Mifamurtide for the treatment of nonmetastatic osteosarcoma

International audienceINTRODUCTION: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60-70% of patients with nonmetastatic osteosarcoma for more than 30 years. AREAS COVERED: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma. EXPERT OPINION: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations

Long-Term Alterations of Cytokines and Growth Factors Expression in Irradiated Tissues and Relation with Histological Severity Scoring

PURPOSE: Beside its efficacy in cancer treatment, radiotherapy induces degeneration of healthy tissues within the irradiated area. The aim of this study was to analyze the variations of proinflammatory (IL-1α, IL-2, IL-6, TNF-α, IFN-γ), profibrotic (TGF-β1), proangiogneic (VEGF) and stem cell mobilizing (GM-CSF) cytokines and growth factors in an animal model of radiation-induced tissue degeneration. MATERIALS AND METHODS: 24 rats were irradiated unilaterally on the hindlimb at a monodose of 30 Gy. Six weeks (n=8), 6 months (n=8) and 1 year (n=8) after irradiation the mediators expression in skin and muscle were analyzed using Western blot and the Bio-Plex® protein array (BPA) technology. Additional histological severity for fibrosis, inflammation, vascularity and cellularity alterations scoring was defined from histology and immnunohistochemistry analyses. RESULTS: A significant increase of histological severity scoring was found in irradiated tissue. Skin tissues were more radio-sensitive than muscle. A high level of TGF-β1 expression was found throughout the study and a significant relation was evidenced between TGF-β1 expression and fibrosis scoring. Irradiated tissue showed a chronic inflammation (IL-2 and TNF-α significantly increased). Moreover a persistent expression of GM-CSF and VEGF was found in all irradiated tissues. The vascular score was related to TGF-β1 expression and the cellular alterations score was significantly related with the level of IL-2, VEGF and GM-CSF. CONCLUSION: The results achieved in the present study underline the complexity and multiplicity of radio-induced alterations of cytokine network. It offers many perspectives of development, for the comprehension of the mechanisms of late injuries or for the histological and molecular evaluation of the mode of action and the efficacy of rehabilitation techniques

Adjuvant synergy: the effects of nasal coadministration of adjuvants

Modern peptide and protein subunit vaccines suffer from poor immunogenicity and require the use of adjuvants. However, none of the currently licensed adjuvants can elicit cell-mediated immunity or are suitable for mucosal immunization. In this study we explored the immunological effect of nasal co-administration of adjuvants with distinct functions: cholera toxin subunit B, a potent mucosal adjuvant that induces strong humoral responses, muramy di-peptide (MDP), an adjuvant known to elicit cell mediated immunity but rarely used nasally, and chitosan, an adjuvant that achieves specific physiological effects on mucosal membranes that improve antigen uptake. Groups of five female BALB/c mice received on days 1 and 56 nasal instillations of the recombinant Helicobacter pylori antigen urease admixed to single or multiple adjuvant combinations. Serum IgG kinetics were followed over 24 weeks. At the conclusion of the experiment, local antibody responses were determined and antigen-specific recall responses in splenocyte cultures were assayed for proliferation and cytokine production. The combination of adjuvants was shown to further contribute to the increased antigenicity of recombinant H. pylori urease. The data presented here outline and support facilitation of increased immunomodulation by an adjuvant previously defined as an effective mucosal adjuvant (chitosan) for another adjuvant (MDP) that is not normally effective via this route