Methods Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 µg/m². Pharmacokinetic analysis and cytokine dosages were performed. Natural Killer cells activity and toll-like receptors 4 polymorphism analysis were also performed.

开始日期2007-03-01

申办/合作机构

Centre Hospitalier Universitaire de Dijon

100 项与地磷莫德相关的临床结果

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100 项与地磷莫德相关的转化医学

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100 项与地磷莫德相关的专利（医药）

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项与地磷莫德相关的文献（医药）

2016-05-03·OncoImmunology2区 · 医学

TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models

2区 · 医学

ArticleOA

作者: Sassi, Nejia ; Racoeur, Cindy ; Jeannin, Jean-François ; Paul, Catherine ; Vergely, Catherine ; Rochette, Luc ; Lamrani, Myriam ; Yousfi, Nadhir ; Labbé, Jérôme ; Athias, Anne ; Bettaieb, Ali ; Boucher, Jean-Luc ; Guerreiro, Romain ; Seignez, Cédric ; Gauthier, Nolwenn

Toll-like receptor (TLR) 4 agonists have emerged as a new group of molecules used for cancer therapy. They have been exploited to enhance the immunogenicity of current chemotherapeutic regimens. However, their effects on cancer cells remain elusive. Here, we showed that a TLR4 agonist, namely a synthetic lipid A analog (ALA), OM-174, exhibits antitumor effects in several mammary tumor mouse models. We also showed that immune components are involved in such effects, as attested to by the failure of ALA to induce tumor regression or an increase of animal survival in mice knocked-out for interferon γ (IFNγ) or TLR4. TLR4 and IFNγ receptor (INFR2) expressed by cancer cells are involved in the antitumor efficacy of ALA since this last did not inhibit tumor growth in mice bearing a tumor but lacking TLR4 or IFNγ receptor 2 (IFNR2). Mechanistic investigations revealed that nitric oxide (NO), superoxide and peroxynitrite produced by uncoupling of inducible NO synthase (NOS II) in cancer cells are key mediators of ALA and IFNγ-mediated tumor growth inhibition. We present here a comprehensive picture of tumor cell death induction, in vivo and in vitro, by immunotherapy and for the first time the involvement of the TLR4/IFNγ/NOS II pathway in immunotherapy was investigated.

2014-11-30·Oncotarget

Senescence of tumor cells induced by oxaliplatin increases the efficiency of a lipid A immunotherapy via the recruitment of neutrophils

Article

作者: Rollet, Claire-Emmanuelle ; Bettaieb, Ali ; Martin, Amandine ; Racoeur, Cindy ; Scagliarini, Alessandra ; Jeannin, Jean-François ; Seignez, Cédric ; Paul, Catherine

Management of advanced colorectal cancer is challenging due to the lack of efficient therapy. The lipid A, OM-174 exhibited antitumor activity in colorectal cancer. We explored the anticancer efficacy of this compound in rats bearing large colorectal tumors in combination with the platinum derivative drugs oxaliplatin and cisplatin. While each drug used alone exhibited partial antitumor activity, sequential treatment with oxaliplatin or cisplatin for one week followed by lipid A injections induced a great regression of colorectal tumors, with more than 95% of rats cured from their tumors. This potent antitumor efficacy of the combined treatments was correlated to the sequential induction of cellular senescence by oxaliplatin, and of apoptosis, mainly triggered by the lipid A. Moreover, a recruitment of tumor-associated neutrophils with N1 phenotype as attested by the expression of inducible nitric oxide synthase was observed with combination of oxaliplatin and lipid A. Neutrophil recruitment within tumor microenvironment was due to oxaliplatin and lipid A-dependent release of neutrophil specific chemoattractants such as cxcl1 and 2. However the N1 phenotype is only dependent of lipid A treatment. These results suggest that the combination of chemotherapy with an immunotherapy is a promising approach to treat patients with advanced colorectal cancer.

2013-12-01·BMC Cancer2区 · 医学

Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

2区 · 医学

ArticleOA

作者: Catherine Paul ; Nicolas Isambert ; Christophe Ferrand ; Marc Bardou ; Kevin Ragot ; Pierre Fumoleau ; Gérard Lizard ; Sylvie Zanetta ; Jean-François Jeannin ; Jacques Bauer

BACKGROUNDLipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion.METHODSPatients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 μg/m(2). Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed.RESULTSSeventeen patients were included. The highest dose administered was 1000 μg/m(2) repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 μg/m(2) of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of TNF-alpha and IL-6 concentrations were detected after the first infusion and decreased progressively suggesting tolerance.CONCLUSIONOM-174 therapy was well tolerated at biologically active concentrations. Whereas the recommended dose was not determined, further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect.TRIAL REGISTRATIONNCT01800812 (ClinicalTrials.gov Identifier).

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床1期	-	Centre Hospitalier Universitaire de Dijon	2007-03-01
接种疫苗	临床1期	瑞士	OM Pharma SA	2000-09-27
接种疫苗	临床1期	英国	GSK Plc	2000-09-27
接种疫苗	临床1期	瑞士	OM Pharma SA	2000-09-27
接种疫苗	临床1期	英国	GSK Plc	2000-09-27
肿瘤	临床1期	-	Vifor Pharma AG	-
肿瘤	临床1期	-	Vifor Pharma AG	-