Papers by Olivier Hermine
bioRxiv (Cold Spring Harbor Laboratory), Mar 12, 2024
Background: Masitinib is an orally administered tyrosine kinase inhibitor that targets activated ... more Background: Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system. We have studied the neuroprotective action of masitinib on the manifestations of experimental autoimmune encephalitis (EAE) induced axonal and neuronal damage. EAE is a model of neuroimmune-driven chronic neuroinflammation and therefore highly relevant to masitinib's mechanism of action in neurodegenerative diseases (NDD). Importantly, neuronal damage, or prevention thereof, can be rapidly assessed by measuring serum neurofilament light chain (NfL) concentration in EAE-induced mice. Methods: EAE induction was performed in healthy female C57BL/6 mice via active MOG 35-55 peptide immunization. Treatments were initiated 14 days post EAE induction. On day-0 (D0), 39 mice with established EAE symptoms were randomly assigned to 3 treatment groups, comprising 13 mice per group; namely, EAE control (CTRL), masitinib 50 mg/kg/day (M50), and masitinib 100 mg/kg/day (M100). Treatment started on D1 and ended on D15. Blood samples were collected at D1, D8 (via tail vein sampling) and D15 (via intracardiac puncture). Assessments included quantification of serum NfL levels along the disease duration, cytokine quantification at D15, and clinical assessments. Results: Masitinib treatment significantly (p <0.0001) limited NfL production with respect to CTRL; specifically, relative change in serum NfL concentration at D8 was 43% and 60% lower for the M50 and M100 groups, respectively. Likewise, for the assessment of absolute serum NfL at D8 and D15, there was a significantly lower NfL concentration for masitinib treatment as compared with CTRL, with a more pronounced treatment effect for M100 as compared with M50. Overall, EAE mice treated with masitinib also showed significantly lower concentrations of several well-established pro-inflammatory cytokines (IFN-gamma, IL-1beta, KC/GRO, TNF-alpha, IL-33, and MIP-2) relative to CTRL at D15. A beneficial effect of masitinib on functional performance was also observed, with both M50 and M100 groups showing significantly less relative deterioration in grip strength at D15 as compared with CTRL (p <0.001). Conclusion: This study is the first demonstration that masitinib can lower serum NfL levels, and by extension therefore, neuronal damage, in a neuroimmune-driven neurodegenerative disease model, with
Springer eBooks, 2015
An introductory remark is necessary. The considerations to come later in the book are part of the... more An introductory remark is necessary. The considerations to come later in the book are part of the vision of the so-called Western medicine, sometimes called scientific medicine, that is to say, the vision prevailing widely in the medical and scientific world of developed countries and those associated with them. Furthermore geography may be abused because when we talk about the countries of the South to set health priorities or dominant pathologies, Australia and New Zealand, to name only these two countries, despite their geographical position, will, of course, not be affected. Anyway, the fight against cancer would be optimized: detect early, closer to population and treatment without delay and having also an active policy in area of prevention. But if the status of Tropical Oncology and reasoning in absolute terms must be improve, it is logical to see cancer winning in the hierarchy of medical concerns.
Orphanet Journal of Rare Diseases, Jun 16, 2015
We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene... more We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene who developed chronic myelomonocytic leukemia (CMML) leading to an uncontrolled and fatal inflammatory syndrome. Plasma levels of IL-6 and IL-18 were found to be very high, as compared to healthy controls and CMML-free FMF patients. Our study unveils the interplay between two different disorders involving the same target cells, suggesting that in myelodysplasia with inflammatory manifestations, mutations in genes causing autoinflammatory syndromes, like MEFV, can be present and thus could be sought. Early chemotherapy with interleukin inhibitors could be proposed in such unusual situations.
The European respiratory journal, Feb 3, 2022
Louis Tharaux 6°, Philippe Ravaud 4° on the behalf of the CORIMUNO-19 collaborative group*
Cancers
Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine L... more Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly,...
Alzheimer's Research & Therapy
European Respiratory Journal
We read with interest the comment of R. Dal-Ré on the CORIMUNO-19 trials design [1-5]. The key ar... more We read with interest the comment of R. Dal-Ré on the CORIMUNO-19 trials design [1-5]. The key argument is that the cohort multiple randomised controlled trial (cmRCT) design implies an alteration of the informed process that can only be justified if three requirements are fulfilled: the research has important social value, it poses no more than minimal risks to participants, and it would be impracticable to carry out without consent process modification [6]. R. Dal-Ré acknowledges that the first two requirements were fulfilled for CORIMUNO-19 trials, but argues that, given the huge number of patients hospitalised with severe or critical coronavirus disease 2019 (COVID-19) in March 2020, trials would have been feasible without consent modification. At the time when CORIMUNO-19 trials were designed, the huge number of COVID-19 patients in French hospitals did not mean that conducting clinical research was facilitated. Indeed, physicians were overwhelmed, the whole hospital and care systems were de-organised, and clinical research infrastructures were not fully operational, for instance because staff were not allowed to go onsite. Let us first recall the situation we faced: 1) It was difficult to plan a trial with scarce knowledge on the disease (e.g. what was the prognosis of patients); 2) Knowledge on the disease was expected to move quickly; 3) Usual care and the prognosis of patients would likely change rapidly; 4) There would be the need to evaluate many different treatments, all of which were not yet identified. Accordingly, our choice of a cmRCT was based on the following considerations: 1) We wanted to plan a series of trials with the same master protocol to be quick and reactive and respond to the urgency of the situation, while keeping high ethical standards; 2) We wanted to set up a cohort to standardise data collection for COVID-19 patients even if they were not eligible/included to a trial; 3) The foreseen rapid evolution of disease management and prognosis, and differences in centre practices, would necessitate comparing patients receiving the evaluated intervention to controls treated in the same sites at the same time. For instance, this third point led us to discard platform designs where new intervention groups are compared to a shared control group comprising participants who have been enrolled to the trial before this new intervention arm was added [7]. Instead of a cmRCT design, R. Dal-Ré recommends using a platform trial. Actually, the CORIMUNO-19 is a platform trial. Indeed, there is no unique platform trial design, which corresponds to a specific form of trial in which substudies can possibly be added or terminated dynamically during the course of the trial, under a common trial infrastructure [8]. This is exactly what the CORIMUNO-19 trials aimed at. The design allowed to quickly set up trials in the early pandemics in France.
European Respiratory Journal
BackgroundOur objective was to determine whether anti-interleukin (IL)-6 receptors improve outcom... more BackgroundOur objective was to determine whether anti-interleukin (IL)-6 receptors improve outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. We report on two cohort-embedded, investigator-initiated, multicentre, open-label, Bayesian randomised controlled clinical trials.MethodsPatients were randomly assigned to receive either usual care (UC) or UC+tocilizumab (TCZ) 8 mg·kg−1 (TOCI-2 trial) or UC or UC+sarilumab (SARI) 200 mg (SARI-2 trial), both intravenously on day 1 and, if clinically indicated, on day 3.ResultsBetween 31 March and 20 April 2020, 97 patients were randomised in the TOCI-2 trial, to receive UC (n=46) or UC+TCZ (n=51). At day 14, numbers of patients who did not need noninvasive ventilation (NIV) or mechanical ventilation (MV) and were alive with TCZ or UC were similar (47% versus 42%; median posterior hazard ratio (HR) 1.19, 90% credible interval (CrI) 0.71–2.04), with a posterior probability of HR >1 of 71.4%. Between 27 Marc...
The initial step in retroviral infection involves specific interactions between viral envelope pr... more The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the HTLV-1 Env were identified by analyzing the effects of neutralizing antibodies and specific mutations in Env on HTLV-1 infectivity. More recent studies have revealed that HTLV-1 infectivity involves interactions with three different molecules: heparan sulfate proteoglycans (HSPG), the VEGF-165 receptor Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT1). Here, we revisit previously published data on the functional domains of Env in regard to the recent knowledge acquired about
JAMA Internal Medicine, 2021
COMMENT & RESPONSE In Reply Our randomized clinical trial, 1 along with several other studies as ... more COMMENT & RESPONSE In Reply Our randomized clinical trial, 1 along with several other studies as detailed by Parr, 2 has demonstrated no differences in mortality at days 28 or 30 when tocilizumab was used in treatment for patients with COVID-19. Benefits of this drug in specific subpopulations of patients, particularly those more seriously ill and inflamed, cannot be excluded. Recently, early results released from the Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) international platform trial showed that tocilizumab was effective in critically ill patients. 3 In an observational study 4 in the Reggio Emilia area, considering 172 patients consecutively treated with tocilizumab, the percentage of patients who died after tocilizumab therapy was similar to that of patients with COVID-19 hospitalized in the same time period and not treated with tocilizumab after a follow-up of more than 1 month. However, when some of our researchers considered the subgroup of patients undergoing noninvasive ventilation, tocilizumab reduced the risk of being intubated or dying. 5 Randomized clinical trials are needed to confirm these results. We completely agree with Rossi et al that C-reactive protein (CRP) is an easy biomarker of interleukin-6 (IL-6) inhibitor efficacy and that CRP serial determinations are useful in evaluating clinical response to tocilizumab. Using general linear model analyses for repeated measures, some of our group observed that CRP serial measurements after tocilizumab therapy are useful in identifying patients developing poor outcomes. 4 A similar marked reduction in CRP levels at day 3 was observed between patients intubated or who died and those with a favorable outcome at the end of follow-up. 4 However, at day 7, a significant and steady decrease continued to be observed only in patients with a favorable outcome, whereas in patients who died or were intubated CRP levels increased again. The proposed association between an anti-IL-6R antibody and an anti-IL-6 antibody to provide synergistic inhibition of IL-6 signaling is intriguing, because in autoimmune conditions the increased level of free IL-6 during tocilizumab treatment closely reflects the disease activity. We also completely agree with Bell and Pollara that there is the urgent need to elucidate the mechanism and the immunopathologic significance of IL-6 inhibition induced by tocilizumab in COVID-19. COVID-19-induced hyperinflammation is a complex interplay among inflammatory cytokines, activated immune cells, viral load, and host immune response. It is a heterogeneous
Blood, 2020
Introduction: Regular red blood cell (RBC) transfusions are the main supportive treatment for chr... more Introduction: Regular red blood cell (RBC) transfusions are the main supportive treatment for chronic anemia due to β-thalassemia. Transfusion-dependent pts require ICT to prevent iron overload from RBC transfusions, and associated complications. Thus, there is a clinical need to reduce transfusions and iron burden in pts with anemia due to β-thalassemia. Luspatercept, an erythroid maturation agent, is approved by the FDA for treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. The phase 3, double-blind, randomized, placebo (PBO)-controlled BELIEVE study is evaluating the efficacy and safety of luspatercept in adult pts with β-thalassemia requiring regular RBC transfusions (NCT02604433; Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Here we assess the effect of long-term luspatercept use on iron loading and ICT use in the BELIEVE trial. Methods: Pts were ≥ 18 years with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassem...
Blood, 2014
Background: Patients (pts) with advanced systemic mastocytosis (SM), including aggressive SM (ASM... more Background: Patients (pts) with advanced systemic mastocytosis (SM), including aggressive SM (ASM) and mast cell leukemia (MCL) ± associated clonal hematologic non–mast cell lineage disease (AHNMD), have a poor prognosis with few effective treatment options. More than 80% of pts express the activating KIT D816V mutation. The oral multikinase inhibitor midostaurin inhibits wild-type and D816-mutated KIT. In this global phase 2 trial (NCT00782067), the largest prospective trial in advanced SM, a planned interim analysis of stage 1 pts demonstrated a high overall response rate (ORR) with reductions in marrow mast cell (MC) burden and a favorable safety profile (Gotlib et al, Blood 2012). Updated stage 1 results showed improvements in symptoms and quality of life (QOL) (Gotlib et al, Blood 2013). Here, we report primary results for the fully accrued trial. Methods: This single-arm trial consisted of an adapted Fleming 2-stage design. Midostaurin 100 mg twice daily was administered in co...
La Presse Médicale, 2004
Intérêt de l'administration à domicile des immunoglobulines intraveineuses chez l'adulte
Hépato-Gastro & Oncologie Digestive, Nov 1, 2014
Quelle est la prevalence de l’anemie par carence martiale et ses principales causes pour les pati... more Quelle est la prevalence de l’anemie par carence martiale et ses principales causes pour les patients referes en consultation specialisee d’hematologie ?La prevalence de l’anemie par carence martiale depend essentiellement de l’âge a laquelle elle survient presente dans 1 % a 5 % de la population dans les pays developpes et plus frequente chez la femme. Elle est d’origine gynecologique ou digestive dans la plupart des cas, liee a un exces de perte de fer mais parfois [...]
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 29, 2016
Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variabilit... more Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and G...
Cancer medicine, Jan 26, 2015
Although most of the mantle cell lymphoma (MCL) patients initially responded well to bortezomib (... more Although most of the mantle cell lymphoma (MCL) patients initially responded well to bortezomib (BTZ), the dose-dependent toxicities have greatly limited the application of BTZ to MCL. To investigate the efficacy and mechanism of arsenic trioxide (ATO) with BTZ in inducing apoptosis of MCL cells, two MCL cell lines, along with primary cells from MCL patients (n = 4), were used. Additionally, the NOD-SCID mice xenograft model of Jeko-1 cells was established to study the anti-MCL mechanisms in an in vivo setting. ATO treatment highly improved BTZ capacity to inhibit proliferation and induce apoptosis of MCL cells. Furthermore, the interaction of Noxa and Mcl-1 leads Bak to release from Mcl-1 or from Bcl-xl, which could further activate Bak and Bax and then induce cell apoptosis. We also found that when lower doses of BTZ were used in combination with ATO, more effective proapoptotic effects in both the cell lines and the primary cells were obtained compared to the effects of BTZ used ...
Orphanet Journal of Rare Diseases, 2015
We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene... more We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene who developed chronic myelomonocytic leukemia (CMML) leading to an uncontrolled and fatal inflammatory syndrome. Plasma levels of IL-6 and IL-18 were found to be very high, as compared to healthy controls and CMML-free FMF patients. Our study unveils the interplay between two different disorders involving the same target cells, suggesting that in myelodysplasia with inflammatory manifestations, mutations in genes causing autoinflammatory syndromes, like MEFV, can be present and thus could be sought. Early chemotherapy with interleukin inhibitors could be proposed in such unusual situations.
The Veterinary Journal, 2012
Masitinib, a selective tyrosine kinase inhibitor, has previously been shown to enhance the antipr... more Masitinib, a selective tyrosine kinase inhibitor, has previously been shown to enhance the antiproliferative effects of gemcitabine in human pancreatic cancer, demonstrating potential as a chemosensitizer. This exploratory study investigated the ability of masitinib to sensitize various canine cancer cell lines to doxorubicin, vinblastine, and gemcitabine. Masitinib strongly sensitized histiocytic sarcoma cells to vinblastine (&amp;amp;gt;70-fold reduction in IC(50) at 5 μM masitinib), as well as osteosarcoma and mammary carcinoma cells to gemcitabine (&amp;amp;gt;70-fold reduction at 5-10 μM). In addition, several cell lines were sensitized to doxorubicin (2-10-fold reduction at 10 μM). These data establish proof-of-concept that masitinib in combination with chemotherapeutic agents can generate synergistic growth inhibition in various canine cancers, possibly through chemosensitization. The findings justify further investigation into those combinations that may potentially yield therapeutic benefit.
Leukemia & Lymphoma, 2012
Tumor-associated macrophages (TAMs) might be associated with worse outcome in classical Hodgkin l... more Tumor-associated macrophages (TAMs) might be associated with worse outcome in classical Hodgkin lymphoma (cHL). Our aim was to determine whether TAMs correlated with refractoriness in cHL. In a cohort of 18 consecutive primary refractory or early relapsed cases and 41 randomly selected controls (responder patients), high TAM infiltration was significantly associated with refractoriness or early relapse (p = 0.004) and remained independently correlated with outcome in multivariate analysis (odds ratio 8.276, 95% confidence interval 1.214-56.408). This study provides evidence that the marker CD68 might accurately predict early outcome of de novo cHL and could be used in combination with c-kit and TiA1 staining.
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Papers by Olivier Hermine