LIPOSOMAL FORMULATION AND ITS USE IN ANTI-TUMOR THERAPY

Abstract

The present invention relates to a liposomal formulation containing exclusively a bacterial lipopolysaccharide (LPS) for its anti-tumor therapeutic use. It also relates to a pharmaceutical combination product comprising: - a liposomal formulation containing exclusively an LPS; and - at least one therapeutic antibody.

Description

LIPOSOMAL FORMULATION AND ITS USE IN ANTI- THERAPY TUMORAL FIELD OF INVENTION The present invention relates to the pharmaceutical field, and more particularly to the field of oncology, specifically to the field of cancer treatment. More particularly, the present invention concerns a pharmaceutical composition intended to treat a tumor, this composition being used as such or as an adjuvant to another therapeutic compound. STATE OF THE ART Cancer is a disease characterized by the uncontrolled multiplication of cells within an organism, this multiplication being linked to genetic mutations affecting the DNA of these cells. These mutations appear spontaneously or are induced following exposure to mutagenic agents, or are transmitted hereditarily. Cancer cells of various origins, having excessive cell proliferation, give rise to a "tumor", that is to say a tissue mass which tends to persist and grow within the tissue of origin, and possibly spread to other tissues. In the case of circulating cancer cells, particularly blood cells, these cells are characterized by an uncontrolled, chaotic growth and division capacity. Today, numerous anti-tumor therapies exist. The available treatments, while not exhaustive, include surgical removal of the tumor, chemotherapy (administration of drugs designed to destroy cancer cells), radiotherapy (irradiation of the tumor), hormonal treatments, anti-angiogenic treatments, and immunotherapy. Immunotherapy is a treatment that involves administering biological substances, usually produced by the immune system, to strengthen and / or stimulate an organism's immune defenses. It has been observed that, when a tumor develops, the affected organism generates its own immune response. An immune response against the tumor occurs when the tumor cells are recognized as such by the immune system. However, this immune response is generally insufficient to eliminate the tumor. The goal of immunotherapy is therefore to support and / or replace this inadequate biological response. Biological substances used in immunotherapy include, for example, antibodies, including monoclonal antibodies, cytokines, interleukins, interferons, and generally any immunostimulatory compound. For each type of tumor, clinicians decide on the treatment(s) to be applied based on previously validated medical protocols and the specific characteristics of each patient. Currently available treatments can still be improved, as none are completely effective or suitable for all types of patients. In immunotherapy, studies have been conducted to enhance the beneficial effects of administering a therapeutic antibody. For example, patent application WO 2013 / 129936 describes the therapeutic use of a combination consisting of an antibody and an immunomodulator encapsulated in a particulate or vesicular material. The encapsulated immunomodulator is typically a cytokine wrapped in a liposome, the co-administration of which stimulates the beneficial effects of the antibody. Liposomes A liposome is an artificial vesicle formed by concentric lipid bilayers that trap molecules between them. Liposomes are most commonly composed of phospholipids, either one or several types. These phospholipids organize themselves in a thermodynamically stable state such that the polar heads cluster together, allowing the formation of a bilayer. Liposomes are structures of nanometer size. Liposomes can retain several types of compounds, whether they are water-soluble (encapsulated in the aqueous phase) or lipid-soluble or amphiphilic (packaged in the lipid bilayer). The use of liposomes in the pharmaceutical industry, as a carrier for various molecules of biological interest, has been the subject of numerous studies and several Drugs of this type are currently approved for intravenous administration. Indeed, encapsulating active substances in liposomes ensures their protection. It also limits the toxic effects of these substances and regulates their release rate. Furthermore, liposomes allow water-soluble substances to pass through the hydrophobic cell membrane. Liposomes are increasingly used in therapy as drug delivery vehicles. Their primary use is the targeting of active ingredients. Bacterial lipopolysaccharide (LPS) Bacterial lipopolysaccharide (LPS) is the main component of the outer membrane of Gram-negative bacteria. LPS possesses strong immunostimulatory capabilities; its presence in an organism stimulates the entire immune system, notably through the secretion of pro-inflammatory cytokines, in order to respond to bacterial infection. Due to this strong immune response, the injection of soluble LPS can be toxic, even lethal at high doses, to mammals. In humans, LPS induces reactions such as hyperthermia, red blood cell aggregation, and septic shock. The LPS molecule is composed of three components: lipid A, the nucleus, and the O antigen. Lipid A, which represents the most toxic part of LPS, is highly conserved; the nucleus is very stable; while the O antigen is specific to the bacterial species from which the LPS originates. The mechanism of action and signaling pathways of LPS are well understood. Its target cells are primarily macrophages, monocytes, granulocytes, and epithelial cells. Once released into the body, LPS binds to the liver-synthesized LPS-Binding Protein (LBP), which allows its presentation and binding to the monocyte membrane receptor CD14. LPS then also associates with the membrane co-receptor MD2 and with the TLR4 receptor in its homodimerized form. The formation of this membrane complex induces the activation of the MAP kinase pathway and the secretion of pro-inflammatory cytokines within the cell. In basic research, LPS is used / n vitro and in vivo, to induce inflammation linked to a strong secretion of pro-inflammatory cytokines by monocyte or macrophage type cells. In therapy and especially in prophylaxis, LPS or its entity 'lipid A' is used as a vaccine adjuvant, to stimulate a targeted immune response against an antigen co-administered with said LPS. Liposomal formulation of LPS It has been shown that the encapsulation of LPS in liposomes minimizes these pro-inflammatory effects both in vitro and in vivo (Bakouche et al., 1987; Dijkstra et al., 1989). In anti-tumor therapy, LPS has been used as an adjuvant to stimulate the immune response to a specific antigen: Neidhart et al. (Vaccine, 2004) described a treatment method for patients with colorectal cancer, including the administration of a therapeutic vaccine consisting of a liposomal formulation comprising both a recombinant KSA protein and monophosphoryl lipid A (active constituent of LPS); the majority of patients treated with this therapeutic vaccine developed specific immunity against the KSA protein. A liposomal formulation of LPS has already been used in the preparation of anti-tumor vaccine compositions, with LPS being used for its adjuvant properties. Its co-formulation with an antigen optimizes the specific immune response against that antigen. However, to date, it had never been envisaged to use LPS as the sole active ingredient, in a liposomal formulation, for therapeutic use. DESCRIPTION OF THE INVENTION Encapsulating LPS in liposomes minimizes its toxic effects, thus allowing the use of this liposomal formulation in therapy, particularly in systemic anti-tumor treatment. The present invention relates to a liposomal formulation containing exclusively a bacterial lipopolysaccharide (LPS) for its anti-tumor therapeutic use. More generally, the present invention relates to a liposomal formulation containing exclusively a bacterial lipopolysaccharide (LPS) for use as a medicinal product. The present invention also relates to a pharmaceutical combination product comprising: - a liposomal formulation containing exclusively LPS; and - at least one therapeutic antibody. The invention also relates to said therapeutic combination product for its simultaneous, separate or sequential use in anti-tumor therapy. DESCRIPTION OF THE FIGURES Figure 1. Tumor volume tracking of untreated (controls) or treated mice bearing RL lymphoma xenografts (reference ATCC CRL-2261 CD20+ human B lymphoma cells) (controls) or treated with unencapsulated LPS, durituximab, empty liposomes, a liposomal formulation of LPS and a combination of rituximab + liposomal formulation of LPS. Figure 2. Weight of treated mouse spleens: control mice (CTRL), treated with empty liposomes (Lipo-Void), treated with Rituximab antibody (Ritux), treated with unencapsulated LPS (LPS), treated with a liposomal formulation of LPS (Lipo-LPS), and treated with a combination of Rituximab antibody and a liposomal formulation of LPS (Ritux + Lipo-LPS). Figure 3. Number of NK cells in the spleens of treated mice: control (untreated) mice, mice treated with the antibody Rituximab (Ritux), mice treated with unencapsulated LPS (LPS), mice treated with empty liposomes (Lipo-Vide), mice treated with a liposomal formulation of LPS (Lipo-LPS), and mice treated with a combination of the antibody Rituximab and a liposomal formulation of LPS (Ritux + Lipo-LPS). Figure 4. Tumor volume monitoring of RL lymphoma xenograft-bearing mice treated with (i) Rituximab, (ii) a combination of Rituximab with a liposomal formulation of LPS, or (iii) a combination of Rituximab with unencapsulated LPS. Figure 5. Tumor volume tracking of scid mice bearing MDA-MB-231 cancer cell xenografts, treated with liposomal formulation of LPS (Lipo LPS, curve in grey) or untreated (CONTROL). DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the identification of novel immunostimulatory properties of bacterial lipopolysaccharide (LPS). Due to its toxicity, this immunostimulatory compound cannot be used as such. LPS has already been used as an adjuvant in vaccines, in a liposomal formulation containing an antigen and LPS. The inventors have highlighted the fact that a liposomal formulation of LPS, containing no other compounds and in particular no antigens, can be used as a drug, and more specifically that this formulation has beneficial therapeutic effects in the context of anti-tumor treatment. According to a first aspect, the invention relates to a liposomal formulation containing exclusively a bacterial lipopolysaccharide (LPS) for its use as a medicinal product. According to a second aspect, the invention relates to a liposomal formulation containing exclusively a bacterial lipopolysaccharide (LPS) for its anti-tumor therapeutic use. In other words, the present invention relates to a pharmaceutical formulation consisting of a bacterial LPS encapsulated in liposomes, for its use in therapy, in particular for its anti-tumor therapeutic use. For the purposes of this invention, "cancer" is defined as a disease characterized by the presence in an organism of cancerous cells, formed by the transformation of initially normal cells of the organism affected by this disease. A living organism exhibiting such cancerous cells is diagnosed as having cancer. There are approximately 200 different types of cancer, depending on the tissue where the first tumor, known as the primary tumor, develops. For the purposes of this invention, "tumor" means a tissue mass resulting from an excessive proliferation of cancerous cells, this tissue mass having a tendency to persist and grow in an unregulated and autonomous manner with respect to the organism. The present invention relates to all types of tumors, but particularly to malignant tumors. Malignant tumors usually grow rapidly and tend to recur after local eradication. Malignant tumors are poorly circumscribed, non-encapsulated, and have irregular borders. The present invention relates to the treatment of primary tumors and secondary tumors resulting from the metastatic dissemination of a primary tumor. Tumors are generally classified according to their tissue of origin: for example, we distinguish between tumors of the skin, bones, or blood cells. Two main categories of tumors have been defined: So-called "solid" tumors develop in tissues such as the skin, Mucous membranes, bones, and organs. These are the most common tumors. common: they account for 90% of human cancers. Among solid tumors, we distinguish carcinomas, which originate from epithelial cells (skin, mucous membranes, glands); and sarcomas, which originate from connective tissue cells. So-called "liquid" tumors originate from blood cells and are not Strictly speaking, they are tissue outgrowths, but are characterized by the presence of cancerous blood cells with the capacity to uncontrolled, chaotic growth and division. Among liquid tumors, a distinction is made between leukemias (cancers of the blood and bone marrow), characterized by the uncontrolled multiplication of precursor cells of white blood cells in the bone marrow; and lymphomas (cancers of the lymphatic system) which affect lymphocytes. According to one particular aspect of the invention, the tumor being treated is a liquid tumor or a solid tumor. According to another particular aspect of the invention, the tumor being treated is chosen from the group consisting of: a breast tumor, a lung tumor, a skin tumor (melanoma), a blood tumor (leukemia), and a lymphoma. Cellular immunotherapy For the purposes of this invention, "anti-tumor treatment" or "anti-tumor therapy" or "anti-tumor therapeutic use" means a therapeutic treatment intended to reduce the volume, inhibit growth, decrease aggressiveness, modify malignant functional characteristics, and / or eliminate a tumor present in an organism. To determine and monitor the effectiveness of anti-tumor treatment, one indicative parameter is the change in tumor size or volume within the body over time. In laboratory animals, tumor size is most often measured after the animals have been euthanized. In patients, tumor size can be measured in vivo using non-invasive imaging techniques, which are well known to medical professionals. As illustrated in Figures 1 and 5, the liposomal formulation containing exclusively LPS significantly reduces the development of a xenografted human tumor in mice, compared to the tumor development observed in untreated control mice. Figure 1 shows the results obtained with mice xenografted with RL lymphoma cells, and Figure 5 shows the results obtained with mice bearing breast cancer tumors (formed from MDA-MB361 cells). The present invention relates in particular to a liposomal formulation containing exclusively an LPS for its use as an immunotherapy agent. The present invention also relates to a liposomal formulation containing exclusively LPS for use as an agent stimulating the innate immune system. More specifically, the present invention relates to a liposomal formulation containing exclusively an LPS for its use as an anti-tumor cell immunotherapy agent. Immunotherapy is a therapeutic approach that involves stimulating the internal immune functions of an organism affected by cancer, so that the body's immune system is able to inhibit the growth or even eliminate a developing tumor within it. Among the immune actors involved in the recognition and destruction of cancer cells are 'Natural Killer' cells, hereinafter referred to as NK cells. These are lymphocytes capable of recognizing tumor tissue, infiltrating it, and exerting specific cytotoxicity towards tumor cells. Anti-tumor cell immunotherapy is a therapeutic approach that involves stimulating NK cells, their development and / or their activity, so that they recognize and lyse tumor cells. As illustrated in Figures 2 and 3, administering a liposomal formulation containing exclusively LPS to mice significantly increases the number of NK cells present in the spleen of the animals. Thus, it appears that a liposomal formulation containing exclusively LPS stimulates the multiplication of NK cells, and therefore acts as a cellular immunotherapy agent, promoting the cytotoxic cellular response against tumor cells. Liposomal formulation For the purposes of the invention, a liposomal formulation means a composition comprising liposomes encapsulating an active ingredient, said active ingredient being referred to as "encapsulated" or "contained in a liposomal formulation". In this application, the terms "liposomal formulation of LPS", "liposomal formulation containing exclusively an LPS", "liposomes-LPS" and "LPS encapsulated in liposomes" are used interchangeably and all refer to the same formulation as defined above, namely a formulation / composition consisting of liposomes encapsulating a bacterial lipopolysaccharide. Liposomes, also known as liposomal particles, are vesicles in which a lipid phase consisting of a bilayer of amphiphilic molecules, such as phospholipids or cholesterol, traps an internal aqueous phase. A distinction is made between unilamellar liposomes, which comprise a single lipid bilayer, and multilamellar liposomes, which comprise several concentric lipid bilayers. Phospholipids are lipids containing a phosphoric acid group. They are lipids composed of a polar (hydrophilic) head and two aliphatic (hydrophobic) tails. This family notably includes phosphatidic acids and phosphoglycerides. The physicochemical properties of phospholipids depend on the nature of the polar head molecule. hydrophilic, and the nature of the aliphatic chains (fatty acids) of their hydrophobic tails. For the preparation of the liposomal formulation according to the invention, different types of phospholipids can be used. For example, the liposomal formulations presented in patent application WO 2013 / 129936 are suitable for implementing the present invention. The following phospholipids, though not exhaustive, may be used in combination: - DOPE' which refers to 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine; - 'DSPE' which refers to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine or distearoylphosphatidylethanolamine; -The 'PEGXXXX' which designates polyethylene glycol, with XXXX indicating the its molecular weight; in particular, PEG350 and the PEG5000; -The 'DSPE-PEGXXXX' which designates 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy-(polyethylene glycol)-XXXX]. - Cholesterol (3B-Hydroxy-5-cholestene, 5-Cholesten-3B-ol). According to a particular embodiment of the invention, the liposomal formulation consists of phospholipids of composition: DOPE: DSPE-PEG 5000: DSPE-PEG-350: Cholesterol (54:8:8:30 mol %). According to another particular embodiment of the invention, the liposomal formulation consists of phospholipids of the following composition: 18:1 (delta£-Cis) DSPE (DOPE) 18:0 PEG5000 DSPE (ammonium salts) 18:0 PEG350 DSPE (ammonium salts), and Cholesterol. Bacterial lipopolysaccharide (LPS) The liposomal formulation according to the invention contains exclusively a bacterial lipopolysaccharide, that is to say it does not contain any other active compound, and in particular does not contain any antigen, with the exception of the O antigen constituting LPS. In the context of the present invention, LPS is used as an agent stimulating the innate immune system, and not as an adjuvant to increase the specific immune response against a particular antigen. LPS, a component of the outer membrane of Gram-negative bacteria, is composed of three molecular entities linked together by covalent bonds: - lipid A; - |e“nucleus” consisting of an oligosaccharide; - and the O antigen. Lipid A, which is the most immunostimulatory part of LPS, is highly conserved from one bacterial species to another, the nucleus is very little variable, and the O antigen is specific to the bacterial species from which the LPS originates. Gram-negative bacteria include, but are not limited to, the following families: - Enterobacteriaceae family: oGenre Sa / monella o Genus Escherichia, for example Escherichia coli Yersinia genus - Vhrionaceae family oGenre Vbrno example: Vibriocholerae (responsible for cholera) - Family Pseudomonadaceae oGenre Pseudomonas - Neisseriaceae family oGenus Neisseria example: Neisseria meningitidis (responsible for bacterial meningitis) - Family of the Arhizohiaceae o Genus Agrobacterium example: Agrobacterium tumefaciens oGenus Rhizobium example: Rhizobium rhizogenes - Family A / caligenaceae oGenre Bordetella According to a particular aspect of the invention, the LPS contained in the liposomal formulation is derived from a bacterium of the Enterobacteriaceae family, in particular of the genus Escherichia, and in particular of the species Escherichia coli. The expression "LPS derived from a bacterium" indicates that the LPS molecule in question has the physicochemical characteristics of the LPS naturally present in the outer membrane of that bacterium. These characteristics include, in particular, the nature of the fatty acids constituting lipid A. LPS can be natural LPS or synthetic LPS. In particular, natural LPS can be purified from a bacterial membrane, using techniques well known to those skilled in the art, or obtained in a purified form from a commercial company such as SIGMA-ALDRICH. Synthetic LPS can be obtained by any synthesis technique known to a person skilled in the art. The LPS used can be encapsulated in liposomes in its full form (lipid A + nucleus + O antigen) or in an incomplete form, with only a fraction of the LPS being used. According to one particular aspect of the invention, the encapsulated LPS is used in an incomplete form, that is to say, as a fraction of LPS. More specifically, the LPS consists exclusively of its O antigen, or of its A lipid, or of a combination of the two. Lipid A of LPS from the bacterial species Escherichia coli is a dimer of B-1-6 glucosamine. More specifically, encapsulated LPS may consist of its lipid A used in the form of monophosphory! lipid A. It is understood that LPS can be modified, particularly to inhibit or potentiate its immunostimulatory properties. LPS may also be modified to alter its solubility or toxicity properties. According to a particular aspect of the invention, in the liposomal formulation for its therapeutic use, in particular anti-tumor, the LPS encapsulated in the liposomes is a modified LPS. Preparation and characterization of the liposomal formulation of LPS Any technique known to a person skilled in the art can be used to prepare a liposomal formulation containing exclusively an LPS. It is understood that the expression "exclusively an LPS" indicates that the liposomal formulation comprises only LPS molecules, to the exclusion of any other active compound and / or antigen. Encapsulated LPS is derived from a specific bacterial species, for example from Escherichia coli. According to a particular embodiment of the invention, said formulation comprises exclusively LPS molecules, these molecules being of different bacterial origins: thus, it may consist of one, two, three, or even more LPS molecules from different bacterial origins. For example, the liposomal formulation may comprise an LPS molecule from E. coli, an LPS molecule from a bacterium of the genus Samonel, and an LPS molecule from a bacterium of the genus Pseudomonas, said LPS molecules being in a complete or incomplete form. In other words, the pharmaceutical formulation consists of at least one bacterial LPS encapsulated in liposomes. As shown in the examples section, the phrase "liposomal formulation containing exclusively LPS" indicates that the LPS is well incorporated / encapsulated within the liposomal particles, and that this is not simply a juxtaposition in a medium. According to one particular aspect, the liposomal formulation preparation process includes successive freezing / thawing steps. According to another aspect of the invention, the process for preparing the liposomal formulation includes a step of sterilizing the liposomal formulation. According to yet another aspect of the invention, the process for preparing the liposomal formulation includes a step of filtering the liposomes, in order to obtain liposomal particles of homogeneous size. According to a preferred aspect of the invention, said liposomal formulation consists of liposomal particles of homogeneous size. Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising, in an acceptable pharmaceutical medium, at least one liposomal formulation containing exclusively a lipopolysaccharide. In other words, the said pharmaceutical composition comprises, in an acceptable pharmaceutical medium, at least one liposomal formulation consisting of a bacterial lipopolysaccharide encapsulated in liposomes. For the purposes of the invention, an acceptable pharmaceutical medium means a vehicle for preserving and administering the liposomal formulation, and optionally excipients, the administration of which to an individual or an animal does not result in significant adverse effects, and which are well known to those skilled in the art. A pharmaceutical composition according to the invention may include any necessary pharmaceutical excipient, such as buffering agents, agents for adjusting pH or isotonicity, or wetting agents. A pharmaceutical composition according to the invention may also include one or more antioxidants and / or one or more preservatives. A liposomal formulation, or a pharmaceutical composition as described above, may be administered by any suitable route, such as the oral, buccal, sublingual, ophthalmic, rectal, topical, or parenteral route, including intraperitoneal, intradermal, subcutaneous, intravenous, or intramuscular route. A pharmaceutical composition according to the invention can be formulated for oral administration in the form of a tablet, capsule or softgel, with prolonged or controlled release, a pill, a powder, a solution, a suspension, a syrup or an emulsion. According to another embodiment, a pharmaceutical composition according to the invention can be prepared for parenteral administration in injectable form. A pharmaceutical composition according to the invention can be sterilized by any known conventional method, such as filtration. The resulting aqueous solution can be packaged for use as is, or lyophilized. A lyophilized preparation can be combined with a sterile solution before use. According to a preferred embodiment of the invention, the pharmaceutical composition comprises an effective amount of a liposomal formulation containing exclusively an LPS. An effective amount of such a formulation corresponds to an amount that induces the desired response, namely a therapeutic effect, and more specifically an antiproliferative effect on tumor cells. The effective amount may depend on one or more parameters, such as the route of administration, whether it is administered as a single or multiple dose, and patient characteristics, including age, physical condition, height, weight, and the presence of any underlying medical conditions. more than that treated. These parameters and their influences are well known to those skilled in the art and can be determined by any known method. The present invention also relates to said pharmaceutical composition, for its use as a medicinal product, and more particularly for its anti-tumor therapeutic use. Administration The liposomal formulation containing exclusively LPS, or a pharmaceutical composition including it, for its anti-tumor therapeutic use, may be administered to a patient with cancer according to all techniques known to those skilled in the art. In particular, said liposomal formulation or pharmaceutical composition comprising it may be administered as a single dose, or in several doses over a continuous period. According to one particular aspect of the invention, the liposomal formulation for its use as described above, or a pharmaceutical composition comprising it, is administered once a week to a patient with cancer. The present invention also relates to a method of therapeutic treatment of a tumor, comprising administering to a patient with said tumor an effective amount of a liposomal formulation containing exclusively an LPS. Pharmaceutical combination product According to a second aspect, the invention relates to a pharmaceutical combination product comprising: - a liposomal formulation containing exclusively LPS; and - at least one other immunotherapy agent, preferably at least a therapeutic antibody. For the purposes of this invention, a pharmaceutical combination product refers to a set of therapeutic agents used together to treat the same condition, their administration being possible simultaneously, separately, or sequentially. Thus, the therapeutic agents may be either mixed in a single therapeutic composition or present in the same kit but administered completely separately, or sequentially. As previously mentioned, a liposomal formulation of LPS can be used in therapy either on its own or in combination with another therapeutic agent. This other therapeutic agent is preferably an immunotherapy agent, such as peptides or small non-peptide molecules exhibiting immunomodulatory activity; more preferably the immunotherapy agent is a therapeutic antibody. A therapeutic antibody is an antibody capable of specifically recognizing cells destined for destruction; in the case of cancer, these are naturally tumor cells. Tumor cells express antigens on their membrane surface, which can be recognized by antibodies directed against them. Therapeutic antibodies are generally coupled to a toxic substance capable of inducing the lysis of the tumor cell recognized by the antibody. Therapeutic antibodies can also act by blocking certain receptors on the membrane surface of tumor cells. These therapeutic antibodies are increasingly used in anti-tumor therapies. One example is rituximab, a monoclonal antibody that binds specifically to the CD20 transmembrane antigen, a protein located on B lymphocytes and expressed in more than 95% of B cells in non-Hodgkin lymphomas. This therapeutic antibody is indicated for the treatment of patients with stage II-IV follicular lymphomas. Another example is trastuzumab, which is specific to the HER2 receptor overexpressed by certain breast cancer tumor cells. According to one particular aspect of the invention, the therapeutic antibody contained in the combination product is a monoclonal antibody. According to another particular aspect of the invention, the therapeutic antibody contained in the combination product is a polyclonal antibody. According to a preferred aspect of the invention, the target of the therapeutic antibody is selected from the group consisting of: CD20, CD52, CD3, CD4, CDS, CD8, CD19, CD22, CD38, CD138, HER2, ErbB2, CD1, CD30, CD33, CD52, CD25, vascular endothelial growth factor (VEGF), endothelial growth factor receptor (EGFR), insulin-like growth factor receptor 1 (IGF1) and CTLA-4. According to yet another preferred aspect of the invention, the therapeutic antibody is chosen from the group of antibodies consisting of: abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, brentuximabvedotin, canakinumab, cetuximab, certolizumabpegol, cixutumumab, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomabtiuxetan, infliximab, ipilimumab (MDX-101), muromonab-CD3, natalizumab, necitumunab, obinutuzumab (GA-101), ocaratuzumab (AME-133v), ocrelizumab, ofatumumab, omalizumab, palivizumab, panitumumab, pertuzumab, PRO131921, ranibizumab, rituximab, SBI-087, tocilzumab, TRU-015, tositumomab, trastuzumab, veltuzumab, and any combination of these antibodies together. It is understood that, for the purposes of the invention, the combination product contains at least one therapeutic antibody, and that it may therefore comprise a combination of several therapeutic antibodies. According to a preferred embodiment of the invention, the therapeutic antibody is an anti-CD20 monoclonal antibody, and preferably is rituximab. The experimental results presented in Figure 1 show that: - in untreated mice with a tumor, the tumor volume increases over time; - if the mice are treated with rituximab, the volume of the The tumor always increases over time, but the volume is twice as large. less important, 46 days after the tumor transplant, than the volume of the tumor in control mice; - if the mice are treated with a combination product containing rituximab and a liposomal formulation of LPS, the tumor volume is identical at 23 days and 46 days post-transplant: the development of the The tumor is therefore completely inhibited. Figure 4 shows the difference observed between mice treated with this combination product, and mice treated with a combination product composed of rituximab and LPS not encapsulated in liposomes: the liposomal formulation of LPS is more effective at inhibiting tumor development. The present invention also relates to a pharmaceutical combination product as described above, for its simultaneous, separate or sequential use in anti-tumor therapy. More specifically, it relates to a pharmaceutical combination product as described above, for its simultaneous, separate or sequential use in anti-tumor immunotherapy. The present invention also relates to a method of therapeutic treatment of a tumor, comprising the administration to a patient with said tumor of at least one therapeutic antibody and a liposomal formulation containing exclusively an LPS, said administration being carried out simultaneously, separately or sequentially. The present invention also relates to a kit comprising: a liposomal formulation containing exclusively LPS; and at least one therapeutic antibody. EXAMPLES Example 1. Preparation, analysis, and characterization of liposomal formulations in which LPS molecules (LPS extracted and purified from Escherichia coli O55:B5) are encapsulated: LPS liposomes Liposome-LPS formulations were synthesized according to the following procedure: Lipid composition of the liposomal formulation: DOPE: DSPE-PEG 5000: DSPE-PEG-350:Chol (54:8:8:30 mol%) Dissolution of lipids in a chloroform / methanol mixture (9:1) Preparation of the lipid film after evaporation of organic solvents. Evaporation is carried out using a rotary evaporator The lipid film is hydrated by adding PBS (buffered saline solution) containing 100 jg of LPS / mL in the flask placed on a rotary evaporator, without vacuum. To improve the encapsulation rate, a series of freezings (in liquid nitrogen) — defrosting (in lukewarm water) is applied to the Liposome-LPS suspension. Extrusion of the liposome-LPS solution yields liposomes of uniform size. To achieve this, the liposome-LPS solutions are filtered through polycarbonate membranes of 800, 400, and 200 nm. After five passes through each membrane, the resulting liposomes are produced. The filter ensures the size of the liposomes is homogeneous and the liposomes-LPS solution is translucent. The size (mean diameter), polydispersity index (PDI), and charge of the liposomal preparations were analyzed by dynamic light scattering using a Zetasizer Nano-S from Malvern Instruments (Worcestershire, UK). Three-month analysis of two liposomal preparations demonstrated their stability (Table 1). Table 1: In vitro analysis of the interaction of the liposomal formulations thus produced (using a fluorescent component) with human blood leukocytes demonstrated a strong interaction of the liposomes with granulocytes and monocytes. Interaction with the lymphocyte fraction was not observed (results not shown). Furthermore, the incubation of human blood leukocytes with LPS liposomes and analysis by flow cytometry allowed us to highlight the activation of phagocytic activity. Confocal microscopy analysis of rhodamine B-labeled liposome-LPS formulations in which LPS molecules are coupled to the fluorochrome FITC allowed us to highlight the incorporation of LPS into liposomal particles. Finally, the homogeneity of the liposomal particles was validated by electron microscopy after negative staining. Example 2. Preclinical evaluation of the adjuvant effect of liposomal LPS formulations on rituximab activity in a mouse model bearing RL cell xenografts In this experiment, six groups of Scid CB17 mice were used. Each group consisted of six mice. Group 1 = control (no treatment) Group 2 = Empty Liposomes Group 3 = LPS 0.5 mA / ml Group 4 = Rituximab 30mg / kg Group 5 = Liposomes-LPS 0.5 mg / kg Group 6 = Liposomes-LPS 0.5 mg / kg + Rituximab 30mg / kg Monitoring tumor growth after weekly injection of the different treatments demonstrated the potentiating effect of rituximab's antitumor activity through the preparation of LPS liposomes. This potentiating effect resulted in a significant reduction in tumor growth after the combination of rituximab and LPS liposomes compared to the group of mice treated with rituximab alone (Figure 1). Analysis of the effect of the different treatments on the size of the spleen after animal sacrifice revealed a significant increase in the size and weight of the spleen in the case of animals treated with liposomes-LPS and the combination of Rituximab and Liposomes-LPS compared with animals in the other groups (Figure 2). NK cells are innate immune cells that are known to play an important role in antitumor responses. Flow cytometry analysis of the effect of different treatments on leukocyte subpopulations in the spleen revealed a significant increase in the number of Natural Killer (NK) cells in the spleen of animals treated with LPS-liposomes and the combination of Rituximab and LPS-liposomes compared with animals in other groups (Figure 3 shows the percentage of NK cells relative to all leukocyte cells in the sample). Figure 4 shows, in the same animal model of SCID mice grafted with RL lymphoma cells, the comparative effects obtained with the once-weekly administration of: rituximab (30 mA / kg) rituximab and "conventional" LPS of E. coli (0.5 mA / kA) rituximab and liposomal formulation of LPS, at the same doses as previously. This latest combination of rituximab and encapsulated LPS provides the best inhibition of tumor development after transplantation. Example 3. Antitumor action of the liposomal formulation of LPS in solid tumor xenograft models The anti-tumor action of the liposomal formulation of LPS has also been shown in another animal model of tumors, SCID mice xenografted with breast cancer tumor cells: MDA-MB-231 cells. The results presented in Figure 5 show the evolution of tumor volume over time, depending on the treatments administered to the mice: Group 1: untreated control mice (3 mice); Group 2: mice treated by intravenous administration of the formulation LPS liposomal. Monitoring tumor growth after weekly injection of the various treatments demonstrated the anti-tumor activity of the LPS liposomes. This activity resulted in a significant reduction in tumor growth after LPS liposomes compared to the untreated mouse group. REFERENCES PATENT WO 2013 / 129936 BIBLIOGRAPHICAL REFERENCES Bakouche O, Koff WC, Brown DC, Lachman LB. / nierleukin 1 released by human monocytes treated with liposome-encapsulated lipopolysaccharide. J. Immunol. 1987 Aug 15; 139(4):1120-6. Dijkstra J, Mellors JW, Ryan JL. Affered in vivo activity of liposome-incorporated lipopolysaccharide and lipid A. Infect Immun. 1989 Nov, 57(11):3357-63. Neidhart J, Allen KO, Barlow DL, Carpenter M, Shaw DR, Triozzi PL, Conry RM. Immunization of colorectal cancer patients with recombinant baculovirus-derived KSA (Ep-CAM) formulated with monophosphoryl lipid A in liposomal emuision, with and without granulocyte-macrophage colony-stimulating factor. Vaccine. 2004 Jan 26; 22(5-6):773-80.

Claims

DEMANDS 1. Liposomal formulation containing exclusively a lipopolysaccharide bacterial (LPS) for its anti-tumor therapeutic use.

2. Liposomal formulation containing exclusively a lipopolysaccharide bacterial (LPS) for its use as a medicinal product.

3. Liposomal formulation for its use according to claim 1 or 2, characterized in that the LPS contained in the liposomal formulation is originating from a bacterium of the Enterobacteriaceae family, notably from genus Escherichia, and in particular of the species Escherichia coli. 4, Liposomal formulation for its use according to any one of the claims 1 to 3, characterized in that the LPS consists exclusively of its Lipid A.

5. Liposomal formulation for use according to one of the claims 1 to 4, characterized in that said liposomal formulation is constituted of liposomal particles of homogeneous size.

6. Liposomal formulation for use according to one of the claims 1 or 3 to 5, characterized in that the tumor is a liquid tumor or a solid tumor. {. Liposomal formulation for use according to one of the claims 1 or 3 to 6, characterized in that the tumor is chosen from the group consisting of: a tumor of the breast, lung, skin (melanoma), of blood (leukemia), and lymphoma.

8. Pharmaceutical combination product comprising: -a liposomal formulation containing exclusively an LPS such as defined in one of claims 1 to 5: and - at least one therapeutic antibody.

9. Pharmaceutical combination product according to claim 8, in which the target of the therapeutic antibody is chosen from the group consisting of: CD20, CD52, CDS, CD4, CD5, CD8, CD19, CD22, CD38, CD138, HER2, ErbB2, CD1, CD30, CD33, CD52, CD25, the factor of vascular endothelial growth factor (VEGF), the receptor for the endothelial growth factor receptor (EGFR) Insulin-like 1 (IGF1) and CTLA-4.

10. Pharmaceutical combination product according to claim 8 or 9, in which the therapeutic antibody is chosen from the group antibodies consisting of: abciximab, adalimumab, alemtuzumab, atlzumab, basiliximab, belimumab, bevacizumab, brentuximabvedotin, canakinumab, cetuximab, certolizumabpegol, cixutumumab, daclizumab, denosumab, eculizumab, efalzumab, gemtuzumab, golimumab, ibritumomabtiuxetan, infliximab, ipilimumab (MDX-101), muromonab-CD3, natalizumab, necitumunab, obinutuzumab (GA-101), ocaratuzumab (AME-133v), Oocrelizumab, ofatumumab, omalizumab, palivizumab, panitumumab, pertuzumab, PRO131921, ranibizumab, rituximab, SBI- 08 / 7, tocilzumab, TRU-015, tocitumomab, trastuzumab, veltuzumab, et any combination of these antibodies with each other.