with MDR/XDR-TB experienced a successful clinical outcome (radiological improve- Adoptive cell therapies: learning from cancer management ments) 6 months after MSC infusion as opposed to only 39% of 36 control patients who did not receive adjunctive MSC therapy The workflow used in anti-cancer adoptive cell therapy (Skrahin et al., 2016). No immunological analysis was performed in programmes using tumour-infiltrating lymphocytes (TIL) provides the second study. Further large, controlled cohort studies are an excellent template for developing personalised cellular HDTs for required to confirm the usefulness of adjunct MSC therapy in MDR-/ MDR-TB. Whole-exome sequencing of genomic DNA isolated from XDR-TB, and the immunological correlates therein. MDR-TB lung granulomas would identify all host- and pathogen- associated mutations, from which mutated protein targets (neo- Building capacity for HDT evaluation in low-resource and high antigens) recognised by the host’s circulating and lung-derived TB endemic settings lymphocytes can be screened using in vitro immunoassays. Lung granuloma tissue specimens from patients with MDR-TB as well as Patients with MDR-TB, further subdued by HIV-co-infection in those with LTBI or healed/calcified lesions (i.e. tissue from countries where MDR-TB/HIV is a major issue i.e. South Africa, lobectomy procedures), peripheral blood, pleural effusion (PE) India, Indonesia, China to name a few (WHO, 2018) (although the and bronchoalveolar lavage (BALF) represent highly valuable rates of HIV-co-infection differ across the countries) are generally sources of TB-specific lymphocytes. Flow cytometric analysis can very weak and frequently anaemic, which poses a major challenge further characterise specific T-cell populations that may be selected to obtaining blood, and worse still, bone marrow aspirates. In for targeted therapy based on (i) surface marker expression (i.e. addition, allogeneic NK, TCR gd T cells and MSCs cells from CXCR3, CCR7, CD45RA) which indicates access to target tissue — a immuno-competent individuals, as opposed to patients with MDR- prerequisite for successful protective immune responses, (ii) TB, may be physiologically fitter, exhibit uncompromised biologi- intracellular cytokine expression/production profiles and (iii) cal activity and able to expand more readily with cytokine multimer-based recognition of specific epitopes which promote conditioning. Similarly, TCRs which can promote disease amelio- Mtb eradication without exacerbating existing immunopathology. ration in patients with MDR-TB – initially discovered from in vitro These initial screening assays will also reveal specific TCRs – αβ and screening of patient material – can be transduced into allogeneic gd alike – and B-cell receptors (BCRs and immunoglobulin profile) NK or Vg9Vd2T cells. The use of allogeneic sources of NK cells, correlating with clearance (sterilising immunity) or optimal control MSCs and Vg9Vd2 T cells for therapy should, therefore, be of Mtb infection. The most promising and non-cross-reactive Mtb encouraged in resource-limited and high TB burden settings since target-specific TCRs can also be transfered into appropriate technological advances must be translated to areas of greatest recipient effector (T or NK cells) either by lentiviral infection or clinical need. This approach is feasible and will also reduce the transient CRISPR-Cas9 technology to develop a genetically modified number of biological samples i.e. blood, tissue as well as the therapeutic cellular product. The most promising TB-specific T cells frequency at which they are obtained from patients with MDR-TB – possibly also mutation-directed subpopulations – can be (Jarry et al., 2016; Veluchamy et al., 2017; Galipeau and Sensébé, expanded in vitro with gamma-chain cytokines i.e. IL-2/IL-15/IL- 2018). Figure 2 is a schematic representation of how personalised 21 (Rao et al., 2018) and assessed further for biological activity and cellular HDTs, as a future possibility, may be incorporated into the re-infusion into patients with MDR-TB. standard MDR-TB treatment programmes in practice in high- burden countries. The strategy proposed here is also explained in Mesenchymal stromal cells detail in the accompanying legend and considers that resource limitation is a crucial factor governing the provision of cutting- Mesenchymal stromal cells (MSC), known for their anti- edge personalised medical care. As previously mentioned, inflammatory, immunomodulatory properties and safety in several personalised HDTs are a suggestion to complement more strati- clinical modalities (Mizukami and Swiech, 2018), are excellent fied/generalised HDTs for suitable patients in combination with candidates for treating patients with MDR-TB. Adjunctive therapy conventional drugs and not a replacement for standard therapy at with a single infusion of bone marrow-derived autologous MSC has this juncture. been clinically evaluated in two separate studies involving patients Public-private partnerships (PPPs) are key in fuelling modern with MDR/XDR-TB. In the first study, 30 patients were enrolled, infrastructure for healthcare provision, the Biovac Institute in Cape comprising 17 MDR-TB cases and 13 XDR-TB cases. 21 patients Town, South Africa and the African Health Markets for Equity showed radiological improvements in the lungs at 6 months post- (AHME) project in Ghana and Kenya (Suchman et al., 2018) serve as MSC therapy (MDR-TB = 12 patients; XDR-TB = 9 patients) while good examples. Cellular therapies may also be developed and stable disease was observed in 2 patients with MDR-TB and 3 patients administered at certain centres with suitable infrastructure i.e. with XDR-TB (Skrahin et al., 2014). This was accompanied by Alberts Cellular Therapy (Gauteng, South Africa), and once the approximately 80% reduction in viable Mtb load in sputum, with only mechanisms of protection and correlates of beneficial clinical 20% of patients displaying positive culture conversion. A total of 16 responses in patients with MDR-TB treated with personalised HDTs patients who received MSC therapy achieved microbiological cure, are better defined, the HDT treatment regimen could potentially be indicated by at least 18 months of Mtb-negative cultures. Only 3 replaced with more generalised biologicals to reach more patients. patients with MDR-TB and 1 patient with XDR-TB experienced Here, timing and dosing of intervention with the appropriate HDTs disease progression, with grade 3 adverse events recorded in only 2 is of paramount importance, based on lessons from cancer patients throughout the study period. In comparison, only 5 out of (Rothschilds and Wittrup, 2019) and inflammatory diseases i.e. 30 patients with MDR/XDR-TB in the control arm who did not ankylosing spondylitis, arthritis and IL-17A blockade (Baraliakos receive adjunctive MSC therapy experienced microbiological cure, and Braun, 2018). Also, MSCs in GVHD work via reduction of IL-6, Descargado para Anonymous User (n/a) en Autonomous University of Barcelona de ClinicalKey.es por Elsevier en marzo 26, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. 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 (co-)funded by pharmaceutical companies. Assessment of clinical- vascular endothelial growth factor (VEGF) production (Wang ly relevant immune reactivity and general immune-modulation in et al., 2016), potentially paving the way for treating more patients the host may identify new, biologically relevant HDT targets and with HDTs targeting the IL-6/TNF-α axis and VEGF supply albeit ultimately revolutionise the clinical management of MDR-TB. with correct timing of intervention. With tantamount funding, specialised GMP-compliant laboratories within mobile container Conclusions units such as the BioGoTM Mobile solution (Germfree, USA) – as an alternative to permanent facilities – can be deployed in suitable Conventional MDR-TB drug treatment needs to be comple- regions to manufacture advanced cellular therapeutics. mented with HDTs to reduce tissue damage and improve These solutions augment the state-of-the-art under technically treatment outcomes. However, the critical question in developing challenging circumstances and can be supported by clinical personalised therapies for TB is whether this strategy is routinely research grants as well as investigator-initiated studies and/or applicable in resource-limited settings. This viewpoint proposes to Descargado para Anonymous User (n/a) en Autonomous University of Barcelona de ClinicalKey.es por Elsevier en marzo 26, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. M. Rao et al. / International Journal of Infectious Diseases 80 (2019) S62–S67 S67 consider the application of personalised cell-based HDTs to mellitus patients with normal renal function: a nationwide cohort study with complement promising small molecule-based and soluble HDT validated diagnostic criteria. PLoS One 2018a;13(10)e0205807-e. Lee Y-J, Han SK, Park JH, Lee JK, Kim DK, Chung HS, et al. The effect of metformin on agents as adjuncts to conventional anti-TB treatment regimens. culture conversion in tuberculosis patients with diabetes mellitus. Korean J Therefore, with the growing number of HDTs, infrastructure for Intern Med 2018b;33(5):933–40. conducting clinical trials of HDTs should be established in Li D, He W, Chen B, Lv P. Primary multidrug-resistant tuberculosis versus drug- sensitive tuberculosis in non-HIV-infected patients: comparisons of CT findings. resource-limited and high TB endemic settings with international PLoS One 2017;12(6)e0176354-e. and local support. Maji A, Misra R, Dhakan DB, Gupta V, Mahato NK, Saxena R, et al. Gut microbiome contributes to impairment of immunity in pulmonary tuberculosis patients by alteration of butyrate and propionate producers. Environ Microbiol 2018;20 Funding (1):402–19. Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK. Giuseppe Ippolito, Sayoki Mfinanga, Francine Ntoumi, Dorothy Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz Yeboah-Manu and Alimuddin Zumla are members of the PANDORA- J Infect Dis 2017;21(3):312–6. ID-NET consortium supported by the European and Developing Mizukami A, Swiech K. Mesenchymal stromal cells: from discovery to manufactur- Countries Clinical Trials Partnership (EDCTP2) programme (Grant ing and commercialization. Stem Cells Int 2018;2018:13. Agreement RIA2016E-1609). GI received support from the Italian Mpande CAM, Dintwe OB, Musvosvi M, Mabwe S, Bilek N, Hatherill M, et al. Functional, antigen-specific stem cell memory (TSCM) CD4+ T cells are induced Ministry of Health (Grant Ricerca Corrente, Research programme n.4: by human Mycobacterium tuberculosis infection. Front Immunol 2018;9:324. Tuberculosis). The views and opinions of authors expressed herein do Nagu T. Improving treatment outcomes for patients with pulmonary tuberculosis in not necessarily state or reflect those of EDCTP. Markus Maeurer reports Tanzania: host and pathogen factors. Stockholm, Sweden: Department of Laboratory Medicine, Karolinska Institutet; 2017 pp. 64. receiving funding from the Champalimaud Foundation. Rao M, Zhenjiang L, Meng Q, Sinclair G, Dodoo E, Maeurer M. 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