Bone Marrow-Derived Mesenchymal Stromal Cell Therapy in Severe COVID-19: Preliminary Results of a Phase I/II Clinical Trial

peer reviewedBackground: Treatment of acute respiratory distress syndrome (ARDS) associated with COronaVIrus Disease-2019 (COVID-19) currently relies on dexamethasone and supportive mechanical ventilation, and remains associated with high mortality. Given their ability to limit inflammation, induce immune cells into a regulatory phenotype and stimulate tissue repair, mesenchymal stromal cells (MSCs) represent a promising therapy for severe and critical COVID-19 disease, which is associated with an uncontrolled immune-mediated inflammatory response. Methods: In this phase I-II trial, we aimed to evaluate the safety and efficacy of 3 intravenous infusions of bone marrow (BM)-derived MSCs at 3-day intervals in patients with severe COVID-19. All patients also received dexamethasone and standard supportive therapy. Between June 2020 and September 2021, 8 intensive care unit patients requiring supplemental oxygen (high-flow nasal oxygen in 7 patients, invasive mechanical ventilation in 1 patient) were treated with BM-MSCs. We retrospectively compared the outcomes of these MSC-treated patients with those of 24 matched control patients. Groups were compared by paired statistical tests. Results: MSC infusions were well tolerated, and no adverse effect related to MSC infusions were reported (one patient had an ischemic stroke related to aortic endocarditis). Overall, 3 patients required invasive mechanical ventilation, including one who required extracorporeal membrane oxygenation, but all patients ultimately had a favorable outcome. Survival was significantly higher in the MSC group, both at 28 and 60 days (100% vs 79.2%, p = 0.025 and 100% vs 70.8%, p = 0.0082, respectively), while no significant difference was observed in the need for mechanical ventilation nor in the number of invasive ventilation-free days, high flow nasal oxygenation-free days, oxygen support-free days and ICU-free days. MSC-treated patients also had a significantly lower day-7 D-dimer value compared to control patients (median 821.0 µg/L [IQR 362.0-1305.0] vs 3553 µg/L [IQR 1155.0-6433.5], p = 0.0085). Conclusions: BM-MSC therapy is safe and shows very promising efficacy in severe COVID-19, with a higher survival in our MSC cohort compared to matched control patients. These observations need to be confirmed in a randomized controlled trial designed to demonstrate the efficacy of BM-MSCs in COVID-19 ARDS. Clinical Trial Registration (www.ClinicalTrials.gov), identifier NCT0444545

Etude du métabolisme énergétique des lymphocytes T CD4+ soumis à une stimulation antigénique chronique

La reprogrammation métabolique est un événement critique dans la fonction et la différenciation des lymphocytes T. Les lymphocytes T quiescents reposent principalement sur la phosphorylation oxydative qui leur permet de produire de grandes quantités d’énergie. Cependant, après activation antigénique, les lymphocytes T subissent une reprogrammation métabolique caractérisée par une augmentation de la glycolyse. Cette situation unique permet aux lymphocytes T activés de diriger rapidement les intermédiaires métaboliques vers la synthèse de macromolécules requises pour leur prolifération et leur fonction effectrice. Néanmoins, l’exposition à un antigène persistant modifie très fortement la fonction lymphocytaire. Les lymphocytes T CD4+ stimulés chroniquement développent un état de non-réponse caractérisé par une perte apparente de leur capacité proliférative et de leurs fonctions effectrices. Le récepteur inhibiteur PD-1 (Programmed cell Death-1) a été identifié comme un régulateur majeur de cet état de non-réponse. L’objectif de notre travail a été de caractériser le métabolisme énergétique des lymphocytes T CD4+ stimulés chroniquement par un antigène. Nous avons, pour cela, développé un modèle murin d’exposition antigénique chronique dans lequel des lymphocytes T CD4+ anti-mâle de souris femelles sont adoptivement transférés dans des receveurs mâles. L’analyse du profil protéomique des lymphocytes T anti-mâle stimulés chroniquement par leur antigène a montré que plusieurs enzymes impliquées dans le métabolisme cellulaire étaient sous-exprimées par ces cellules en comparaison avec des cellules naïves. Nous avons ensuite montré que ces lymphocytes T stimulés chroniquement présentaient un flux glycolytique bas et une capacité respiratoire limitée comparativement à des lymphocytes T effecteurs. De plus, l'expression du transporteur de glucose GLUT1 ainsi que la masse mitochondriale étaient réduites dans ces lymphocytes T CD4+ stimulés chroniquement. Suite à leur activation, ces cellules présentaient une capture de glucose et une synthèse d’ATP limitées. Le blocage de la voie inhibitrice PD-1/PD-L1 a permis de restaurer rapidement la fonction effectrice, et en particulier la sécrétion d’interféron gamma, des lymphocytes T CD4+ soumis à une stimulation antigénique chronique. Cependant, ce blocage n’a induit aucune reprogrammation métabolique en faveur de la glycolyse aérobique dans ces cellules. Par contre, l'absence de régulation médiée par PD-1 a entraîné une perturbation de la chaîne mitochondriale de transport des électrons, une augmentation de la production de superoxyde mitochondrial et une réduction de la survie et de la capacité effectrice des lymphocytes T CD4+ exposés à un antigène persistant. En conclusion, nos observations démontrent que l'inhibition médiée par PD-1 limite la production de superoxyde mitochondrial dans les lymphocytes T CD4+ stimulés chroniquement, améliorant ainsi leur viabilité et leur capacité à développer des fonctions effectrices.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)info:eu-repo/semantics/nonPublishe

Functional profile of S100A4-deficient T cells

The protein S100A4 is best known for its significant role in promoting motility and invasive capacity of cancer cells. Since S100A4 expression has been reported also in T cells, we analyzed its potential role in T cell motility and inflammation. Using S100a4 +/Gfp mice, we show here that S100A4 is exclusively expressed by memory T cells of CD4 + or CD8 + subpopulations, predominantly of the effector memory T cell subtype. However, the protein was not required for in vitro memory T cell migration toward gradients of the inflammatory chemokine CXCL10. Moreover, T cell memory response was normal in S100A4-deficient mice and lack of S100a4 gene expression did not induce any defect in promoting the development of protective immunity or inflammatory reactions leading to autoimmunity. Taken together, our results demonstrate that S100A4 activity is dispensable for T cell motility/migration and inflammatory potential.info:eu-repo/semantics/publishe

Long-term antigen exposure deeply modifies metabolic requirements for T cell function

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, using a model of T cell transfer in mice, we report that long-term antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronically stimulated T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronically stimulated T cells appeared to rely on oxidative phosphorylation (OXPHOS) to produce ATP. PD-1 inhibition, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1 inhibition appears essential for limiting oxidative metabolism linked to effector function in chronically stimulated T cells, thereby promoting survival and functional fitness

Safety and efficacy of a single intraarticular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/ III study

peer reviewedBackground: New minimally invasive treatments are vital to delay joint replacement surgery in patients with knee osteoarthritis. This study was designed to select the most effective among three formulations of an enhanced protein solution containing clonidine, hyaluronic acid, and human plasma (JTA-004), and compare the safety and efficacy of intra-articular administration of the selected formulation with a reference treatment (hyaluronic acid) in symptomatic knee osteoarthritis patients. Methods: In this two-stage, double-blind, phase II/III study conducted in 12 Belgian centers, 50–79 year-old patients with primary knee osteoarthritis were randomized (1:1:1:1) to receive one dose of one of three JTA 004 formulations (differing in clonidine concentration [50 or 100 μg/ml] and volume [2 or 4 ml]) or the reference treatment (hylan G-F 20). Patients were evaluated using Western Ontario McMaster Universities (WOMAC®) Scores and the Short-Form health survey up to 6 months post-injection (Month 6). Drug consumption and safety were evaluated. Results: Among 164 treated patients, 147 completed the study. The JTA-004 formulation containing 200 μg clonidine and 20 mg hyaluronic acid in 2 ml (JTA-200/2) was selected based on interim results at Month 6. The difference in adjusted mean change in WOMAC Pain Subscale Score from baseline (JTA-200/2 minus reference group) at Month 6 was − 9.49 mm; statistical superiority of JTA-200/2 over the reference was not demonstrated. No statistically significant differences in adjusted mean changes from baseline between JTA-200/2 and reference groups were observed for Pain, Physical Function and Stiffness Subscales WOMAC Scores, Total WOMAC Score, and Well being Score at any timepoint, although JTA-200/2 induced larger improvements in WOMAC Scores than the reference. Statistically significantly larger improvements in WOMAC Pain Subscale Scores for JTA-004 versus the reference were observed in post-hoc analyses on pooled data from all JTA-004 formulations at Month 6 (p = 0.030) and Month 3 (p = 0.014). All JTA-004 formulations had clinically acceptable safety profiles. Conclusions: This study provided preliminary evidence of the safety of intra-articular injection of JTA 004 in knee osteoarthritis patients. Phase III randomized controlled trials with larger sample sizes are needed to evaluate the efficacy of JTA-004 in knee osteoarthritis

High prevalence of high-risk human papillomavirus in palatine tonsils from healthy children and adults.

The aim of this study was to determine the prevalence of human papillomavirus (HPV) in 80 tumor-free tonsils from healthy children and adults using a sensitive E6/E7 type-specific polymerase chain reaction (PCR).Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study

Background: New minimally invasive treatments are vital to delay joint replacement surgery in patients with knee osteoarthritis. This study was designed to select the most effective among three formulations of an enhanced protein solution containing clonidine, hyaluronic acid, and human plasma (JTA-004), and compare the safety and efficacy of intra-articular administration of the selected formulation with a reference treatment (hyaluronic acid) in symptomatic knee osteoarthritis patients. Methods: In this two-stage, double-blind, phase II/III study conducted in 12 Belgian centers, 50–79-year-old patients with primary knee osteoarthritis were randomized (1:1:1:1) to receive one dose of one of three JTA-004 formulations (differing in clonidine concentration [50 or 100 μg/ml] and volume [2 or 4 ml]) or the reference treatment (hylan G-F 20). Patients were evaluated using Western Ontario McMaster Universities (WOMAC®) Scores and the Short-Form health survey up to 6 months post-injection (Month 6). Drug consumption and safety were evaluated. Results: Among 164 treated patients, 147 completed the study. The JTA-004 formulation containing 200 μg clonidine and 20 mg hyaluronic acid in 2 ml (JTA-200/2) was selected based on interim results at Month 6. The difference in adjusted mean change in WOMAC Pain Subscale Score from baseline (JTA-200/2 minus reference group) at Month 6 was − 9.49 mm; statistical superiority of JTA-200/2 over the reference was not demonstrated. No statistically significant differences in adjusted mean changes from baseline between JTA-200/2 and reference groups were observed for Pain, Physical Function and Stiffness Subscales WOMAC Scores, Total WOMAC Score, and Well-being Score at any timepoint, although JTA-200/2 induced larger improvements in WOMAC Scores than the reference. Statistically significantly larger improvements in WOMAC Pain Subscale Scores for JTA-004 versus the reference were observed in post-hoc analyses on pooled data from all JTA-004 formulations at Month 6 (p = 0.030) and Month 3 (p = 0.014). All JTA-004 formulations had clinically acceptable safety profiles. Conclusions: This study provided preliminary evidence of the safety of intra-articular injection of JTA-004 in knee osteoarthritis patients. Phase III randomized controlled trials with larger sample sizes are needed to evaluate the efficacy of JTA-004 in knee osteoarthritis. Trial registration: Clinicaltrials.gov/identifier NCT02740231; clinicaltrialsregister.eu/identifier 2015–002117-30. Retrospectively registered 13/4/2016.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Safety and efficacy of intra-articular injection of JTA-004, a novel viscosupplement, in symptomatic knee osteoarthritis: a randomized, double-blind controlled phase II/III study

Objective: The objective was to assess the safety and efficacy of a single intra-articular administration of JTA-004, a novel viscosupplement, in patients suffering from symptomatic knee osteoarthritis (OA) at 6 months. Design and methods: In this prospective, multicenter, double-blind phase II/III trial (NCT02740231), 164 patients with primary OA knee pain were randomly assigned to one of the three JTA-004 strengths or the comparator treatment (Hylan G-F 20) in a 1:1:1:1 ratio. Safety was assessed by monitoring and reporting vital signs, physical examination, adverse events and concomitant medications. The primary efficacy endpoint was the change from baseline at 6 months in WOMAC® VA3.1 pain subscale. Results: JTA-004 was shown to be well tolerated at all strengths evaluated. At 6 months, patients in the three JTA-004 groups showed a better improvement in pain compared to patients in the comparator group although statistical significance was not achieved. As the three JTA-004 strengths had a similar efficacy, a post hoc analysis was subsequently performed between the pooled JTA-004 treated patients and the comparator group. The exploratory analysis showed a 26.1±2.4 (adjusted mean±SE) mm improvement in pain in the pooled JTA-004 group vs. 15.6±4.1 mm in the comparator group at 6 months, demonstrating a statistically significant superiority of JTA-004 over the comparator (p = 0.030). Conclusions: This study provides first evidences of safety and efficacy of JTA-004 in the treatment of symptomatic knee OA. Efficacy will be further confirmed in a subsequent pivotal Phase III study