Human Muscle Progenitor Cells Displayed Immunosuppressive Effect through Galectin-1 and Semaphorin-3A

In human skeletal muscle, myoblasts represent the main population of myogenic progenitors. We previously showed that, beside their myogenic differentiation capacities, myoblasts also differentiate towards osteogenic and chondrogenic lineages, some properties generally considered being hallmarks of mesenchymal stem cells (MSCs). MSCs are also characterized by their immunosuppressive potential, through cell-cell contacts and soluble factors, including prostaglandin E-2 (PGE-2), transforming growth factor-β1 (TGF-β1), interleukine-10, or indoleamine 2,3-dioxygenase. We and others also reported that Galectin-1 (Gal-1) and Semaphorin-3A (Sema-3A) were involved in MSCs-mediated immunosuppression. Here, we show that human myoblasts induce a significant and dose-dependant proliferation inhibition, independently of PGE-2 and TGF-β1. Our experiments revealed that myoblasts, in culture or in situ in human muscles, expressed and secreted Gal-1 and Sema-3A. Furthermore, myoblasts immunosuppressive functions were reverted by using blocking antibodies against Gal-1 or Sema-3A. Together, these results demonstrate an unsuspected immunosuppressive effect of myoblasts that may open new therapeutic perspectives

Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: The randomized MabEase study

I Intravenous rituximab plus chemotherapy is standard treatment for diffuse large B-cell lymphoma. A subcutaneous formulation of rituximab is expected to simplify and shorten drug preparation and administration, and to reduce treatment burden. MabEase (clinicaltrials.gov Identifier: 01649856) examined efficacy, safety and patient satisfaction with subcutaneous rituximab plus chemotherapy in treatment- naïve patients with diffuse large B-cell lymphoma. Patients were randomized 2:1 to subcutaneous rituximab (intravenous 375 mg/m2 cycle 1; subcutaneous 1,400 mg cycles 2-8) or intravenous rituximab (375 mg/m2 cycles 1-8) plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 or 21 days. The primary endpoint was investigatorassessed complete response/unconfirmed complete response. Secondary endpoints included safety, treatment satisfaction (Cancer Treatment Satisfaction Questionnaire and Rituximab Administration Satisfaction Questionnaire), time savings, and survival. Of 576 randomized patients, 572 (378 subcutaneous; 194 intravenous) received treatment. End of induction complete response/unconfirmed complete response rates were 50.6% (subcutaneous) and 42.4% (intravenous). After a median 35 months, median overall, event-free and progression-free survivals were not reached. Grade ≥3 adverse events (subcutaneous 58.3%; intravenous 54.3%) and administration-related adverse events (both groups 21%) were similar between arms. Injection-site reactions were more common with subcutaneous injections (5.7% versus 0%, respectively). Rituximab Administration Satisfaction Questionnaire scores for ‘impact on activities of daily living’, ‘convenience’, and ‘satisfaction’ were improved with subcutaneous versus intravenous injections; Cancer Therapy Satisfaction Questionnaire scores were similar between arms. Median administration time (6 minutes vs. 2.6 to 3.0 hours), chair/bed and overall hospital times were shorter with subcutaneous versus intravenous rituximab. Overall, subcutaneous and intravenous rituximab had similar efficacy and safety, with improved patient satisfaction and time savings

A Phase 2 Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

International audienceBackground Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and treatment options are limited for those patients who relapse or fail to respond following initial therapy. We conducted a dose-escalation/expansion phase 2, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. Patients and Methods The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (up to 8 weekly doses); responding patients were eligible for maintenance therapy (biweekly administrations for up to 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m2. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. Results A total of 36 patients were treated: 19 during dose escalation; 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m2 (grade 3 peripheral motor neuropathy), and therefore 70 mg/m2 was selected for the dose-expansion phase. Five patients discontinued therapy due to adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of 17 evaluable patients treated at the selected dose, 4 responded (estimated ORR using Bayesian methodology: 25.47% [80% confidence interval: 14.18-39.6%]); DOR was 1.94 (range: 1-5.6) months. Based on these results, the study was prematurely discontinued. Conclusions Coltuximab ravtansine is well tolerated but is associated with a low clinical response rate in patients with relapsed/refractory AL

Thérapie cellulaire de l’insuffisance cardiaque

L’insuffisance cardiaque est un problème majeur de santé publique dans les pays industrialisés, et sa thérapeutique incomplètement efficace. C’est pourquoi la thérapie cellulaire a été développée comme nouvelle stratégie visant à améliorer la structure et la fonction du myocarde défaillant. Cet article décrit les différents types cellulaires envisagés dans cette perspective, ainsi que les premiers essais cliniques entrepris. La plupart des études ont été menées dans le cadre de l’insuffisance cardiaque post-ischémique. La transplantation de cardiomyocytes foetaux ou néonataux améliore chez l’animal la performance cardiaque, mais des problèmes immunologiques, logistiques et éthiques bloquent les perspectives cliniques d’une telle utilisation chez l’homme. En revanche, il semble que des cardiomyocytes adultes, autologues, pourraient être préparés à partir de cellules souches présentes dans différents tissus (moelle osseuse, vaisseaux, coeur adulte, tissu adipeux). Par ailleurs, des précurseurs vasculaires issus de la moelle osseuse ou du sang circulant pourraient promouvoir la néo-angiogenèse au sein du myocarde infarci, stimulant ainsi un pool de cardiomyocytes hibernants. L’utilisation de cellules souches hématopoïétiques issues de la moelle osseuse ou du sang circulant a également été proposée, mais leur capacité réelle de différenciation en tissu cardiaque ou endothélial, controversée, semble restreinte. Enfin, la transplantation de cellules musculaires squelettiques (myoblastes) améliore la fonction du myocarde infarci dans les modèles animaux et entraîne la formation in situ de tissu musculaire squelettique différencié. Ces données ont ouvert la voie au premier essai clinique mondial de phase I, qui s’est déroulé à Paris de juin 2000 à novembre 2001. Cet essai a nécessité la mise au point de la production de cellules musculaires squelettiques humaines à large échelle, selon les bonnes pratiques de fabrication. Ses résultats ont justifié la mise en place, en novembre 2002, d’un essai clinique de phase II randomisé, multicentrique, en double aveugle. En parallèle, des essais cliniques de phase I visent à évaluer la faisabilité et la tolérance d’injections de différents types de cellules préparées à partir d’autres tissus comme la moelle osseuse ou le sang périphérique. Cependant, des effets potentiellement délétères, qui seraient liés aux propriétés biologiques des cellules utilisées ou à leur voie d’administration, ont été récemment rapportés. Des essais cliniques de qualité, fondés sur des arguments précliniques solides, permettront de juger de la future place de la thérapie cellulaire dans la prise en charge de l’insuffisance cardiaque.Heart failure is becoming a major issue for public health in western countries and the effect of currently available therapies is limited. Therefore cell transplantation was developed as an alternative strategy to improve cardiac structure and function. This review decribes the multiple cell types and clinical trials considered for use in this indication. Most studies have been developed in models of post-ischemic heart failure. The transplantation of fetal or neonatal cardiomyocytes has proven to be functionally successful, but ethical as well as immunological and technical reasons make their clinical use limited. Recent reports, however, suggested that adult autologous cardiomyocytes could be prepared from stem cells present in various tissues (bone marrow, vessels, adult heart itself, adipose tissue). Alternatively, endothelial progenitors originating from bone marrow or peripheral blood could promote the neoangiogenesis within the scar tissue. Hematopietic stem cells prepared from bone marrow or peripheral blood have been proposed but their differentiation ability seems limited. Finally, the transplantation of skeletal muscle cells (myoblasts) in the infarcted area improved myocardial function, in correlation with the development of skeletal muscle tissue in various animal models. The latter results paved the way for the development of a first phase I clinical trial of myoblast transplantation in patients with severe post-ischemic heart failure. It required the scale-up of human cell production according to good manufacturing procedures, started in june 2000 in Paris and was terminated in november 2001, and was followed by several others. The results were encouraging and prompted the onset of a blinded, multicentric phase II clinical trial for skeletal muscle cells transplantation. Meanwhile, phase I clinical trials also evalutate the safeness and efficacy of various cell types originating from the bone marrow or the peripheral blood. However, potential side effects related to the biological properties of the cells or the delivery procedures are being reported. High quality clinical trials supported by strong pre-clinical data will help to evaluate the role of cell therapy as a potential treatment for heart failure

Place de la tomographie par emission de positons dans la prise en charge du lymphome folliculaire (expérience d'Amiens)

Introduction : la tomographie par émission de positons (TEP) est validée dans les lymphomes hodgkiniens et dans le lymphome B à grandes cellules mais sa place reste à préciser dans le lymphome folliculaire. Les objectifs de cette étude sont de préciser la place du TEP dans la prise en charge du lymphome folliculaire et de rechercher l existence d une corrélation entre le SUVmax et les marqueurs histologiques. Matériel et méthodes : tous les patients suivis au CHU d Amiens pour un lymphome folliculaire au diagnostic et/ou en rechute ayant eu au moins un TEP entre 2004 et 2011 ont été inclus rétrospectivement : soit 27 patients ayant eu 89 TEP. Nous avons évalué l expression des marqueurs GLUT-1 et Ki-67 et analysé le microenvironnement sur les biopsies initiales. Résultats : le TEP initial modifie le stade Ann Arbor dans 46% des cas, l augmente dans 33% des cas et accroît le FLIPI dans 25% des cas. Il n engendre pas de modification thérapeutique. La négativité du TEP de fin de traitement est associée à une PFS supérieure (39 mois versus 16 mois, p = 0,0002). Le TEP de surveillance n est pas prédictif du pronostic des patients et n a pas de place dans la prise en charge des lymphomes folliculaires. Cette étude ne comprend pas assez de patients pour conclure sur la place du TEP intermédiaire. L étude histologique montre une corrélation entre le pourcentage de macrophages dans la tumeur et le SUVmax (p = 0,04). Il n existe pas de corrélations entre le SUVmax et GLUT-1 ou Ki-67. Conclusion : le TEP de fin de traitement est corrélé au pronostic mais n a pas d incidence sur la prise en charge thérapeutique du patient. Une étude prospective plus large avec adaptation thérapeutique en fonction des résultats du TEP doit être envisagée.Introduction : PET is a powerful post therapy prognostic tool in Hodgkin Lymphoma and in Diffuse Large B Cell Lymphoma but its interest in Follicular Lymphoma remains indeterminate. This study aims at assessing the usefulness of PET in restaging follicular lymphoma and looking for a correlation between SUV and histology. Materials and methods : Data from 27 patients with Follicular Lymphoma at diagnostic or at relapse from 2004 to 2011 were retrospectively studied. GLUT-1 and Ki-67 expression and microenvironment have been analyzed from initial biopsies. Results : Initial PET modifies Ann Arbor staging in 46% of cases and increases it in 33% of cases. PET increases FLIPI in 25% of cases. It doesn t imply patients management modification. PFS of patients with negative end treatment PET (39 months) is higher than PFS of patients with positive PET (16 months) (p = 0,0002). The surveillance PET isn t correlated with prognosis and has not to be realized. There are a too small number of patients to conclude on intermediary PET interest. The histological study shows a correlation between macrophage number in tumor and SUVmax (p = 0,04). There isn t any correlation between GLUT-1 expression and SUVmax. Conclusion : End treatment PET is correlated with prognosis but there is no impact on patient management. A larger prospective study with modification of therapeutic strategy according to PET has to be realized.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Lymphomes de bas grade du sujet âgé de plus de 75 ans (étude rétrospective multicentrique de 65 cas en Picardie)

Introduction : La population des plus de 75 ans devrait tripler en 2030. La prévalence des LNH a triplé chez les >80 ans. Peu d études cliniques portent sur les LNH de bas grade. Matériel et Méthodes : Etude rétrospective et multicentrique de 65 patients âgés de plus de 75 ans suivis pour un LNH de bas grade : 38 pts avec un LF et 27 pts suivis pour LZM. L analyse a porté sur des données de SG et de PFS ainsi que sur l impact du Charlson, du FLIPI, des taux de LDH et d albumine. Résultats : Le bilan initial est incomplet pour environ des pts, évaluation gériatrique faite pour de 20% des pts. LF: avec un follow-up médian de 23,5 mois, 31 pts ont reçu une chimiothérapie avec un taux de RG de 74%. La SG des 38 pts est de 62,5% (58-72) à 2 ans, meilleure chez les 11 pts en WW. En analyse univariée et multivariée, le Charlson >= 2 et le FLIPI > 2 sont des facteurs pronostics péjoratifs de la SG (p=0.04 et p=0.001) mais pas de la PFS. Seul un taux de LDH > N est associé à une diminution de la PFS (p=0.03). LZM : Avec un follow-up médian de 25 mois, la SG des LZM est de 71% (59-83) à 2 ans chez les pts traités, de 92,5% pour les patients en WW (p=0.03). En univariée, des taux d Hb N sont associés à une diminution de la SG (p=0.003, p=0.03, p=0.03) ; un taux d Hb < 12g/dl a un impact péjoratif sur la PFS. Ces facteurs ne sont pas significatifs pour les pts en WW. Discussion et conclusion : L évaluation initiale des patients est incomplète. Un FLIPI ajusté à l âge serait nécessaire, la Bendamustine pourrait être évaluée chez ces patients. Dans les LZM quels critères de traitement retenir ? Le Rituximab doit il être proposé en 1ère intention chez ces malades ?AMIENS-BU Santé (800212102) / SudocSudocFranceF

Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells