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WO2025141323A1 - Compositions utilisées en combinaison avec des traitements immunomodulateurs pour traiter des cancers - Google Patents

Compositions utilisées en combinaison avec des traitements immunomodulateurs pour traiter des cancers Download PDF

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Publication number
WO2025141323A1
WO2025141323A1 PCT/IB2024/000769 IB2024000769W WO2025141323A1 WO 2025141323 A1 WO2025141323 A1 WO 2025141323A1 IB 2024000769 W IB2024000769 W IB 2024000769W WO 2025141323 A1 WO2025141323 A1 WO 2025141323A1
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cells
composition
pharmaceutical composition
tls
microorganisms
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Nathalie Corvaia
Carole SCHWINTNER
Cyrielle GASC
Mathieu Fontaine
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Maat Pharma SA
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Maat Pharma SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/085—Staphylococcus
    • 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
    • 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
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • the present invention relates to the field of anticancer treatments.
  • the present invention concerns therapeutic compositions for use in combination with immune modulatory treatments (IMTs) for treating cancers.
  • IMTs immune modulatory treatments
  • the present invention also concerns kits of parts comprising said compositions and immune modulatory treatments.
  • the present invention further concerns in vitro methods for screening said compositions.
  • TEE tumor microenvironment
  • Current therapeutic approaches comprise surgery, small molecules usage such as chemotherapy, radiation-based therapies, cellular therapies, vaccines and/or targeted therapies such as immunotherapy.
  • Immune Checkpoint Inhibitors are a novel class of immunotherapy drugs that have revolutionized patient care and significantly improved outcomes of patients with solid tumors. They became the standard of care for several solid tumors, including metastatic melanoma, Non-Small Cell Lung Cancer (NSCLC), Renal Cell Cancer (RCC) or colorectal cancer.
  • TLSs are composed of a large variety of organized cell types such as naive B cells, memory B cells, plasma cells, CD4+ and CD8+ T cells, T helper 1 , T follicular helper (TFH) cells and regulatory T (Treg) cells (intracellular forkhead box P3 + (FOXP3+) especially), follicular dendritic cells (FDC), dendritic cells (DC), neutrophils, macrophages and high endothelial venules (Sautes- Fridman et al, 2019 - Tertiary lymphoid structures in the era of cancer immunotherapy, Nat Rev Cancer, 2019 Jun;19(6):307-325).
  • FDC follicular dendritic cells
  • DC dendritic cells
  • neutrophils macrophages and high endothelial venules
  • TLS T-cell-exhausted, inflamed, and/or immunosuppressive TME.
  • mTLS mature TLS
  • PD-1 programmed death 1
  • CXCR5 C-X-C chemokine receptor type 5
  • TFH cells are in contact with B cells.
  • the B cell zone contains a network of FDCs expressing CD21 in primary follicles as well as CD23 in secondary follicles (Fridman et al., 2023).
  • naive or memory B cells can be activated by tumor-associated antigens presented by FDC, further triggered by signals delivered by TFH cells and mature into antibody-producing plasma cells (PC) or memory B cells.
  • PC can also come from extrafollicular response zones as described in inflamed tissues.
  • PCs travel into tumor beds in contrast to germinal center B cells and plasmablasts that are retained in TLS. This is also the case for memory T and B cells that can also migrate to peripheral lymphoid organs and to the bone marrow where they can be reactivated by a subsequent tumor recurrence or metastasis.
  • B cells can internalize, process and present tumor-associated antigens to CD4+ T cells through MHCII molecules upon recognition via their B cell receptor.
  • Antigen presentation via MHCI may also be relevant: B cells in ovarian cancer can present antigenic peptides to CD8+ T cells via MHCI molecules.
  • TLS density has a favourable impact on overall survival and disease-free survival of patients irrespective of the detection method on sections of tumoral tissues such as lung cancer, colorectal cancer, pancreatic cancer, oral squamous cell carcinoma and invasive breast cancer.
  • presence of TLSs is correlated with a good response to immunotherapies and especially Immune Checkpoint Inhibitors (ICIs).
  • ICIs Immune Checkpoint Inhibitors
  • TLS activation could improve immunotherapy and survival in melanoma patients (Cabrita et al, 2020 - Tertiary lymphoid structures improve immunotherapy and survival in melanoma, Nature, 2020 Jan;577(7791):561-565). Impact of some therapeutic modalities has been reported on TLS modulation.
  • anti-CD40 therapy in glioma revealing that immunotherapies can modulate TLS formation in the brain of a mouse model (Van Hooren et al, 2021 - Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma, Nat Commun, 2021 Jul 5; 12(1 ):4127).
  • Radiation therapy has also been reported to modulate TLS structures (Boivin et al, 2018 - Cellular Composition and Contribution of Tertiary Lymphoid Structures to Tumor Immune Infiltration and Modulation by Radiation Therapy, Front Oncol, 2018 Jul 9:8:256).
  • Hhep colonization triggers CD4+ T cells differentiation into Treg or TFH states, but under immunodeficient settings the presence of Hhep drives the differentiation of inflammatory Hhep-specific T helper 1 and Th 17 cells and the development of colitis (Kullberg et aL, 2003 - Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope, Proc Natl Acad Sci U S A, 2003 Dec 23;100(26):15830-5; Xu et aL, 2018 - c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont, Nature, 2018 Feb 15;554(7692):373-377).
  • dysbiosis an altered composition of gut microbiota, called dysbiosis, caused by several factors, including the disease itself and/or administered treatments such as antibiotics
  • infections Chaput et aL, 2017 - Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol, 2017 Jun 1 ;28(6):1368-1379; Nakatsu et aL 2015 - Gut mucosal microbiome across stages of colorectal carcinogenesis, Nat Commun, 2015 Oct 30:6:8727; Zitvogel L.
  • Dysbiosis has been reported in patients with solid tumors such as metastatic melanoma and colorectal cancer (Chaput et aL, 2017 - Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol, 2017 Jun 1 ;28(6):1368-1379; Nakatsu et aL 2015 - Gut mucosal microbiome across stages of colorectal carcinogenesis, Nat Commun, 2015 Oct 30:6:8727). Furthermore, dysbiosis often leads to intestinal colonization by pathogenic microorganisms leading to infections in this patient population.
  • TLS maturation appears pivotal to increase the intra-tumoral immune loop and enhance sensitivity of tumors to IMTs. Nonetheless, patients in need for TLS maturation display an immunosuppressed state and most of the time dysbiosis.
  • a complementary strategy to improve tumor sensitivity to IMTs would be to trigger the formation of TLS exclusively in the tumor microenvironment.
  • the inventors have shaped therapeutic microbial compositions composed of populations of microorganisms and demonstrated their ability to trigger TLS maturation alone or in combination with an IMT in in vitro or in vivo models of TLS.
  • the therapeutic microbial compositions according to the invention are able to trigger TLS formation in the tumor microenvironment specifically.
  • the therapeutic compositions according to the invention are able to trigger TLS formation, and maturation (i.e. induce B cell differentiation into plasmablast) via microbial antigen presentation by both dendritic cells and B cells to T follicular helper cells and subsequent activation of B cells.
  • the inventors have surprisingly found that such therapeutic microbial compositions increase IMT efficacy in activating TLS maturation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Faecalibacterium prausnitzii, Flavonifractor plautii, Ruminococcus bromii, Coprococcus comes, Roseburia intestinalis, Dysosmobacter sp. BX15 and Phocaeicola vulgatus, for use in combination with an immune checkpoint inhibitor (I Cl ) for treating a cancer in a patient, wherein the cancer is a solid tumor comprising a tertiary lymphoid structure (TLS) in its microenvironment.
  • I Cl immune checkpoint inhibitor
  • the pharmaceutical composition of the invention may comprise a population of microorganisms that includes bacteria, viruses, archaea, bacteriophages, fungi or mixtures thereof.
  • the pharmaceutical composition of the invention comprises a population of microorganisms that includes bacteria and fungi.
  • the pharmaceutical composition of the invention may comprise a stool derived microorganism.
  • the pharmaceutical composition of the invention comprises microorganisms that are exclusively stool derived microorganisms.
  • the pharmaceutical composition of the invention may advantageously trigger the maturation of tertiary lymphoid structures (TLS) in the tumor microenvironment. Still advantageously, the pharmaceutical composition of the invention may trigger the formation of tertiary lymphoid structure (TLS) in the tumor microenvironment.
  • TLS tertiary lymphoid structure
  • the pharmaceutical composition of the invention may trigger an efficient IgG production by B cells in tertiary lymphoid structures (TLS).
  • Said efficient IgG production by B cells may be observed in in vitro or in vivo models of tertiary lymphoid structures (TLS), preferentially a human tonsil-based in vitro model.
  • the pharmaceutical composition of the invention may induce expansion of at least one of the following cell populations: T cells specific to the microorganisms present within the pharmaceutical composition, tumor specific T cells, mature dendritic cells, ILC3 T cells, plasmablasts and/or T follicular helper (TFH).
  • T cells specific to the microorganisms present within the pharmaceutical composition tumor specific T cells, mature dendritic cells, ILC3 T cells, plasmablasts and/or T follicular helper (TFH).
  • the expansion of at least one cell populations as previously defined may be observed in in vitro or in vivo models of tertiary lymphoid structures (TLS), preferentially a human tonsil-based in vitro model.
  • TLS tertiary lymphoid structures
  • the pharmaceutical composition of the invention may induce B cell differentiation into plasmablast via microbial antigen presentation by both dendritic cells and B cells to T follicular helper cells and subsequent activation of B cells.
  • bacterial subpopulation selected from: Alistipes, Odoribacter, Parabacteroides, Coprococcus, Barnesiella, Roseburia, Bilophila, Ruminococcus, Clostridium, Subdoligranulum, Dysosmobacter, Oscillibacter, Lachnospira, Eubacterium, Mediterraneibacter, Anaerostipes, Anaerobutyricum, Paraprevotella, Sutterella, Phascolarctobacterium, Bifidobacterium, Akkermansia, Butyricimonas, Collinsella, Fusicatenibacter, Faecalicatena, Prevotella, Dialister, Ruthenibacterium, Escherichia, Enterocloster, Eisenbergiella, Erysipelatoclostridium, Lachnoclostridium, Hu ng atelia and Holdemania.
  • the invention pertains to a kit of parts comprising a pharmaceutical composition according to the invention and an immune modulatory treatment for simultaneous or sequential administration to a patient.
  • kits which includes a pharmaceutical composition comprising a population of microorganisms as described herein, and an immune modulatory treatment (IMT).
  • the kits can also include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition as described herein to a patient having cancer (e.g., a solid tumor).
  • the kits may include multiple packages of the singledose pharmaceutical compositions each containing an effective amount of the pharmaceutical composition comprising a population of microorganisms as described herein and/or an immune modulatory treatment for a single administration in accordance with the methods or uses provided according to the present invention.
  • Microbial composition Microbial composition
  • the pharmaceutical composition (also called microbial composition or therapeutic microbial composition) to be used in combination with the I MT according to the invention may comprise at least a microorganism derived from stool, stool being preferably of mammalian origin, more preferably of human origin.
  • the microbial composition may include exclusively stool derived microorganisms. These stool derived microorganisms can be bacteria, viruses, archaea, bacteriophages, fungi (comprising yeasts) or mixtures thereof.
  • Stool derived microorganisms according to the invention include cultivated microorganisms, non-cultivated microorganisms and mixtures thereof. Furthermore, they include also isolated microorganisms, non-isolated microorganisms and mixtures thereof.
  • the pharmaceutical composition (also called microbial composition or therapeutic microbial composition) of the invention may comprise a population (or ecosystem) of microorganisms comprising at least a stool derived microorganism.
  • This microorganism may be isolated alone or isolated as a fraction of microorganisms from stools e.g. spores and vegetative forms.
  • the stool derived microorganism can further have been cultivated or not in a bioreactor between stool donation and pharmaceutical product formulation steps. Mixing cultivated and non-cultivated forms of the stool derived microorganism is also part of the invention.
  • the stool derived microorganism may be added to a composition comprising microorganisms from non-fecal origin such as food, vegetal, environmental, skin and other animal mucosae.
  • the term “animal” means human and non-human animals in this context.
  • Microorganisms from non-fecal origin can be cultivated or not in a bioreactor between collection and mixing with the stool derived microorganism.
  • Non fecal microorganisms and the stool derived microorganism can be cultivated together or not after mixing.
  • Those microorganisms from non-fecal origin can be isolated or not before mixing with the stool derived microorganism.
  • Such compositions according to the invention comprising non fecal microorganisms may comprise from one to several hundreds of distinct individual species.
  • the stool derived microorganism may be frozen and banked alone or part of a composition comprising microorganisms from non-fecal origin, in a stool sample library.
  • the microbial composition of the invention may include exclusively stool derived microorganisms.
  • Microorganisms can be obtained from stool donations with techniques known by the skilled person such as filtration, centrifugation and isolation. Those microorganisms can be planktonic, can form biofilms or can be in a vegetative form such as a spore. Mixtures of microorganisms thereof are also encompassed according to the present invention.
  • Microorganisms can come from a single donor or from multiple donors. In this later case, stools from different donors are pooled together.
  • Microorganisms can also come from several donations of the same donor, pooled together. Microorganisms can be cultivated or not in a bioreactor between stool donation and pharmaceutical product formulation steps.
  • Microorganisms can have been isolated or not before product formulation. Combination of isolation and cultivation steps to generate the composition to be formulated can also be covered by the present invention. Stool derived microorganisms may be frozen and banked alone or part of a composition comprising multiple individual species, in a stool sample library.
  • Stool derived microorganisms may include cultivated microorganisms, non-cultivated microorganisms and mixtures thereof.
  • Cultivated microorganisms can be grown in a single bioreactor or several bioreactors.
  • the term “bioreactor” preferably means every way of cultivating microorganisms known by the skilled person such as solid, liquid cultivation or liquid cultivation with particles for microorganism adhesion. If multiple bioreactors are needed, they can be used in parallel or in series.
  • Microorganisms cultivated in multiple bioreactors can be similar in terms of taxonomy or different.
  • the different bioreactors can comprise from one to several hundreds of distinct individual species of microorganisms at the same time.
  • Non cultivated microorganisms may be directly obtained from stool donations with techniques known by the skilled person such as filtration, centrifugation and isolation. Those microorganisms can be planktonic, can form biofilms or can be in a vegetative form such as a spore. Mixtures of microorganisms thereof may also be encompassed according to the present invention. Cultivated or not, microorganisms of the present invention can come from a single donor or from multiple donors. In this later case, stools from different donors may be pooled together and microorganisms may be extracted from such pool.
  • Microorganisms can also come from several donations of the same donor, pooled together.
  • the composition of the invention can also comprise mixes of cultivated and non-cultivated microorganisms. Microorganisms may be frozen and banked alone or part of a composition comprising multiple individual species, in a stool sample library.
  • Stool derived microorganisms may include isolated microorganisms, nonisolated microorganisms and mixtures thereof.
  • Isolated microorganism preferably refers to a microorganism that has been separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or produced, prepared, purified, and/or manufactured.
  • Isolated microorganisms may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which it was initially associated.
  • Isolated microorganisms may be more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure.
  • the term “pure” preferably means that the complex community of microorganisms is substantially free of other components.
  • the terms “purify,” “purifying” and “purified” preferably refer to a microorganism that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production.
  • a microorganism may be considered purified if it is isolated at or after production, such as from a material or environment containing the microorganism, and a purified microorganism may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered "isolated.”
  • the microorganism is more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure.
  • the microorganism can be independently purified from one or more complex community of microorganisms produced and/or can be present in the material or environment containing the microorganism.
  • the microorganism may be purified from residual habitat products.
  • Non limiting examples of purification or isolation methods comprise, but are not limited to, filtration, centrifugation, dilution, solid or liquid cultivation.
  • Non isolated microorganisms may be directly obtained from stool donations with techniques known by the skilled person such as filtration, centrifugation, isolation.
  • Those microorganisms can be planktonic, can form biofilms or can be in a vegetative form such as a spore.
  • the composition of the invention can also comprise mixes of isolated and non-isolated microorganisms. Microorganisms may be frozen and banked alone or as part of a composition comprising multiple individual species in a stool sample library.
  • Microorganisms from the microbial composition of the invention that engraft in subjects’ gut may be different from a subject to another.
  • Microorganism selection is advantageously operated by subject’s gut depending on its needs in microorganisms and missing functions to be recovered to restore a symbiotic microbiota.
  • One or several different microorganisms can advantageously engraft within subject’s gut.
  • each individual has a unique microbiota composition, similar main physiological functions are fulfilled thanks to the capacity of different microorganisms to perform the same chemical reaction.
  • needs in microorganisms may differ from a subject to another.
  • Therapeutic microbial compositions of the present invention may comprise a rich and diverse equilibrium of microorganism composed of different species, in quantities reflecting those of a healthy gut flora, allowing subject’s gut to pick up species I functions it needs for recovering a healthy gut status.
  • the therapeutic microbial composition of the present invention allows subject’s gut to select microorganisms able to perform functions that are missing in preexisting flora.
  • quantities of microorganisms present in the composition correspond to those found in healthy gut consortia allowing a controlled colonization of subject’s gut.
  • at least 10 different species not present within subject’s gut before treatment with the therapeutic microbial composition may engraft in subject’s gut.
  • between 10 and 400 different species not present within subject’s gut before treatment with the therapeutic microbial composition may engraft in subject’s gut.
  • Microorganisms present in the composition of the invention may be capable of producing some or all of the following metabolites (as shown in Table 1 below): Acetate, butyrate, propionate, valerate, indole, indole 3-acetic acid, indole 3- propionic acid, indole-3-carboxaldehyde, indole-3-lactic acid, cholic acid, hyocholic acid, beta-Muricholic acid, chenodeoxycholic acid, deoxycholic acid, 7-Ketodeoxycholic acid, omega-Muricholic acid, ursocholic acid, ursodeoxycholic acid, 7-Ketolithocholic acid, 12- Ketolithocholic acid, hyodeoxycholic acid, 3-Oxocholic acid, dioxolithocholic acid, lithocholic acid, nordeoxycholic acid, norursodeoxycholic acid, trimethylamine (TMA), lysine, choline, y-
  • Table 1 Production in metabolites of interest of a therapeutic microbial composition. The analysis exhibited in table 1 was performed on conditioned medium collected during manufacturing of a specific cultivated product (Composition 5 - Cult). With respect to table 1 , metabolite production by microbiota was quantified by LC- MRM/MS. Results exhibited in table 1 represent mean values ⁇ SEM of 6 different cultivated products. These metabolites act on different metabolic pathways of interest in gut homeostasis and immuno-oncology.
  • the first category Short Chain Fatty Acids (SCFA), designates a group of metabolites known to possess anti-inflammatory properties. This category includes acetate, butyrate, propionate and valerate (pentanoate).
  • SCFA Short Chain Fatty Acids
  • Metabolites belonging to the indole pathway are also known to be involved in gut homeostasis such as indole, indole 3-acetic acid, indole 3-propionic acid, indole-3-carboxaldehyde, indole- 3-lactic acid.
  • Desulfovibrionaceae Acidaminococcaceae, Eubacteriaceae, Prevotellaceae, Akkermansiaceae, Coriobacteriaceae, Veillonellaceae, Clostridiales Family XIII. Incertae Sedis, Enterobacteriaceae or Selenomonadaceae.
  • it can be anti-CTLA-4, anti-PD-L1 or anti-PD-1 antibodies such as Cadonilimab, PUYOUHENG (Pucotenlimab), IMJUDO (Tremelimumab), AIBINING (Geptanolimab), KEYTRUDA (Pembrolizumab), OPDIVO (Nivolumab), YERVOY (Ipilimumab) or LIBTAYO (cemiplimab), Penpulimab, Socazolimab, Adebrelimab, Tagitanlimab, Toripalimab, Tislelizumab, Retifanlimab, Sintilimab, Cosibelimab, Camrelizumab, Sugemalimab, IBI310, Nofazinlimab, Erfonrilimab.
  • Cadonilimab PUYOUHENG (Pucotenlimab), IMJUDO (T
  • Activated B cells will then either differentiate into IgG-producing plasmablasts or memory B cells capable of being reactivated upon stimulation with specific antigens. Indeed, it is documented in the literature that whatever the maturation stage of TLS, B cells at all maturation stages are present in TLS including naive and memory B cells (Meylan et aL, 2022). Such phenomenon is exhibited in Figure 1 B.
  • lower generally may mean a decrease by a statistically significant amount.
  • “lower”, ’’reduced”, “reduction”, “decrease,” or “inhibit” may mean a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (i.e. absent level as compared to a reference sample), or any decrease between 10- 100% as compared to a reference level.
  • compositions include the active ingredients recited, excludes any other active ingredients, but does not exclude any pharmaceutical excipients or other components that are not therapeutically active. It is contemplated that embodiments described in the context of the term “comprising” may also be implemented in the context of the term “consisting of’ or “consisting essentially of.”
  • compositions, methods, and respective components thereof may refer to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
  • a stated range may be understood to be any value between and at the limits of the stated range.
  • a range between 1 and 5 may include 1 , 2, 3, 4, and 5;
  • a range between 1 and 10 may include 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • a range between 1 and 100 may include 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18,
  • Heat-inactivated bacteria of Composition 5 - Cult and their respective controls at 2 dilutions (1/100 and 1/1000) were assessed for their ability to promote activation of human tonsil-derived immune cells through their secretion of IgG in the supernatant over a 7-day period. Tested items were applied in the absence or presence of SEB at one dose (0,1 ng/mL), in the absence or the presence of Nivolumab at one dose (1 pg/mL) and in the presence of both.
  • Heat inactivated bacteria and their respective controls were prepared according to the following steps:
  • compositions of the invention trigger maturation of TLS through an increase in IgG production. Such maturation was observed whatever the dilution of the compositions.
  • IgG production is amplified when the compositions of the invention are combined with Nivolumab, compared to Nivolumab alone, whatever the compositions dilutions. Nonetheless, activation of TFH cells is lower than in the presence of the whole immune population. Indeed, in absence of DCs, there is less presentation of microbial antigens to TFH cells, and solely memory B cells are capable of activating TFH cells present in this model.

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Abstract

La présente invention a trait au domaine des traitements anticancéreux. En particulier, la présente invention concerne des compositions thérapeutiques destinées à être utilisées en combinaison avec des traitements immunomodulateurs (IMT) pour traiter des cancers. La présente invention concerne également des kits de pièces comprenant lesdites compositions et lesdits traitements immunomodulateurs. La présente invention concerne en outre des méthodes in vitro de criblage desdites compositions.
PCT/IB2024/000769 2023-12-29 2024-12-27 Compositions utilisées en combinaison avec des traitements immunomodulateurs pour traiter des cancers Pending WO2025141323A1 (fr)

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