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EP2714078A1 - Agents for treating tumours - Google Patents

Agents for treating tumours

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Publication number
EP2714078A1
EP2714078A1 EP12723201.5A EP12723201A EP2714078A1 EP 2714078 A1 EP2714078 A1 EP 2714078A1 EP 12723201 A EP12723201 A EP 12723201A EP 2714078 A1 EP2714078 A1 EP 2714078A1
Authority
EP
European Patent Office
Prior art keywords
tumor
product according
cancer
cpg
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12723201.5A
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German (de)
French (fr)
Inventor
Antoine Carpentier
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Assistance Publique Hopitaux de Paris APHP
Universite Sorbonne Paris Nord Paris 13
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Universite Sorbonne Paris Nord Paris 13
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Publication of EP2714078A1 publication Critical patent/EP2714078A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • C—CHEMISTRY; METALLURGY
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/17—Immunomodulatory nucleic acids
    • C—CHEMISTRY; METALLURGY
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
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    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy

Definitions

  • the invention relates to the treatment of patients with a brain tumor or tumor meningitis, using a TRL9 receptor agonist agent in combination with an antiangiogenic product.
  • CpG-ODNs are short synthetic single-stranded DNA molecules containing a "C” cytosine followed by a “G” guanine.
  • the "p” refers to the phosphodiester spine of DNA, but most CpGs have a phosphorothioate backbone. When these CpG motifs are unmethylated, they have an immunostimulatory effect (Weiner et al., 1997, Proc Natl Acad Sci USA 94 (20): 10833-7).
  • CpG-ODNs are also described in the literature as immunostimulatory oligonucleotides.
  • CpG-ODN are TLR9 receptor agonists (Toll-like Receptor 9, also known as CD289, OMIM: 605474; MGI: 1932389; HomoloGene: 68126) which is expressed by dendritic cells and B cells (Rothenfusser et al. al., 2002 Human immunology 63 (12): 1-11).
  • Activation of TRL9 receptors of dendritic cells by CpG-ODN leads to the activation of these cells and the production of cytokines such as interleukin (IL) 12 or interferons (IFN) type I (such as IFN- ⁇ or IFN- ⁇ ).
  • IL interleukin
  • IFN interferons
  • CpG-ODN CpG-ODN
  • Clinical Cancer Research 2000 6: 2469-73
  • several clinical trials have been conducted in glioblastomas with this molecule, which has shown good tolerance, but still insufficient efficacy (Carpentier et al., Neuro-oncology, 2006 8: 60- 2006; Carpentier et al. ., 2010, op.cit.).
  • VEGF Vascular Endothelial Growth Factor
  • Bevacizumab marketed by Roche under the name Avastin
  • Avastin has already been obtained in several cancer indications, such as colon cancer, lung cancer and glioblastoma recurrence.
  • Tumor meningitis results from the invasion of intraventricular and meningeal spaces (subarachnoid spaces) by tumor cells (from a brain tumor or corresponding to a meningeal metastasis of a systemic cancer with or without cerebral localizations) .
  • the diagnosis is based on a lumbar puncture, and the use of MRI which can highlight tumor nodules or abnormal enhancement, particularly at the medullary level.
  • neoplastic meningitis secondary to solid tumors The prognosis of neoplastic meningitis secondary to solid tumors is catastrophic.
  • the majority of patients have a median spontaneous survival of about 4 months (between 3 and 7 months) but this figure varies according to the type of primary cancer (breast cancer: 7 months, small cell lung cancer: 4 months, melanoma : 3.6 months, malignant gliomas: 3 months)
  • No therapy is effective (with the exception of Methotrexate and Depocyte (Cytarabine) in hematological cancers).
  • Carpentier et al (“Intracerebral Administration of CpG Oligonucleotide for Patients with Recurrent Glioblastoma: a Phase II Study.”, Neuro-Oncology, 2010) discloses the use of CpG ODN for the treatment of brain tumor.
  • Chamberlain et al. (Cancer, 2010) ivulgue the use of anti VEGF antibodies to treat glioblastomas.
  • the associations discussed in Peak et al (op cit) are also mentioned. Others are suggested or tested (erlotinib, etoposide, fotemustine, carbamazepine).
  • bevacizumab to treat tumor meningitis is suggested.
  • Carpentier et al (Cancer Immunotherapy with CpG-ODN., Médecine Sciences, 2005) discusses the interest of immunostimulatory oligonucleotides in cancer immunotherapy.
  • the association of CpG ODNs with antigens, antibodies or dendritic cells is reported to be effective.
  • the associations discussed are OVA (melanoma), herceptin (breast cancer) and rituxan (non-Hodgkin lymphoma).
  • OVA melanoma
  • herceptin breast cancer
  • rituxan non-Hodgkin lymphoma
  • Zhao et al (“Carbon Nanotubes Enhance CpG Uptake and Potentate Antiglioma Immunity", Clinical Cancer Research, Feb. 15, 201 1) describes a study on the administration of CpG in the brain using carbon nanotubes (summary).
  • El Andaloussi et al (“Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and probongs survival of mite with experimental brain tumors", Glia, 2006) discloses the beneficial effect of CpG in an experimental model of brain tumor.
  • Sorrentino et al show that administration of CpG ODN increases VEGF production in a murine carcinoma model of the lung. This result is similar to those reported by Pinhal-Enfield et al (op.cit.). None of these documents describe or suggest the use of a combination of TRL9 receptor agonist and antiangiogenic agent for the treatment of a brain tumor or tumor meningitis, although many discuss interest of a combination of different drugs for the treatment of brain tumor. In particular, none of these documents makes it possible to envisage the unexpected effect reported in the present application, of synergy or cooperation between a TRL9 receptor agonist and antiangiogenic agent for the treatment of a brain tumor or a tumor. tumor meningitis.
  • TLR9 is restricted in humans mainly to B lymphocytes and plasmocytoid dendritic cells (pDC), whereas the expression is broader in mice including the myeloid lineage (macrophages, monocytes, myeloid dendritic cells). (Carpentier, 2003).
  • mice can not be generalized systematically in humans.
  • effective animal models combining CpG-ODN with other molecules (eg Damiano et al., (Clin Cancer Res 2006; 12: 577-583) which describes the combined use of CpG-ODN with cetuximab or gefitinib in xenograft models of colon cancers on nude mice) or the combination of bevacizumab with other molecules, the results of which could not be confirmed in humans.
  • the invention thus relates to a product containing at least one TRL9 (Toll-like Receptor 9) receptor agonist agent in combination with an antiangiogenic agent for its simultaneous therapeutic use, separated or spread over time in the treatment of a patient with a tumor.
  • This tumor is preferably a tumor meningitis or an intracerebral tumor.
  • This patient is of the human race.
  • said TRL9 receptor agonist agent is an oligonucleotide, and in particular a cytosine-phosphorothioate-guanine CpG-ODN, oligodeoxynucleotide containing non-methylated cytosines and guanines.
  • This agonist oligonucleotide TLR9 type "CpG-ODN" or not
  • the immunostimulatory properties of nucleic acids, and CpG-ODN in particular are generally related to unmethylated 5'-CG motifs, under-represented motifs in vertebrate DNA (Krieg AM et al Nature 1995, 374: 546-549)
  • CpG-ODN synthetic oligodeoxynucleotides
  • CpG-ODNs synthetic oligodeoxynucleotides containing such motifs
  • CpG-ODNs retain marked immunostimulatory properties, particularly phosphorothioate ODNs that are resistant to nucleases.
  • CpG-ODNs are internalized by cells by endocytosis and bind to TLR9 in endosomes. In humans, TLR9s are predominantly selectively by B cells and plasmocytoid dendritic cells (pDCs).
  • Activation of B cells by CpG-ODN results in secretion of cytokines such as IL-6 or IL-10, cell proliferation, inhibition of apoptosis induced by various agents and immunoglobulin secretion (Klinman, Nat Rev Immunol 2004, 4: 249-59, Krieg, Curr Oncol Rep 2004, 6: 88-95, Carpentier et al, Front Biosci 2003, 8: El 15-27).
  • cytokines such as TNF ⁇ , interferon alpha or gamma, IL-6 or IL-12 and the expression of co-stimulatory molecules ( CD40, CD80, CD86) and CCR7, a receptor controlling migration to ganglion T regions.
  • co-stimulatory molecules CD40, CD80, CD86
  • CCR7 a receptor controlling migration to ganglion T regions.
  • the secretion of IL-12 and IFN gamma directs the immune response to the Th1 profile, and can even transform a Th2 response into Th1.
  • oligonucleotide The biological activity of an oligonucleotide depends on many variables, still imperfectly known, such as the chemical modifications of the backbone, the sequence of nucleotides surrounding the CpG motif or the number of CpG motifs. Some immunostimulatory oligonucleotides without CpG motifs have thus been described (US 20040006032).
  • the most CpG-ODN frequently used are phosphorothioate oligodeoxynucleotides, or mixed phosphorothioate / phosphodiester oligodeoxynucleotides (for example phosphorothioate / phosphodiester ends, or phosphorothioate ODNs, with the exception of cytosine-guanosine linkages which are phosphodiesters).
  • the oligodeoxynucleotides synthesized can also be purified according to their stereoisomerism to modify or improve their biological activity.
  • Type B (or “K)
  • Type A (or “D) ODNs are characterized by strong activation of NK and secretion of interferon alpha by pDCs.
  • Type C ODNs Combine the Properties of the 2 Previous Types Reviews have been published (Klinman, Nat Rev Immunol 2004, 4: 249-59, Krieg Curr Oncol Rep 2004, 6: 88-95).
  • CpG-ODNs A new class of CpG-ODNs, called class P, has recently been described (Samulowitz et al., Oligonucleotides, 2010 Apr; 20 (2): 93-101). These oligonucleotides contain two palindromic sequences and can thus form multimeric units. The efficiency of these class P molecules (especially as regards the ability to induce the expression of type I interferons) is greater than that of C-type CpG-ODNs.
  • Angiogenesis is a process that describes the growth of new blood vessels (neovascularization) from preexisting vessels. This process is controlled by different activators and inhibitors produced by healthy and tumor cells.
  • the activators include pro-angiogenic molecules (VEGF, FGF (Fibroblast Growth Factor), PDGF (Platelet-Derived Growth Factor)), inhibitors of anti-angiogenic molecules (angiostatin, thrombospondin).
  • anti-angiogenic agent any endogenous or exogenous agent capable of inhibiting angiogenesis.
  • any inhibitor of VEGF, FGF or PDGF may be mentioned.
  • This anti-angiogenic agent is preferably an inhibitor of VEGF, that is to say an agent limiting or inhibiting the action of endogenous VEGF.
  • the VEGF inhibitory agent may be an antibody (such as bevacizumab, monoclonal antibody) or a small organic molecule (such as sorafenib or sunitinib that inhibit VEGF receptors but also other receptors).
  • Other types of agents may also be mentioned, such as aflibercept, a fusion protein being developed by Sanofi Aventis, which "traps" VEGF or prolactin.
  • the VEGF inhibitor is preferably a monoclonal antibody.
  • said tumor is a benign or malignant primary brain tumor, such as a meningioma, a glial tumor (glioma), a medulloblastoma, or a pineal region tumor.
  • a benign or malignant primary brain tumor such as a meningioma, a glial tumor (glioma), a medulloblastoma, or a pineal region tumor.
  • the tumor is in particular an anaplastic glioma, such as anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, or a glioblastoma.
  • anaplastic glioma such as anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, or a glioblastoma.
  • said tumor is a metastatic brain extension of an extra-brain cancer, such as lung cancer, breast cancer, digestive cancer, melanoma or gynecological cancer.
  • an extra-brain cancer such as lung cancer, breast cancer, digestive cancer, melanoma or gynecological cancer.
  • said tumor is a tumor meningitis consecutive to a primary brain tumor, or a subarachnoid metastasis of an extra-cerebral cancer.
  • said tumor meningitis is consecutive to a benign or malignant primary brain tumor selected from a meningioma, a tumor glial (glioma), medulloblastoma, pineal region tumor, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, and glioblastoma.
  • a benign or malignant primary brain tumor selected from a meningioma, a tumor glial (glioma), medulloblastoma, pineal region tumor, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, and glioblastoma.
  • Said meningitis may also be consecutive to meningeal metastasis of lung cancer, breast cancer, digestive cancer (in particular colon or stomach cancer), melanoma or of a gynecological cancer.
  • said tumor is lung cancer (including small cell cancer), breast cancer, digestive cancer (including colon or stomach cancer), melanoma or gynecological cancer.
  • the agents making up the combination are administered to the patient after the completion of the antitumor treatment, in particular when the antitumor treatment is surgical excision, or radiotherapy, the administration of anti-cancer substances such as chemotherapy. , immunotherapy or any other form of treatment (ultrasound, electromagnetic fields), or a combination of these treatments.
  • the invention also relates to a method of treating a tumor patient (as defined above) comprising the step of administering a TRL9 receptor agonist agent in combination with an antiangiogenic agent patient audit.
  • the TRL9 receptor agonist agent is administered at a frequency of between once a week and once every two months, preferably between once a week and once a month, more preferably once every two weeks.
  • This agent is preferably administered intrathecally for brain tumors and tumor meningitis and / or subcutaneously.
  • this agent is preferably administered from local way (especially directly in the tumor for solid tumors, or near the tumor), to induce immunostimulation in the vicinity of the tumor. It is therefore in a form suitable for such administration intrathecally and / or subcutaneously, or in a form suitable for intravenous administration.
  • the anti-angiogenic agent is administered according to the recommendations of each molecule.
  • bevacizumab is administered at a frequency between once a week and once every two months, preferably once every two weeks.
  • the dose of use is determined by the practitioner, and is generally less than 15 mg / kg, more particularly 10 mg / kg.
  • the anti-angiogenic agent is administered intravenously.
  • Figure 1 Effect of anti-VEGF vaccination combined with local immunotherapy on tumor growth in a model of subcutaneous syngeneic glioma in rats.
  • Figure 2 Effect of anti-VEGF vaccination combined with local immunotherapy on animal survival in a rat subcutaneous syngeneic glioma model. (Animals are sacrificed when tumors reach 30mm in diameter).
  • Figure 3 Evolution of brain MRI in a patient as treatment progresses. The treatment administered between each MRI (compound used and number of injections) is specified. Examples
  • the CpG-ODNs used have the sequence SEQ ID No. 1, on a phosphorothioate backbone.
  • Example 1 Rats were immunized against VEGF-A using a recombinant VEGF protein and an immune adjuvant (polyarginine). This administration of VEGF thus induces an immune response which ultimately leads to an anti-angiogenic effect.
  • an immune adjuvant polyarginine
  • Figures 1 and 2 show that in a syngeneic glioma model
  • Example 2 Four patients had high-grade glioma with meningeal extension.
  • the treatment protocol for the patients was as follows:
  • Novel Toll-Like Receptor 9 Agonist Induces Epidermal Growth Factor Receptor (EGFR) Inhibition and Synergistic Antitumor Activity with EGFR Inhibitors

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Abstract

The invention relates to the treatment of patients with a brain tumour or tumour meningitis, using a TRL9 receptor agonist in combination with an anti-angiogenic product.

Description

AGENTS POUR LE TRAITEMENT DE TUMEURS  AGENTS FOR THE TREATMENT OF TUMORS
L'invention se rapporte au traitement de patients présentant une tumeur cérébrale ou une méningite tumorale, par utilisation d'un agent agoniste du récepteur TRL9 en combinaison avec un produit anti-angiogénique. The invention relates to the treatment of patients with a brain tumor or tumor meningitis, using a TRL9 receptor agonist agent in combination with an antiangiogenic product.
Au cours des dernières années, les essais cliniques dans le domaine de l'immunothérapie anticancéreuse se sont multipliés. Bien que les approches utilisées se soient parfois révélées efficaces en terme d'induction d'une réponse immune chez les patients, la proportion de patients développant une réponse clinique objective est quant à elle demeurée très faible. In recent years, clinical trials in the field of cancer immunotherapy have proliferated. Although the approaches used were sometimes effective in terms of inducing an immune response in patients, the proportion of patients developing an objective clinical response remained very low.
Ainsi, une approche d'immunothérapie de patients présentant un glioblastome récurrent par injection locale d'oligodéoxynucléotides présentant au moins un di-nucléotide CpG (Cytosine-phosphorothioate-Guanine) (CpG-ODN) (Carpentier ei a/., Neuro Oncol. 2010 Apr;12(4):401 -8) a été testée. Cette étude n'a pas permis d'atteindre le bénéfice attendu en termes de survie des patients, bien que certains patients aient présenté une survie à long terme.  Thus, an immunotherapy approach of patients with recurrent glioblastoma by local injection of oligodeoxynucleotides having at least one CpG (Cytosine phosphorothioate-guanine) di-nucleotide (CpG-ODN) (Carpentier et al., Neuro Oncol, 2010). Apr; 12 (4): 401-8) was tested. This study did not achieve the expected benefit in terms of patient survival, although some patients had long-term survival.
Les CpG-ODN sont des courtes molécules d'ADN simple brin de synthèse contenant une cytosine «C» suivie d'une guanine "G". Le «p» se réfère à la colonne vertébrale phosphodiester de l'ADN, mais la plupart des CpG ont un squelette phosphorothioate. Lorsque ces motifs CpG ne sont pas méthylés, ils ont un effet immunostimulant (Weiner et al., 1997, Proc. Natl Acad Sci USA 94 (20): 10833-7). CpG-ODNs are short synthetic single-stranded DNA molecules containing a "C" cytosine followed by a "G" guanine. The "p" refers to the phosphodiester spine of DNA, but most CpGs have a phosphorothioate backbone. When these CpG motifs are unmethylated, they have an immunostimulatory effect (Weiner et al., 1997, Proc Natl Acad Sci USA 94 (20): 10833-7).
Ces CpG-ODN sont aussi décrits dans la littérature comme des oligonucléotides immunostimulants.  These CpG-ODNs are also described in the literature as immunostimulatory oligonucleotides.
Les CpG-ODN sont des agonistes du récepteur TLR9 (Toll-like Receptor 9, aussi connu en tant que CD289, OMIM: 605474 ; MGI: 1932389 ; HomoloGene: 68126) qui est exprimé par les cellules dendritiques et les lymphocytes B (Rothenfusser et al., 2002 Human immunology 63 (12): 1 1 1 1-9).  CpG-ODN are TLR9 receptor agonists (Toll-like Receptor 9, also known as CD289, OMIM: 605474; MGI: 1932389; HomoloGene: 68126) which is expressed by dendritic cells and B cells (Rothenfusser et al. al., 2002 Human immunology 63 (12): 1-11).
L'activation des récepteurs TRL9 des cellules dendritiques par les CpG- ODN mène à l'activation de ces cellules et à la production de cytokines telles que l'interleukine (IL) 12 ou les interférons (IFN) de type I (tels que l'IFN-α ou l'IFN-β).  Activation of TRL9 receptors of dendritic cells by CpG-ODN leads to the activation of these cells and the production of cytokines such as interleukin (IL) 12 or interferons (IFN) type I (such as IFN-α or IFN-β).
L'administration de CpG-ODN dans ou à proximité d'une tumeur permet d'induire le rejet tumoral dans de multiples modèles animaux (Carpentier et al., Clinical Cancer Research, 2000 6: 2469-73 ; Carpentier et al., Front Biosci. 2003 8: E1 15-27). Chez l'homme, plusieurs essais cliniques ont été réalisés dans les glioblastomes avec cette molécule, laquelle a montré une bonne tolérance, mais une efficacité encore insuffisante (Carpentier et al., Neuro-oncology, 2006 8: 60- 2006 ; Carpentier et al., 2010 op. cit.). The administration of CpG-ODN in or near a tumor makes it possible to induce tumor rejection in multiple animal models (Carpentier et al. Clinical Cancer Research, 2000 6: 2469-73; Carpentier et al., Front Biosci. 2003 8: E1 15-27). In humans, several clinical trials have been conducted in glioblastomas with this molecule, which has shown good tolerance, but still insufficient efficacy (Carpentier et al., Neuro-oncology, 2006 8: 60- 2006; Carpentier et al. ., 2010, op.cit.).
Le VEGF (Vascular Endothelial Growth Factor) est un agent pro- angiogénique qui joue un rôle clé dans la croissance tumorale. Un anticorps monoclonal dirigé contre le VEGF, le Bevacizumab, commercialisé par la société Roche sous le nom d'Avastin, a déjà obtenu ΓΑΜΜ dans plusieurs indications de cancer, tels que le cancer du colon, le cancer du poumon et le glioblastome en récidive.  VEGF (Vascular Endothelial Growth Factor) is a pro-angiogenic agent that plays a key role in tumor growth. A monoclonal antibody against VEGF, Bevacizumab, marketed by Roche under the name Avastin, has already been obtained in several cancer indications, such as colon cancer, lung cancer and glioblastoma recurrence.
Un essai de phase III utilisant cet anticorps dans l'indication contre les glioblastomes de novo, en association avec le traitement standard de cette pathologie (radiothérapie et témozolomide) est actuellement en cours. Il n'a pas d'indication reconnue dans les méningites tumorales.  A phase III trial using this antibody in the indication against de novo glioblastoma, in combination with the standard treatment of this pathology (radiotherapy and temozolomide) is currently in progress. It has no recognized indication in tumor meningitis.
Les méningites tumorales résultent de l'envahissement des espaces intraventriculaires et méningés (espaces sous-arachnoïdiens) par des cellules tumorales (provenant d'une tumeur cérébrale ou correspondant à une métastase méningée d'un cancer systémique s'accompagnant ou non de localisations cérébrales). Le diagnostic repose sur une ponction lombaire, et l'utilisation de l'IRM qui peut mettre en évidence des nodules tumoraux ou des prises de contraste anormales, notamment au niveau médullaire. Tumor meningitis results from the invasion of intraventricular and meningeal spaces (subarachnoid spaces) by tumor cells (from a brain tumor or corresponding to a meningeal metastasis of a systemic cancer with or without cerebral localizations) . The diagnosis is based on a lumbar puncture, and the use of MRI which can highlight tumor nodules or abnormal enhancement, particularly at the medullary level.
Le pronostic des méningites néoplasiques secondaires aux tumeurs solides est catastrophique. La majorité des patients présentent une médiane de survie spontanée de 4 mois environ (comprise entre 3 et 7 mois) mais ce chiffre varie selon le type de cancer primitif (cancers du sein : 7 mois, cancers bronchiques à petites cellules : 4 mois, mélanome : 3,6 mois, gliomes malins : 3 mois) Aucune thérapeutique n'est efficace (à l'exception du méthotrexate et du Depocyte (Cytarabine) dans les cancers hématologiques).  The prognosis of neoplastic meningitis secondary to solid tumors is catastrophic. The majority of patients have a median spontaneous survival of about 4 months (between 3 and 7 months) but this figure varies according to the type of primary cancer (breast cancer: 7 months, small cell lung cancer: 4 months, melanoma : 3.6 months, malignant gliomas: 3 months) No therapy is effective (with the exception of Methotrexate and Depocyte (Cytarabine) in hematological cancers).
Ainsi, il n'existe pas à ce jour de traitement pour la plupart des méningites tumorales, qui pourraient permettre de soulager les patients et/ou augmenter leur survie (Recht et Phuphanich Expert Rev Neurother 2004 Jul; 4(4 Suppl): SI 1 -7 ; Glantz et al, Clin Cancer Res. 1999 Nov; 5(1 1 ):3394-402 ; Siegal J Neurooncol 1998 Jun-Jul;38(2-3): 15-17 ; Chamberlain. Neurosurgery. 2003, 52:324-29). Peak et al ("Robe of bevacizumab therapy in the management of glioblastoma", Cancer Management and Research, 2010) divulgue l'utilisation d'anticorps anti VEGF pour traiter des glioblastomes. Différentes associations d'anticorps anti VEGF avec irinotecan, temozolomide, de la chimiothérapie et des anticoagulants sont discutées, ainsi que leur intérêt. Thus, there is currently no treatment for most tumor meningitis, which could help relieve patients and / or increase their survival (Recht and Phuphanich Expert Neurother Rev 2004 Jul; 4 (4 Suppl): SI 1 Glantz et al, Clin Cancer Res, 1999 Nov; 5 (11): 3394-402; Siegal J Neurooncol 1998 Jun-Jul; 38 (2-3): 15-17; Chamberlain Neurosurgery, 2003, 52 : 324-29). Peak et al. (Cancer Management and Research, 2010) discloses the use of anti-VEGF antibodies to treat glioblastomas. Various associations of anti-VEGF antibodies with irinotecan, temozolomide, chemotherapy and anticoagulants are discussed, as well as their interest.
Carpentier et al ("Intracerebral administration of CpG oligonucleotide for patients with récurrent glioblastoma: a phase II study.", Neuro-Oncology, 2010) divulgue l'utilisation de CpG ODN pour le traitement de tumeur cérébrale.  Carpentier et al ("Intracerebral Administration of CpG Oligonucleotide for Patients with Recurrent Glioblastoma: a Phase II Study.", Neuro-Oncology, 2010) discloses the use of CpG ODN for the treatment of brain tumor.
Chamberlain et al ("Ernerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas", Cancer, 2010) ivulgue l'utilisation d'anticorps anti VEGF pour traiter des glioblastomes. Les associations discutées dans Peak et al (op. cit.) sont également mentionnées. D'autres sont suggérées ou testées (erlotinib, etoposide, fotemustine, carbamazepine). L'utilisation de bevacizumab pour traiter une méningite tumorale est suggérée.  Chamberlain et al. (Cancer, 2010) ivulgue the use of anti VEGF antibodies to treat glioblastomas. The associations discussed in Peak et al (op cit) are also mentioned. Others are suggested or tested (erlotinib, etoposide, fotemustine, carbamazepine). The use of bevacizumab to treat tumor meningitis is suggested.
Carpentier et al ("Cancer immunotherapy with CpG-ODN.", Médecine Sciences, 2005) discute de l'intérêt des oligonucléotides immunostimulants dans l'immunothérapie des cancers. L'association des CpG ODN avec des antigènes, des anticorps ou des cellules dendritiques est rapportée être efficace. Les associations discutées sont OVA (mélanome), herceptin (cancer du sein) et rituxan (lymphome non-hodgkinien). L'utilisation de CpG pour le traitement de tumeur cérébrale est évoquée.  Carpentier et al (Cancer Immunotherapy with CpG-ODN., Médecine Sciences, 2005) discusses the interest of immunostimulatory oligonucleotides in cancer immunotherapy. The association of CpG ODNs with antigens, antibodies or dendritic cells is reported to be effective. The associations discussed are OVA (melanoma), herceptin (breast cancer) and rituxan (non-Hodgkin lymphoma). The use of CpG for the treatment of brain tumors is mentioned.
Pinhal-Enfield et al ("An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors.", The American Journal of Pathology, 2003) montre que des agonistes de TLR2, TLR4, TLR7 et TLR9 augmentent l'expression du VEGF dans des macrophages murins, induisant un changement de leur phénotype de l'inflammation vers l'angiogenèse. Bien qu'un tel mécanisme puisse être d'intérêt dans le traitement de certaines maladies, ni la tumeur cérébrale ni la méningite tumorale ne sont citées. Ce document suggère que les agonistes du TLR9 induisent l'angiogenèse.  Pinhal-Enfield et al ("An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A (2A) receptors.", The American Journal of Pathology, 2003) shows that agonists of TLR2, TLR4, TLR7 and TLR9 increase VEGF expression in murine macrophages, inducing a change in their phenotype from inflammation to angiogenesis. Although such a mechanism may be of interest in the treatment of certain diseases, neither cerebral tumor nor tumor meningitis are mentioned. This document suggests that TLR9 agonists induce angiogenesis.
Zhao et al ("Carbon Nanotubes Enhance CpG Uptake and Potentiate Antiglioma Immunity", Clinical Cancer Research, 15 février 201 1 ) décrit une étude portant sur l'administration de CpG dans le cerveau à l'aide de nanotubes de carbone (résumé). El Andaloussi et al ("Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and probongs the survival of mite with expérimental brain tumors", Glia, 2006) divulgue l'effet bénéfique de CpG dans un modèle expérimental de tumeur cérébrale. Zhao et al ("Carbon Nanotubes Enhance CpG Uptake and Potentate Antiglioma Immunity", Clinical Cancer Research, Feb. 15, 201 1) describes a study on the administration of CpG in the brain using carbon nanotubes (summary). El Andaloussi et al ("Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and probongs survival of mite with experimental brain tumors", Glia, 2006) discloses the beneficial effect of CpG in an experimental model of brain tumor.
Sorrentino et al (Int J Cancer. 201 1 Jun 15;128 (12) :2815-22) montrent que l'administration de CpG ODN augmente la production de VEGF dans un modèle murin de carcinome du poumon. Ce résultat est à rapprocher de ceux rapportés par Pinhal-Enfield et al (op. cit.). Aucun de ces documents ne décrit ni ne suggère l'utilisation d'un mélange d'agoniste du récepteur TRL9 et d'agent anti angiogénique pour le traitement d'une tumeur cérébrale ou d'une méningite tumorale, bien que beaucoup discutent de l'intérêt d'une association de différents médicaments pour le traitement de tumeur cérébrale. En particulier, aucun de ces documents ne permet d'envisager l'effet inattendu rapporté dans la présente demande, de synergie ou coopération entre un agoniste du récepteur TRL9 et d'agent anti angiogénique pour le traitement d'une tumeur cérébrale ou d'une méningite tumorale.  Sorrentino et al (Int J Cancer, Jun. 1, 128 (12): 2815-22) show that administration of CpG ODN increases VEGF production in a murine carcinoma model of the lung. This result is similar to those reported by Pinhal-Enfield et al (op.cit.). None of these documents describe or suggest the use of a combination of TRL9 receptor agonist and antiangiogenic agent for the treatment of a brain tumor or tumor meningitis, although many discuss interest of a combination of different drugs for the treatment of brain tumor. In particular, none of these documents makes it possible to envisage the unexpected effect reported in the present application, of synergy or cooperation between a TRL9 receptor agonist and antiangiogenic agent for the treatment of a brain tumor or a tumor. tumor meningitis.
Les résultats rapportés dans la présente demande montrent que l'utilisation d'un agent agoniste du TRL-9 et d'un agent anti-angiogénique permet d'améliorer la survie de patients présentant des méningites tumorales, et qu'il permet de contrôler l'évolution d'une tumeur dans un modèle animal pertinent. The results reported in the present application show that the use of a TRL-9 agonist agent and an anti-angiogenic agent makes it possible to improve the survival of patients with tumor meningitis, and to control the evolution of a tumor in a relevant animal model.
Damiano et al (Proc. Natl. Acad. Sci. USA 2007, 104(30), 12468-12473) décrivent l'utilisation combinée d'un CpG-ODN et du bevacizumab dans un modèle animal (souris nude) sur une xénogreffe d'une tumeur du colon. Toutefois, les CpG-ODN sont injectés de manière intrapéritonéale, ce qui ne correspond pas à une utilisation clinique appropriée. De plus, les ODN phosphorothioates ne passent pas la barrière hématro-encaphalique (Agrawal, 1991 ), ce qui ne permet pas d'extrapoler ces résultats aux tumeurs situées en intracérébral. Enfin, l'expression de TLR9 est restreinte chez l'homme principalement aux lymphocytes B et aux cellules dendritiques plasmocytoïdes (pDC), alors que l'expression est plus large chez la souris incluant la lignée myéloïde (macrophages, monocytes, cellules dendritiques myéloïdes) (Carpentier, 2003).  Damiano et al (Proc Natl Acad Sci USA 2007, 104 (30), 12468-12473) describe the combined use of a CpG-ODN and bevacizumab in an animal model (nude mouse) on a xenograft of a colon tumor. However, the CpG-ODNs are injected intraperitoneally, which does not correspond to an appropriate clinical use. Moreover, the phosphorothioate ODNs do not pass the hematro-encaphalic barrier (Agrawal, 1991), which makes it impossible to extrapolate these results to intracerebral tumors. Finally, the expression of TLR9 is restricted in humans mainly to B lymphocytes and plasmocytoid dendritic cells (pDC), whereas the expression is broader in mice including the myeloid lineage (macrophages, monocytes, myeloid dendritic cells). (Carpentier, 2003).
Ainsi les résultats obtenus chez la souris ne peuvent pas être généralisés de façon systématique chez l'homme. Il existe d'ailleurs de nombreux exemples de modèles animaux efficaces combinant des CpG-ODN avec d'autres molécules (par exemple Damiano et al., (Clin Cancer Res 2006;12:577-583) qui décrit l'utilisation combinée de CpG-ODN avec le cetuximab ou le géfitinib dans des modèles de xénogreffes de cancers du colon sur souris nude) ou la combinaison de bevacizumab avec d'autres molécules , dont les résultats n'ont pas pu être confirmés chez l'homme. Un autre exemple, parmi d'autres, est celui de la combinaison [agoniste TLR9 + chimiothérapie par dacarbazine (DTIC)], prometteuse dans un modèle de mélanome chez l'animal (Najar et Dutz, 2008) mais sans efficacité dans un essai randomisé chez l'homme ( Weber et al, 2009) La demande WO 2004/103301 mentionne également que l'on pourrait utiliser des CpG-ODN avec le bevacizumab, mais ne fournit pas d'exemple de combinaison avec cet anticorps. De plus, aucun des résultats rapportés l'a été chez l'homme. Ainsi les résultats de l'art antérieur obtenus chez l'animal ne peuvent pas être généralisés ni chez l'homme, ni dans le cas des tumeurs intracérébrales. La présente demande rapporte, pour la première fois et de façon surprenante, l'efficacité de la combinaison CpG-ODN + anti-VEGF a la fois chez l'homme, dans le cadre d'un essai clinique, et dans un modèle animal Thus the results obtained in mice can not be generalized systematically in humans. There are many examples of effective animal models combining CpG-ODN with other molecules (eg Damiano et al., (Clin Cancer Res 2006; 12: 577-583) which describes the combined use of CpG-ODN with cetuximab or gefitinib in xenograft models of colon cancers on nude mice) or the combination of bevacizumab with other molecules, the results of which could not be confirmed in humans. Another example, among others, is that of the combination [TLR9 agonist + dacarbazine chemotherapy (DTIC)], promising in a model of melanoma in animals (Najar and Dutz, 2008) but without efficacy in a randomized trial in humans (Weber et al, 2009) The application WO 2004/103301 also mentions that CpG-ODN could be used with bevacizumab, but does not provide an example of a combination with this antibody. Moreover, none of the reported results were in humans. Thus the results of the prior art obtained in animals can not be generalized either in humans or in the case of intracerebral tumors. The present application reports, for the first time and surprisingly, the efficacy of the combination CpG-ODN + anti-VEGF both in humans, as part of a clinical trial, and in an animal model
L'invention se rapporte ainsi à un produit contenant au moins un agent agoniste du récepteur TRL9 (Toll-like Receptor 9) en combinaison avec un agent anti-angiogénique pour son utilisation thérapeutique simultanée, séparée ou étalée dans le temps dans le traitement d'un patient atteint d'une tumeur. Cette tumeur est de préférence une méningite tumorale ou une tumeur intracérébrale. Ce patient est du genre humain.  The invention thus relates to a product containing at least one TRL9 (Toll-like Receptor 9) receptor agonist agent in combination with an antiangiogenic agent for its simultaneous therapeutic use, separated or spread over time in the treatment of a patient with a tumor. This tumor is preferably a tumor meningitis or an intracerebral tumor. This patient is of the human race.
Dans un mode de réalisation particulier ledit agent agoniste du récepteur TRL9 est un oligonucléotide, et notamment un CpG-ODN, oligodéoxynucléotide cytosine-phosphorothioate-guanine contenant des cytosines et guanines non- méthylées.  In a particular embodiment, said TRL9 receptor agonist agent is an oligonucleotide, and in particular a cytosine-phosphorothioate-guanine CpG-ODN, oligodeoxynucleotide containing non-methylated cytosines and guanines.
Cet oligonucléotide agoniste du TLR9, de type « CpG-ODN » ou non This agonist oligonucleotide TLR9, type "CpG-ODN" or not
(certains peuvent avoir des motifs qui ne sont pas des motifs CpG en tant que tels, mais qui incluent des modifications de motifs CpG) est donc un oligonucléotide que l'on peut qualifier d'immunostimulant, (some may have motifs that are not CpG motifs as such, but which include modifications of CpG motifs) is therefore an oligonucleotide that can be described as immunostimulant,
Ainsi que vu plus haut, les propriétés immunostimulantes des acides nucléiques, et des CpG-ODN en particulier sont généralement en rapport avec des motifs 5'-CG non méthylés, motifs sous-représentés dans l'ADN des vertébrés (Krieg AM et al. Nature 1995; 374: 546-549) As seen above, the immunostimulatory properties of nucleic acids, and CpG-ODN in particular are generally related to unmethylated 5'-CG motifs, under-represented motifs in vertebrate DNA (Krieg AM et al Nature 1995, 374: 546-549)
Diverses demandes de brevets ou brevets décrivent de tells oligonucléotides : on peut ainsi citer US 20040006034, US 20030212029, US 6,653,292, US 6,239,1 16, US 6,207,646, US 6,194,388, US 6,429,199, US 6,406,705, US 6,218,371 , US 6,214,806, US 6,218,371 , 6,727,230, WO 01/51500, WO 03/035695, EP 1 162982.  Various patent applications or patents disclose such oligonucleotides: US Pat. No. 4,005,234, US Pat. No. 6,253,292, US Pat. No. 6,239,116, US Pat. No. 6,207,646, US Pat. No. 6,194,388, US Pat. No. 6,429,199, US Pat. No. 6,406,705, US Pat. No. 6,218,371, US Pat. , 6,727,230, WO 01/51500, WO 03/035695, EP 1 162982.
Ainsi, les oligodésoxynucléotides synthétiques (ODN) contenant de tels motifs (CpG-ODN) gardent des propriétés immunostimulantes marquées, particulièrement les ODN phosphorothioates qui sont résistants aux nucléases. Les CpG-ODN sont internalisées par les cellules par endocytose et se lient au TLR9 dans les endosomes. Chez l'homme, les TLR9 sont de façon prédominante sélectivement par les lymphocytes B et les cellules dendritiques plasmocytoïdes (pDC).  Thus, synthetic oligodeoxynucleotides (ODNs) containing such motifs (CpG-ODN) retain marked immunostimulatory properties, particularly phosphorothioate ODNs that are resistant to nucleases. CpG-ODNs are internalized by cells by endocytosis and bind to TLR9 in endosomes. In humans, TLR9s are predominantly selectively by B cells and plasmocytoid dendritic cells (pDCs).
L'activation des lymphocytes B par les CpG-ODN résulte en une sécrétion de cytokines comme l'IL-6 ou l'IL-10, une prolifération cellulaire, une inhibition de l'apoptose induite par divers agents et une sécrétion d'immunoglobulines (Klinman, Nat Rev Immunol 2004 ; 4: 249-59 ; Krieg, Curr Oncol Rep 2004 ; 6: 88-95 ; Carpentier et al, Front Biosci 2003 ; 8: El 15-27).  Activation of B cells by CpG-ODN results in secretion of cytokines such as IL-6 or IL-10, cell proliferation, inhibition of apoptosis induced by various agents and immunoglobulin secretion (Klinman, Nat Rev Immunol 2004, 4: 249-59, Krieg, Curr Oncol Rep 2004, 6: 88-95, Carpentier et al, Front Biosci 2003, 8: El 15-27).
L'activation des cellules dendritiques plasmocytoïdes humaines entraîne leur maturation, la sécrétion de nombreuses cytokines comme le TNFa, l'interféron alpha ou gamma, l'IL-6 ou l'IL-12 et l'expression de molécules de co-stimulation (CD40, CD80, CD86) et de CCR7, un récepteur contrôlant la migration vers les zones T ganglionnaires. La sécrétion d'IL-12 et d'IFN gamma oriente la réponse immunitaire vers le profil Th1 , et peut même transformer une réponse Th2 en Th1.  The activation of human plasmocytoid dendritic cells leads to their maturation, the secretion of many cytokines such as TNFα, interferon alpha or gamma, IL-6 or IL-12 and the expression of co-stimulatory molecules ( CD40, CD80, CD86) and CCR7, a receptor controlling migration to ganglion T regions. The secretion of IL-12 and IFN gamma directs the immune response to the Th1 profile, and can even transform a Th2 response into Th1.
L'activité biologique d'un oligonucléotide dépend de nombreuses variables, encore imparfaitement connues, comme par exemple les modifications chimiques du squelette, la séquence des nucléotides entourant le motif CpG ou le nombre de motifs CpG. Quelques oligonucléotides immunostimulants sans motifs CpG ont ainsi été décrits (US 20040006032).  The biological activity of an oligonucleotide depends on many variables, still imperfectly known, such as the chemical modifications of the backbone, the sequence of nucleotides surrounding the CpG motif or the number of CpG motifs. Some immunostimulatory oligonucleotides without CpG motifs have thus been described (US 20040006032).
La modification chimique du squelette naturellement constitué dans l'ADN par les liaisons phophodiesters (sensibles aux nucléases), joue un rôle important à la fois en améliorant la stabilité de l'ODN mais aussi en modifiant ses propriétés immunostimulantes. Plusieurs types d'oligonucléotides stabilisés ont ainsi été créés (lyer (1999) Curr Opinion Mol Therap 1 ; 344-358). Les CpG-ODN les plus fréquemment utilisés sont les oligodésoxynucléotides phosphorothioates, ou des oligodésoxynucléotides mixtes phosphorothioates /phosphodiesters (par exemple extrémités phosphorothioates/centre phosphodiester ; ou des ODN phosphorothioates, à l'exception des liaisons cytosine-guanosine qui sont phosphodiesters). Les oligodésoxynucléotides synthétisés peuvent également être purifiés en fonction de leur stéréoisomérie pour modifier ou améliorer leur activité biologique. L'activité immunostimulante d'oligonucléotides synthétiques très modifiés, en raison de la présence de bases purines ou pyrimidines non naturelles (US 20030181406 ; US 20020137714 ; US 6,562,798 ; US 20030186912), de molécules chimériques ADN/ARN ou d'ODN-linker-ODN (US 20040052763 ; US 20030225016 ; US 20030199466 ; US 20030175731 ; Wagner. Curr Opin Immunol. 2008 Aug;20(4):396-400 ; Struthers et al., Cell Immunol. 2010 Mar 10) ou l'adjonction de ligands non oligonucléotidiques a également été rapportée (revue par Uhlmann et Vollmer, Curr. Opin. Drug Discov. Devel., 2003, 6, 204-217). The chemical modification of the backbone naturally constituted in the DNA by the phophodiesters bonds (sensitive to nucleases), plays an important role both by improving the stability of the ODN but also by modifying its immunostimulatory properties. Several types of stabilized oligonucleotides have thus been created (Lyer (1999) Curr Opinion Mol Therap 1; 344-358). The most CpG-ODN frequently used are phosphorothioate oligodeoxynucleotides, or mixed phosphorothioate / phosphodiester oligodeoxynucleotides (for example phosphorothioate / phosphodiester ends, or phosphorothioate ODNs, with the exception of cytosine-guanosine linkages which are phosphodiesters). The oligodeoxynucleotides synthesized can also be purified according to their stereoisomerism to modify or improve their biological activity. The immunostimulatory activity of highly modified synthetic oligonucleotides, due to the presence of unnatural purine or pyrimidine bases (US 20030181406, US 20020137714, US 6,562,798, US 20030186912), chimeric DNA / RNA molecules or ODN-linker- ODN (US 20040052763; US 20030225016; US 20030199466; US 20030175731; Wagner, Curr Opin Immunol., 2008 Aug; 20 (4): 396-400; Struthers et al., Cell Immunol. 2010 Mar 10) or the addition of ligands. Nonionic oligonucleotides have also been reported (reviewed by Uhlmann and Vollmer, Curr Opin. Drug Discov Devel., 2003, 6, 204-217).
Plusieurs familles de CpG-ODN ont déjà été caractérisées. La plus classique, dénommée " type B " (ou " K "), se caractérise par une forte activation des lymphocytes B et des cellules dendritiques. Les ODN de " type A " (ou " D ") se caractérisent par une forte activation des NK et une sécrétion d'interféron alpha par les pDC. Les ODN de type C combinent les propriétés des 2 types précédents Des revues à ce sujet ont été publiées (Klinman, Nat Rev Immunol 2004; 4: 249-59 ; Krieg Curr Oncol Rep 2004; 6: 88-95). Several families of CpG-ODN have already been characterized. The most classic, called "type B" (or "K"), is characterized by a strong activation of B cells and dendritic cells. "Type A" (or "D") ODNs are characterized by strong activation of NK and secretion of interferon alpha by pDCs. Type C ODNs Combine the Properties of the 2 Previous Types Reviews have been published (Klinman, Nat Rev Immunol 2004, 4: 249-59, Krieg Curr Oncol Rep 2004, 6: 88-95).
On a décrit récemment une nouvelle classe de CpG-ODNs, appelée classe P (Samulowitz et al., Oligonucleotides. 2010 Apr;20(2):93-101 ). Ces oligonucléotides contiennent deux séquences palindromiques et peuvent ainsi former des unités multimériques. L'efficacité de ces molécules de classe P (notamment pour ce qui est de la capacité à induire l'expression d'interférons de type I) est supérieure à celle des CpG-ODN de type C. Dans un mode de réalisation particulière, on utilise un CpG-ODN de séquence SEQ ID N° 1 , 5'-TAAACGTTATAACGTTATGACGTCAT-3' dans lequel le squelette est phosphorothioate.  A new class of CpG-ODNs, called class P, has recently been described (Samulowitz et al., Oligonucleotides, 2010 Apr; 20 (2): 93-101). These oligonucleotides contain two palindromic sequences and can thus form multimeric units. The efficiency of these class P molecules (especially as regards the ability to induce the expression of type I interferons) is greater than that of C-type CpG-ODNs. In a particular embodiment, uses a CpG-ODN of sequence SEQ ID No. 1, 5'-TAAACGTTATAACGTTATGACGTCAT-3 'in which the backbone is phosphorothioate.
L'angiogenèse est un processus décrivant la croissance de nouveaux vaisseaux sanguins (néovascularisation) à partir de vaisseaux préexistants. Ce processus est contrôlé par différents activateurs et inhibiteurs produits par les cellules saines et tumorales. Les activateurs sont notamment des molécules pro-angiogéniques (VEGF, FGF (Fibroblast Growth Factor), PDGF (Platelet-Derived Growth Factor)), les inhibiteurs des molécules anti-angiogéniques (angiostatine, thrombospondine). Angiogenesis is a process that describes the growth of new blood vessels (neovascularization) from preexisting vessels. This process is controlled by different activators and inhibitors produced by healthy and tumor cells. The activators include pro-angiogenic molecules (VEGF, FGF (Fibroblast Growth Factor), PDGF (Platelet-Derived Growth Factor)), inhibitors of anti-angiogenic molecules (angiostatin, thrombospondin).
Par agent anti-angiogénique, on entend tout agent endogène ou exogène susceptible d'inhiber l'angiogenèse. On peut notamment citer tout inhibiteur du VEGF, du FGF ou du PDGF.  By anti-angiogenic agent is meant any endogenous or exogenous agent capable of inhibiting angiogenesis. In particular, any inhibitor of VEGF, FGF or PDGF may be mentioned.
Un certain nombre d'agents inhibiteurs de l'angiogenèse sont connus. A titre d'illustration, on peut citer une revue sur ces produits (Samant et Shevde Oncotarget. 201 1 Mar;2(3): 122-34 : Récent Advances in Anti-Angiogenic Therapy of Cancer).  A number of angiogenesis inhibitory agents are known. As an illustration, we can cite a review of these products (Samant and Shevde Oncotarget 201 1 Mar; 2 (3): 122-34: Recent Advances in Anti-Angiogenic Therapy of Cancer).
Cet agent anti-angiogénique est préférentiellement un inhibiteur du VEGF, c'est-à-dire un agent limitant ou inhibant l'action du VEGF endogène. L'agent inghibiteur du VEGF peut être un anticorps (tel que le bevacizumab, anticorps monoclonal) ou une petite molécule organique (telle que le sorafenib ou le sunitinib qui inhibent les récepteurs du VEGF mais également d'autres récepteurs). On peut également citer d'autres types d'agents, tels que l'aflibercept, protéine de fusion en développement chez Sanofi Aventis, qui «piège » le VEGF ou la prolactine.  This anti-angiogenic agent is preferably an inhibitor of VEGF, that is to say an agent limiting or inhibiting the action of endogenous VEGF. The VEGF inhibitory agent may be an antibody (such as bevacizumab, monoclonal antibody) or a small organic molecule (such as sorafenib or sunitinib that inhibit VEGF receptors but also other receptors). Other types of agents may also be mentioned, such as aflibercept, a fusion protein being developed by Sanofi Aventis, which "traps" VEGF or prolactin.
L'inhibiteur du VEGF est préférentiellement un anticorps monoclonal.  The VEGF inhibitor is preferably a monoclonal antibody.
Dans un mode de réalisation préféré, ladite tumeur est une tumeur cérébrale primitive bénigne ou maligne, comme un méningiome, une tumeur gliale (gliome), un médulloblastome, ou une tumeur de la région pinéale. In a preferred embodiment, said tumor is a benign or malignant primary brain tumor, such as a meningioma, a glial tumor (glioma), a medulloblastoma, or a pineal region tumor.
Dans ce mode de réalisation particulier, la tumeur est notamment un gliome anaplasique, comme un astrocytome anaplasique, un oligodendrogliome anaplasique, un gliome mixte anaplasique, ou un glioblastome.  In this particular embodiment, the tumor is in particular an anaplastic glioma, such as anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, or a glioblastoma.
Dans un autre mode der réalisation, ladite tumeur est une extension cérébrale métastastique d'un cancer extra cérébral, tel qu'un cancer du poumon, un cancer du sein, un cancer digestif, un mélanome ou un cancer gynécologique.  In another embodiment, said tumor is a metastatic brain extension of an extra-brain cancer, such as lung cancer, breast cancer, digestive cancer, melanoma or gynecological cancer.
Dans un autre mode de réalisation préféré, ladite tumeur est une méningite tumorale consécutive à une tumeur cérébrale primitive, ou une métastase méningée d'un cancer extra cérébral.  In another preferred embodiment, said tumor is a tumor meningitis consecutive to a primary brain tumor, or a subarachnoid metastasis of an extra-cerebral cancer.
En particulier, ladite méningite tumorale est consécutive à une tumeur primitive cérébrale bénigne ou maligne, choisie parmi un méningiome, une tumeur gliale (gliome), un médulloblastome, une tumeur de la région pinéale, un astrocytome anaplasique, un oligodendrogliome anaplasique, un gliome mixte anaplasique, et un glioblastome. In particular, said tumor meningitis is consecutive to a benign or malignant primary brain tumor selected from a meningioma, a tumor glial (glioma), medulloblastoma, pineal region tumor, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, and glioblastoma.
Ladite méningite tumorale peut également être consécutive à une métastase méningée d'un cancer du poumon, d'un cancer du sein, d'un cancer digestif (notamment d'un cancer du colon ou de l'estomac), d'un mélanome ou d'un cancer gynécologique.  Said meningitis may also be consecutive to meningeal metastasis of lung cancer, breast cancer, digestive cancer (in particular colon or stomach cancer), melanoma or of a gynecological cancer.
Dans un autre mode de réalisation, ladite tumeur est un cancer du poumon (notamment un cancer à petites cellules), un cancer du sein, un cancer digestif (notamment un cancer du colon ou de l'estomac), un mélanome ou un cancer gynécologique  In another embodiment, said tumor is lung cancer (including small cell cancer), breast cancer, digestive cancer (including colon or stomach cancer), melanoma or gynecological cancer.
Dans un mode de réalisation particulier, les agents composant l'association sont administrés au patient après la réalisation du traitement antitumoral, en particulier lorsque le traitement antitumoral est une exérèse chirurgicale, ou une radiothérapie, l'administration de substances anti-cancéreuses comme une chimiothérapie, une immunothérapie ou toute autre forme de traitement (ultrasons, champs électromagnétiques), ou une combinaison de ces traitements. In a particular embodiment, the agents making up the combination are administered to the patient after the completion of the antitumor treatment, in particular when the antitumor treatment is surgical excision, or radiotherapy, the administration of anti-cancer substances such as chemotherapy. , immunotherapy or any other form of treatment (ultrasound, electromagnetic fields), or a combination of these treatments.
Il est également possible de procéder à l'administration de la combinaison d'agents selon l'invention de façon concomitante à l'administration d'autres agents antitumoraux, ou avant un autre traitement antitumoral, tel que mentionné ci- dessus.  It is also possible to administer the combination of agents according to the invention concomitantly with the administration of other antitumor agents, or before another antitumor treatment, as mentioned above.
L'invention se rapporte également à une méthode de traitement d'un patient atteint d'une tumeur (telle que défini plus haut) comprenant l'étape d'administration d'un agent agoniste du récepteur TRL9 en combinaison avec un agent anti- angiogénique audit patient.  The invention also relates to a method of treating a tumor patient (as defined above) comprising the step of administering a TRL9 receptor agonist agent in combination with an antiangiogenic agent patient audit.
L'administration de ces composés n'est pas nécessairement concomitante. Dans un mode de réalisation préféré, on administre l'agent agoniste du récepteur TRL9 à une fréquence comprise entre une fois par semaine et une fois tous les deux mois, de préférence entre une fois par semaine et une fois par mois, de façon plus préférée, une fois toutes les deux semaines. On utilise une dose comprise entre 0,5 à 40 mg, de préférence comprise entre 10 et 20 mg d'oligonucléotide. Cet agent est administré de préférence par voie intrathécale pour les tumeurs cérébrales et les méningites tumorales et/ou voie sous-cutanée. Pour d'autres types de tumeurs, cet agent est préférentiellement administré de façon locale (notamment directement dans la tumeur pour les tumeurs solides, ou à proximité de la tumeur), afin d'induire l'immunostimulation dans le voisinage de la tumeur. Il se présente donc sous une forme adaptée à une telle administration par voie intrathécale et/ou voie sous-cutanée, ou sous une forme adaptée à une administration par voie intraveineuse. The administration of these compounds is not necessarily concomitant. In a preferred embodiment, the TRL9 receptor agonist agent is administered at a frequency of between once a week and once every two months, preferably between once a week and once a month, more preferably once every two weeks. A dose of between 0.5 and 40 mg, preferably between 10 and 20 mg of oligonucleotide, is used. This agent is preferably administered intrathecally for brain tumors and tumor meningitis and / or subcutaneously. For other types of tumors, this agent is preferably administered from local way (especially directly in the tumor for solid tumors, or near the tumor), to induce immunostimulation in the vicinity of the tumor. It is therefore in a form suitable for such administration intrathecally and / or subcutaneously, or in a form suitable for intravenous administration.
L'agent anti-angiogénique est administré suivant les recommandations de chaque molécule. Ainsi, le bevacizumab est administré à une fréquence comprise entre une fois par semaine et une fois tous les deux mois, de préférence 1 fois toutes les deux semaines. La dose d'utilisation est déterminée par le praticien, et est généralement inférieure à 15 mg/kg, plus particulièrement de 10mg/kg. Dans un mode de réalisation préféré, l'agent anti-angiogénique est administré par voie intraveineuse.  The anti-angiogenic agent is administered according to the recommendations of each molecule. Thus, bevacizumab is administered at a frequency between once a week and once every two months, preferably once every two weeks. The dose of use is determined by the practitioner, and is generally less than 15 mg / kg, more particularly 10 mg / kg. In a preferred embodiment, the anti-angiogenic agent is administered intravenously.
Description des Figures Description of the Figures
Figure 1 : Effet d'une vaccination anti-VEGF combinée avec une immunothérapie locale sur la croissance tumorale dans un modèle de gliome syngénique sous- cutané chez le Rat. Cercles blancs : contrôle ; carrés blancs : immunisation anti- VEGF ; cercles noirs : CpG-ODN ; carrés noirs : immunisation anti-VEGF + CpG- ODN. Figure 1: Effect of anti-VEGF vaccination combined with local immunotherapy on tumor growth in a model of subcutaneous syngeneic glioma in rats. White circles: control; white squares: anti-VEGF immunization; black circles: CpG-ODN; black squares: anti-VEGF + CpG-ODN immunization.
Figure 2 : Effet d'une vaccination anti-VEGF combinée avec une immunothérapie locale sur la survie des animaux dans un modèle de gliome syngénique sous- cutané chez le Rat. (les animaux sont sacrifiés lorsque les tumeurs atteignent 30mm de diamètre). Cercles blancs : contrôle ; carrés blancs : immunisation anti- VEGF ; cercles noirs : CpG-ODN ; carrés noirs : immunisation anti-VEGF + CpG- ODN. Figure 2: Effect of anti-VEGF vaccination combined with local immunotherapy on animal survival in a rat subcutaneous syngeneic glioma model. (Animals are sacrificed when tumors reach 30mm in diameter). White circles: control; white squares: anti-VEGF immunization; black circles: CpG-ODN; black squares: anti-VEGF + CpG-ODN immunization.
Figure 3 : évolution des IRM cérébrales chez un patient au fur et à mesure du traitement. Le traitement administré entre chaque IRM (composé utilisé et nombre d'injections) est précisé. Exemples  Figure 3: Evolution of brain MRI in a patient as treatment progresses. The treatment administered between each MRI (compound used and number of injections) is specified. Examples
Dans l'ensemble des exemples, les CpG-ODN utilisés présentent la séquence SEQ ID N° 1 , sur un squelette phosphorothioate.  In all of the examples, the CpG-ODNs used have the sequence SEQ ID No. 1, on a phosphorothioate backbone.
Exemple 1 Des rats ont été immunisés contre le VEGF-A au moyen d'une protéine VEGF recombinante et d'un adjuvant immunitaire (polyarginine). Cette administration de VEGF induit ainsi une réponse immunitaire qui mène in fine à un effet anti-angiogénique. Example 1 Rats were immunized against VEGF-A using a recombinant VEGF protein and an immune adjuvant (polyarginine). This administration of VEGF thus induces an immune response which ultimately leads to an anti-angiogenic effect.
Les Figures 1 et 2 montrent que, dans un modèle de gliome syngénique Figures 1 and 2 show that in a syngeneic glioma model
(RG2- Rat Fischer), cette vaccination anti-VEGF agit en synergie avec un traitement par immunothérapie locale (injections péri-tumorales de CpG-ODN) pour inhiber la croissance tumorale et augmenter la survie des animaux. Le traitement (vaccination et/ou immunothérapie locale) a été administré 7 jours après l'implantation de la tumeur RG2 et répété 14 jours plus tard (n = 12 animaux par groupe). (RG2-Rat Fischer), this anti-VEGF vaccination works in synergy with local immunotherapy (peri-tumoral injection of CpG-ODN) to inhibit tumor growth and increase animal survival. The treatment (vaccination and / or local immunotherapy) was administered 7 days after the implantation of the tumor RG2 and repeated 14 days later (n = 12 animals per group).
Protocole  Protocol
Animaux: rats femelles Fisher de 5 semaines  Animals: 5 weeks old female Fisher rats
A jours -5 ou -7, inoculation sous-cutanée de 100,000 cellules de Gliome de Rat (RG2) (flanc gauche).  At days -5 or -7, subcutaneous inoculation of 100,000 Rat Glioma (RG2) cells (left flank).
A jours 0 et 14, injection sous-cutanée distante du vaccine anti-VEGF (hVEGF-A+ adjuvant) et injection péritumorale de CpG-ODN.  At days 0 and 14, remote subcutaneous injection of vaccinia anti-VEGF (hVEGF-A + adjuvant) and peritumoral injection of CpG-ODN.
Tableau I - Résumé du protocole appliqué aux souris On a mesuré la croissance tumorale (2 fois par semaine) et observé la survie des animaux (euthanasie lorsque le diamètre tumoral excède 30 mm)  Table I - Summary of the protocol applied to the mice Tumor growth was measured (twice a week) and observed the survival of the animals (euthanasia when the tumor diameter exceeds 30 mm)
Ainsi, la combinaison d'un produit injecté induisant une immunité contre le VEGF (donc induisant in fine un effet anti-angiogénique) et d'un agoniste des TLR9 permet bien de contrôler la tumeur dans ce modèle murin. Thus, the combination of an injected product inducing an immunity against VEGF (thus ultimately inducing an anti-angiogenic effect) and a TLR9 agonist makes it possible to control the tumor in this murine model.
Exemple 2 Quatre patients présentaient un gliome de haut grade avec une extension méningée. Le protocole de traitement des patients était le suivant : Example 2 Four patients had high-grade glioma with meningeal extension. The treatment protocol for the patients was as follows:
- Injection de 0,3 mg/kg de CpG-ODN en sous-cutané à J0, J7, J14, J21 et J28 (plafonnée à 25mg par injection, pour les patients > 83kg)  - Injection of 0.3 mg / kg of CpG-ODN subcutaneously on D0, D7, D14, D21 and D28 (capped at 25 mg per injection, for patients> 83 kg)
- Administration de CpG-ODN (7mg) par voie intrathécale (dans le liquide céphalorachidien) à trois reprises, à deux semaines d'intervalle entre chaque injection (J0, J14 et J28). (Chez 2 patients, ces injections intrathécales ont été poursuivies toutes les 2 à 4 semaines, pendant plusieurs mois). (D'autres injections intrathécales de quantités supérieures de CpG-ODN (14mg, ou 17mg), toujours en trois étapes à deux semaines d'intervalle entre chaque injection sont actuellement testées, chez d'autres patients dans le cadre d'un essai clinique.) - Administration of CpG-ODN (7mg) intrathecally (in the cerebrospinal fluid) three times, two weeks apart between each injection (D0, D14 and D28). (In 2 patients, these intrathecal injections were continued every 2 to 4 weeks for several months). (Other intrathecal injections of higher amounts of CpG-ODN (14mg, or 17mg), still in three steps at two-week intervals between each injection are currently being tested, in other patients in a clinical trial .)
- Perfusions d'Avastin en intraveineux de 5 à 10 mg/kg toutes les 2 semaines, débutées suivant les cas avant, pendant ou après le début des CpG- ODN. - Avastin intravenous infusions of 5 to 10 mg / kg every 2 weeks, started as before, during or after the onset of CpG-ODN.
Parmi ces 4 patients, 2 ont présenté une évolution remarquable : alors que la médiane de survie chez de tels patients est de l'ordre de 3 mois, ils ont présenté une amélioration clinique et radiologique, et sont étaient presque asymptomatiques, 6 et 7 mois respectivement après le début du traitement combiné. Ces patients avaient reçu différentes séries de trois injections de CpG selon le protocole indiqué ci-dessus (7 mg de CpG par injection).  Of these 4 patients, 2 showed a remarkable evolution: while the median survival in such patients is of the order of 3 months, they showed a clinical and radiological improvement, and were almost asymptomatic, 6 and 7 months respectively after the beginning of the combined treatment. These patients had received different series of three injections of CpG according to the protocol indicated above (7 mg of CpG per injection).
Cet effet ne peut être attribué aux CpG seuls, les 2 patients ayant seulement présenté une légère progression sous CpG, avant le début du traitement combiné avec le bevacizumab. Le bevacizumab pourrait en théorie être a l'origine d'une telle stabilisation, mais un des patients a présenté une progression sous entretien par bevacizumab seul, puis une réponse à la reprise des CpG en intrathécal (Figure 2). Ainsi, chez ce patient au moins, la combinaison des CpG et de l'Avastin semble être à l'origine de cette efficacité.  This effect can not be attributed to CpG alone, both patients having only slightly progressed under CpG, before the start of the combination treatment with bevacizumab. Bevacizumab could theoretically be the cause of such stabilization, but one of the patients showed maintenance progression with bevacizumab alone, followed by a response to CpG uptake in intrathecal (Figure 2). Thus, in this patient at least, the combination of CpG and Avastin seems to be at the origin of this effectiveness.
Références References
Carpentier et al. (2000). Successful treatment of intracranial gliomas in rats with oligodeosynucleotides containing CpG motifs. Clinical Cancer Research, 6: 2469- 73. Carpentier et al. (2000). Successful treatment of intracranial gliomas in rats with oligodeosynucleotides containing CpG motifs. Clinical Cancer Research, 6: 2469-73.
Carpentier et al. (2003). CpG-oligonucleotides for cancer immunotherapy: review of the literature and potential applications in malignant glioma. Front Biosci. 8: E1 15- 27. Carpentier et al. (2006). Phase I trial of a CpG oligodeoxynucleotide for patients with récurrent glioblastoma. Neuro-oncology, 8: 60-6. Carpentier et al. (2003). CpG-oligonucleotides for cancer immunotherapy: review of the literature and potential applications in malignant glioma. Front Biosci. 8: E1 15-27. Carpentier et al. (2006). Phase I trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro-oncology, 8: 60-6.
Carpentier et al., Neuro Oncol. 2010 Apr;12(4):401 -8) Carpentier et al., Neuro Oncol. 2010 Apr; 12 (4): 401-8)
Chamberlain. Neurosurgery. 2003, 52:324-29 Chamberlain. Neurosurgery. 2003, 52: 324-29
Damiano et al Clin Cancer Res 2006;12:577-583. Novel Toll-Like Receptor 9 Agonist Induces Epidermal Growth Factor Receptor (EGFR) Inhibition and Synergistic Antitumor Activity with EGFR Inhibitors Damiano et al Clin Cancer Res 2006; 12: 577-583. Novel Toll-Like Receptor 9 Agonist Induces Epidermal Growth Factor Receptor (EGFR) Inhibition and Synergistic Antitumor Activity with EGFR Inhibitors
Damiano et al. Proc. Natl. Acad. Sci. USA 2007, 104(30), 12468-12473 Damiano et al. Proc. Natl. Acad. Sci. USA 2007, 104 (30), 12468-12473
Glantz. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. I 999 Nov; 5(1 1 ):3394-402. Glantz. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. I 999 Nov; 5 (11): 3394-402.
Iver et al. Nucleotide analogs as novel anti-hepatitis B virus agents. Curr Opin Pharmacol. 2005 Oct;5(5):520-8. Review Iver et al. Nucleotide analogs as novel anti-hepatitis B virus agents. Curr Opin Pharmacol. 2005 Oct; 5 (5): 520-8. Review
Klinman. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004 Apr;4(4):249-58. Review. No abstract available.  Klinman. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004 Apr; 4 (4): 249-58. Review. No abstract available.
Krieg et al. CpG motifs in bacterial DNA trigger direct B-cell activation, Nature. 1995 Apr 6;374(6522):546-9.  Krieg et al. CpG motifs in bacterial DNA trigger direct B-cell activation, Nature. 1995 Apr 6; 374 (6522): 546-9.
Krieg. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep. 2004 Mar;6(2):88-95.  Krieg. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep. 2004 Mar; 6 (2): 88-95.
Recht et Phuphanich : Treatment of neoplastic meningitis: what is the standard of care? Expert Rev Neurother 2004 Jul; 4(4 Suppl): SI 1 -7. Recht and Phuphanich: Treatment of neoplastic meningitis: what is the standard of care? Expert Rev Neurother 2004 Jul; 4 (4 Suppl): SI 1 -7.
Rothenfusser et al., 2002 Human immunology 63 (12): 1 1 1 1-9.  Rothenfusser et al., 2002 Human immunology 63 (12): 1-11 1-9.
Samulowitz et al., Oligonucleotides. 2010 Apr;20(2):93-101 A novel class of immune-stimulatory CpG oligodeoxynucleotides unifies high potency in type I interferon induction with preferred structural properties.  Samulowitz et al., Oligonucleotides. 2010 Apr; 20 (2): 93-101 A novel class of immune-stimulatory CpG oligodeoxynucleotides unites high potency in type I interferon induction with preferred structural properties.
Siegal : Leptomeningeal métastases: rationale for systemic chémotherapy or what is the rôle of intra-'CSF-chemotherapy? J Neurooncol I 998 Jun-Jul;38(2-3): 15 1 -7. Siegal: Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-'CSF-chemotherapy? J Neurooncol I 998 Jun-Jul; 38 (2-3): 15-1-7.
Struthers et al. Synthesis and immunological activities of novel agonists of toll-like receptor 9. Cell Immunol. 2010 Mar 10. Struthers et al. Synthesis and immunological activities of novel agonists of toll-like receptor 9. Cell Immunol. 2010 Mar 10.
Uhlmann et Vollmer, Curr. Opin. Drug Discov. Devel., 2003, 6, 204-217). Récent advances in the development of immunostimulatory oligonucleotides. Uhlmann and Vollmer, Curr. Opin. Drug Discov. Devel., 2003, 6, 204-217). Recent advances in the development of immunostimulatory oligonucleotides.
Wagner. The sweetness of the DNA backbone drives Toll-like receptor 9. Curr Opin Wagner. The sweetness of the DNA backbone drives Toll-like receptor 9. Curr Opin
Immunol. 2008 Aug;20(4):396-400 Immunol. 2008 Aug; 20 (4): 396-400
Weiner et al., 1997, Proc. Natl Acad Sci USA 94 (20): 10833-7)  Weiner et al., 1997, Proc. Natl Acad Sci USA 94 (20): 10833-7)

Claims

REVENDICATIONS
1 . Produit contenant au moins un agent agoniste du récepteur TRL9 (Toll-like Receptor 9) en combinaison avec un agent anti-angiogénique pour son utilisation thérapeutique simultanée, séparée ou étalée dans le temps dans le traitement d'un patient atteint d'une tumeur cérébrale ou d'une méningite tumorale. 1. Product containing at least one TRL9 (Toll-like Receptor 9) agonist agent in combination with an antiangiogenic agent for its simultaneous, separate or time-varying therapeutic use in the treatment of a patient with a brain tumor or tumor meningitis.
2. Produit selon la revendication 1 , caractérisé en ce que ledit agent agoniste du récepteur TRL9 est un oligonucléotide. 2. Product according to claim 1, characterized in that said TRL9 receptor agonist agent is an oligonucleotide.
3. Produit selon la revendication 2, caractérisé en ce que ledit oligonucléotide est un oligodéoxynucléotide cytosine-phosphorothioate-guanine contenant des cytosines et guanines non-méthylées. 3. Product according to claim 2, characterized in that said oligonucleotide is a cytosine phosphorothioate-guanine oligodeoxynucleotide containing unmethylated cytosines and guanines.
4. Produit selon l'une des revendications 2 ou 3, caractérisé en ce que ledit oligonucléotide présente un squelette phosphorothioate. 4. Product according to one of claims 2 or 3, characterized in that said oligonucleotide has a phosphorothioate backbone.
5. Produit selon l'une des revendications 2 à 4, caractérisé en ce que ledit oligonucléotide est la séquence SEQ ID N° 1 . 5. Product according to one of claims 2 to 4, characterized in that said oligonucleotide is the sequence SEQ ID No. 1.
6. Produit selon la revendication 1 , caractérisé en ce que ledit agent anti- angiogénique est un inhibiteur du VEGF (Vascular Endothelial Growth Factor). 6. Product according to claim 1, characterized in that said anti-angiogenic agent is an inhibitor of VEGF (Vascular Endothelial Growth Factor).
7. Produit selon la revendication 6, caractérisé en ce que ledit agent inhibiteur du VEGF est un anticorps. 7. Product according to claim 6, characterized in that said VEGF inhibitory agent is an antibody.
8. Produit selon la revendication 7, caractérisé en ce que ledit anticorps est le bevacizumab. 8. Product according to claim 7, characterized in that said antibody is bevacizumab.
9. Produit selon l'une des revendications 1 à 8, caractérisée en ce que ladite tumeur est un gliome ou un glioblastome. 9. Product according to one of claims 1 to 8, characterized in that said tumor is a glioma or a glioblastoma.
10. Produit selon l'une des revendications 1 à 8, caractérisée en ce que ladite tumeur est une extension cérébrale métastastique d'un cancer extra cérébral, tel qu'un cancer du poumon, un cancer du sein, un cancer digestif, mélanome ou un cancer gynécologique. 10. Product according to one of claims 1 to 8, characterized in that said tumor is a metastatic cerebral extension of an extra brain cancer, such as lung cancer, breast cancer, digestive cancer, melanoma or gynecological cancer.
1 1 . Produit selon l'une des revendications 1 à 8, caractérisé en ce que ladite tumeur est une méningite tumorale consécutive à une tumeur cérébrale primitive, ou une métastase méningée d'un cancer extra cérébral. 1 1. Product according to one of claims 1 to 8, characterized in that said tumor is a tumor meningitis consecutive to a primary brain tumor, or a meningeal metastasis of an extra-cerebral cancer.
12. Produit selon la revendication 1 1 , caractérisé en ce que ladite méningite tumorale est consécutive à une tumeur primitive cérébrale bénigne ou maligne, choisie parmi un méningiome, une tumeur gliale (gliome), un médulloblastome, une tumeur de la région pinéale, un astrocytome anaplasique, un oligodendrogliome anaplasique, un gliome mixte anaplasique, et un glioblastome. 12. Product according to claim 1 1, characterized in that said tumor meningitis is consecutive to a benign or malignant brain primary tumor, selected from a meningioma, a glial tumor (glioma), a medulloblastoma, a tumor of the pineal region, a anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed glioma, and glioblastoma.
13. Produit selon la revendication 1 1 , caractérisé en ce que ladite méningite tumorale est consécutive à une métastase méningée d'un cancer du poumon, d'un cancer du sein, d'un cancer digestif, d'un mélanome ou d'un cancer gynécologique. 13. Product according to claim 1 1, characterized in that said tumor meningitis is consecutive to a meningeal metastasis of lung cancer, breast cancer, digestive cancer, melanoma or a malignancy. gynecological cancer.
14. Produit selon l'une des revendications 1 à 13, caractérisé en ce que l'agent agoniste du récepteur TRL9 est administré par voie intrathécale et/ou voie sous-cutanée. 14. Product according to one of claims 1 to 13, characterized in that the TRL9 receptor agonist agent is administered intrathecally and / or subcutaneously.
15. Produit selon l'une des revendications 1 à 14, caractérisé en ce que l'agent anti-angiogénique est administré par voie intraveineuse. 15. Product according to one of claims 1 to 14, characterized in that the anti-angiogenic agent is administered intravenously.
16. Produit selon l'une des revendications 1 à 15, caractérisé en ce que l'agent agoniste du récepteur TRL9 est administré par voie intrathécale à une fréquence comprise entre une fois par semaine et une fois tous les deux mois. 16. Product according to one of claims 1 to 15, characterized in that the TRL9 receptor agonist agent is administered intrathecally at a frequency of between once a week and once every two months.
17. Produit selon l'une des revendications 1 à 15, caractérisé en ce que l'agent agoniste du récepteur TRL9 est administré à une dose comprise entre 0,5 et 40 mg. 17. Product according to one of claims 1 to 15, characterized in that the TRL9 receptor agonist agent is administered at a dose of between 0.5 and 40 mg.
EP12723201.5A 2011-05-24 2012-05-24 Agents for treating tumours Withdrawn EP2714078A1 (en)

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Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009323766B2 (en) 2008-12-02 2016-10-06 Wave Life Sciences Ltd. Method for the synthesis of phosphorus atom modified nucleic acids
BR112012000828A8 (en) 2009-07-06 2017-10-10 Ontorii Inc NEW NUCLEIC ACID PRO-DRUGS AND METHODS OF THEIR USE
WO2012039448A1 (en) 2010-09-24 2012-03-29 株式会社キラルジェン Asymmetric auxiliary group
WO2013012758A1 (en) 2011-07-19 2013-01-24 Ontorii, Inc. Methods for the synthesis of functionalized nucleic acids
AU2013289880B2 (en) 2012-07-13 2018-08-02 Wave Life Sciences Ltd. Chiral control
WO2014010250A1 (en) 2012-07-13 2014-01-16 Chiralgen, Ltd. Asymmetric auxiliary group
AR095882A1 (en) * 2013-04-22 2015-11-18 Hoffmann La Roche ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R WITH A TLR9 AGONIST
AR097584A1 (en) 2013-09-12 2016-03-23 Hoffmann La Roche ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R AND ANTIBODIES AGAINST HUMAN PD-L1
US10149905B2 (en) 2014-01-15 2018-12-11 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
WO2015108047A1 (en) * 2014-01-15 2015-07-23 株式会社新日本科学 Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
US10322173B2 (en) * 2014-01-15 2019-06-18 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent
SG11201605782UA (en) 2014-01-16 2016-08-30 Wave Life Sciences Ltd Chiral design
WO2017191147A1 (en) * 2016-05-04 2017-11-09 Transgene Sa Combination therapy with cpg tlr9 ligand
JP7138094B2 (en) 2016-08-25 2022-09-15 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Intermittent administration of anti-CSF-1R antibody in combination with macrophage activator
CA3036978A1 (en) * 2016-09-15 2018-03-22 Idera Pharmaceuticals, Inc. Immune modulation with tlr9 agonists for cancer treatment
WO2018115051A1 (en) 2016-12-22 2018-06-28 F. Hoffmann-La Roche Ag Treatment of tumors with an anti-csf-1r antibody in combination with an anti-pd-l1 antibody after failure of anti-pd-l1/pd1 treatment
CN110678182B (en) * 2017-02-24 2022-08-23 大邱庆北尖端医疗产业振兴财团 Pharmaceutical composition containing a compound capable of penetrating the blood-brain barrier as an active ingredient for preventing or treating brain cancer

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6727230B1 (en) 1994-03-25 2004-04-27 Coley Pharmaceutical Group, Inc. Immune stimulation by phosphorothioate oligonucleotide analogs
ATE420171T1 (en) 1994-07-15 2009-01-15 Univ Iowa Res Found IMMUNOMODULATORY OLIGONUCLEOTIDES
US6429199B1 (en) 1994-07-15 2002-08-06 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules for activating dendritic cells
US6239116B1 (en) 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6207646B1 (en) 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
AU738513B2 (en) 1997-02-28 2001-09-20 University Of Iowa Research Foundation, The Use of nucleic acids containing unmethylated CpG dinucleotide in the treatment of LPS-associated disorders
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
US20040006034A1 (en) 1998-06-05 2004-01-08 Eyal Raz Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
ATE356630T1 (en) 1998-04-03 2007-04-15 Univ Iowa Res Found METHOD AND PRODUCTS FOR STIMULATING THE IMMUNE SYSTEM USING IMMUNOTHERAPEUTIC OLIGONUCLEOTIDES AND CYTOKINE
US6562798B1 (en) 1998-06-05 2003-05-13 Dynavax Technologies Corp. Immunostimulatory oligonucleotides with modified bases and methods of use thereof
FR2790955B1 (en) * 1999-03-19 2003-01-17 Assist Publ Hopitaux De Paris USE OF STABILIZED OLIGONUCLEOTIDES AS ANTI-TUMOR ACTIVE INGREDIENT
ATE378348T1 (en) 2000-01-14 2007-11-15 Us Health OLIGODEOXYNUCLEOTIDES AND THEIR USE FOR INDUCING AN IMMUNE RESPONSE
US6815429B2 (en) 2000-01-26 2004-11-09 Hybridon, Inc. Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides
CA2412026A1 (en) 2000-06-07 2001-12-13 Biosynexus Incorporated Immunostimulatory rna/dna hybrid molecules
KR100894767B1 (en) 2000-09-26 2009-04-24 이데라 파마슈티칼즈, 인코포레이티드 Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes
AU2001297693A1 (en) * 2000-12-08 2002-09-12 Coley Pharmaceutical Gmbh Cpg-like nucleic acids and methods of use thereof
US7176296B2 (en) 2001-04-30 2007-02-13 Idera Pharmaceuticals, Inc. Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides
US8114418B2 (en) 2001-06-21 2012-02-14 Dynavax Technologies Corporation Chimeric immunomodulatory compounds and methods of using the same—IV
US7785610B2 (en) 2001-06-21 2010-08-31 Dynavax Technologies Corporation Chimeric immunomodulatory compounds and methods of using the same—III
CN1642982A (en) 2001-07-26 2005-07-20 唐诚公司 Agents that activate or inhibit Toll-like receptor 9
CA2388049A1 (en) 2002-05-30 2003-11-30 Immunotech S.A. Immunostimulatory oligonucleotides and uses thereof
US7605138B2 (en) * 2002-07-03 2009-10-20 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
EP1628531A4 (en) 2003-05-16 2010-06-30 Idera Pharmaceuticals Inc Synergistic treatment of cancer using immunomers in conjunction with chemotherapeutic agents
AU2005266225A1 (en) * 2004-06-25 2006-02-02 Centre National De La Recherche Scientifique Products containing at least one anticancer active principle with low diffusion and an immunostimulatory active principle
WO2007059041A2 (en) * 2005-11-11 2007-05-24 Pfizer, Inc. Combinations and methods of using an immunomodulatory oligodeoxynucleotide
CN101918030B (en) * 2007-11-09 2015-10-14 派瑞格恩医药公司 The compositions of VEGF antibody and method
WO2009155332A1 (en) * 2008-06-17 2009-12-23 Cedars-Sinai Medical Center Use of toll-like receptor ligands as adjuvants to vaccination therapy for brain tumors
CA2745295C (en) * 2008-12-09 2017-01-10 Gilead Sciences, Inc. Modulators of toll-like receptors
CA3080983C (en) * 2009-05-27 2023-02-28 Pct Therapeutics, Inc. Method of inhibiting and reducing a viral infection
US8829020B2 (en) * 2009-07-16 2014-09-09 Mallinckrodt Llc Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
US20130210896A1 (en) * 2011-11-09 2013-08-15 City Of Hope Immunotheraphy of Brain Tumors Using a Nanoparticle CpG Delivery System

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012160153A1 *

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