Preliminary Results of an Experimental Medicine Trial of Adjunctive Host-Directed Therapy in Adults with Moderately or Far-Advanced Rifampin-Susceptible Pulmonary Tuberculosis

Wallis, Robert S.; Ginindza, Sibuse; Beattie, Trevor; Arjun, Nishanee; Likoti, Morongwe; Edward, Vinodh; Rassool, Mohammed; Ahmed, Khatija; Fielding, Katherine; Ahidjo, Bintou Ahmadou; Vangu, M.D.T.H.W.; Churchyard, Gavin

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a7388

Cited by 5 publications

(9 citation statements)

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“…11,12 Interventions that limit lung damage from TB disease should also receive increased attention, including tools allowing earlier TB diagnosis 13 , and new regimens that protect lung function during TB treatment. 14 Given this potentially large burden of disease associated with post-tuberculosis, several lines of future research are important. First, clinical evidence on post-tuberculosis points to a highly heterogeneous set of symptoms and conditions, which need to be understood to enable more tailored post-tuberculosis care.…”

mentioning

confidence: 99%

Post-tuberculosis mortality and morbidity: valuing the hidden epidemic

Quaife

Houben

Allwood

et al. 2020

The Lancet Respiratory Medicine

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confidence: 99%

Post-tuberculosis mortality and morbidity: valuing the hidden epidemic

Quaife

Houben

Allwood

et al. 2020

The Lancet Respiratory Medicine

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“…Taking these mechanistic differences into account, our results strongly suggest the superior therapeutic potential of combined interruption of both mTORC1 and mTORC2 signaling by an mTOR kinase inhibitor as adjunctive HDT for TB, as opposed to the partial inhibition of mTORC1 observed with rapamycin and its analogs. Considering the modest benefits recently observed with addition of everolimus to a regimen of rifabutin plus HZE in a clinical study (14), the therapeutic advantages of CC214-2 observed here suggest that an mTOR kinase inhibitor that more effectively targets both mTORC1 and mTORC2 may deliver superior outcomes in the clinical setting.…”

Section: Discussionmentioning

confidence: 77%

“…Everolimus, while more soluble and orally bioavailable, is also a substrate of CYP 3A4 and P-gp, and its metabolism is induced by rifampin, the cornerstone drug in the RHZE regimen (27). Hence, the requirement to substitute rifabutin for rifampin when everolimus was evaluated as adjunctive HDT in the aforementioned clinical trial (14). CC214-2 has superior physicochemical and pharmacokinetic properties, and has demonstrated efficacy in vivo across multiple solid tumor models when dosed orally.…”

Section: Discussionmentioning

confidence: 99%

“…The widely discrepant effects observed between the mTOR inhibitors evaluated here may be attributable to the properties and selectivity of the mTOR inhibitors. Although rapamycin and especially analogs such as everolimus have been explored (7, 12, 14, 24, 25) for use as adjunctive HDT for TB, to our knowledge, they have not been studied previously with combination chemotherapy in a mouse model of TB. Due to their effects on the AKT/mTOR pathway and autophagy, they only partially inhibit mTORC1 and do not inhibit mTORC2.…”

Section: Discussionmentioning

confidence: 99%

“…The rapamycin analog everolimus has improved bioavailability and recently was evaluated as an adjunct to the standard-of-care chemotherapy regimen in a clinical trial (#NCT02968927). Preliminary interim analyses suggested reduced inflammation and trends toward improved lung function and accelerated culture conversion with addition of everolimus (14). These results suggest that chemical modulation of mTOR and autophagy has potential as a novel HDT approach for TB treatment.…”

Section: Introductionmentioning

confidence: 99%

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Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis

Tasneen

Mortensen²,

Converse

et al. 2021

Preprint

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Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-treated mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.

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Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

DiNardo

Rajapakshe

Gandhi

et al. 2020

Preprint

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Rationale: Host response is a critical factor determining susceptibility to tuberculosis (TB). A delicate balance should be maintained between intracellular immunity against Mycobacterium tuberculosis (Mtb) and minimizing detrimental immunopathology. Studies have identified incongruous immune responses that can lead to a similar TB disease phenotype. Instead of envisioning that susceptibility to TB follows a singular path, we propose the hypothesis that varied host endotypes exist within the TB clinical phenotype. Methods and Results: Unbiased clustering analysis from 12 publicly available gene expression datasets consisting of data from 717 TB patients and 527 controls, identified 4 TB patient endotypes with distinct immune responses. The two largest endotypes exhibit divergent metabolic, epigenetic and immune pathways. TB patient endotype A, comprising 333 TB patients (46.4%), is characterized by increased expression of genes important for i) glycolysis, ii) IL-2-STAT5, IL-6-STAT3, Type I and II Interferon IFN-γ and TNF signaling and iii) epigenetic-modifying genes. In contrast, TB patient endotype B, comprising 313 TB patients (43.6%), is characterized by i) upregulated NFAT and hormone metabolism, and ii) decreased glycolysis, IFN-γ and TNF signaling. In silico evaluation suggests therapies beneficial for endotype A could be detrimental to endotype B, and vice versa. Multiplex ELISA completed from an external validation cohort confirmed a TB patient sub-group with decreased immune upregulation. Conclusions: Host immunity to TB is heterogenous. Unbiased clustering analysis identified distinct TB endotypes with divergent metabolic, epigenetic and immune gene expression profiles that may enable stratified or personalized treatment management in the future.

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Preliminary Results of an Experimental Medicine Trial of Adjunctive Host-Directed Therapy in Adults with Moderately or Far-Advanced Rifampin-Susceptible Pulmonary Tuberculosis

Cited by 5 publications

References 0 publications

Post-tuberculosis mortality and morbidity: valuing the hidden epidemic

Post-tuberculosis mortality and morbidity: valuing the hidden epidemic

Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

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