WO2023217109A1 - Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs - Google Patents

Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs Download PDF

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WO2023217109A1
WO2023217109A1 PCT/CN2023/092911 CN2023092911W WO2023217109A1 WO 2023217109 A1 WO2023217109 A1 WO 2023217109A1 CN 2023092911 W CN2023092911 W CN 2023092911W WO 2023217109 A1 WO2023217109 A1 WO 2023217109A1
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cancer
cells
inhibitor
stm2457
tumor
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PCT/CN2023/092911
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Chinese (zh)
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陈捷凯
孔祥谦
吴凯昕
吴红玲
汤同柯
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中国科学院广州生物医药与健康研究院
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • 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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This disclosure belongs to the field of biomedicine and relates to the combined treatment of tumors with an m6A RNA methylase inhibitor and an immune checkpoint inhibitor.
  • m6A N6 methyladenosine
  • mRNA eukaryotic messenger RNA
  • m6A modified proteins include METTL3, METTL14, YTHDC1, YTHDF2, etc.
  • m6A modification plays a key role in regulating RNA processing, splicing, nucleation, translation and stability, which is critical for the development of various human diseases such as cancer.
  • m6A modifications are abnormal in various types of cancer and are associated with patient prognosis. Abnormalities in m6A modification are closely related to the occurrence, development and drug resistance of malignant tumors. As oncogenic factors, m6A-modified proteins promote tumor progression by upregulating oncogenes or downregulating tumor suppressor genes.
  • PD-1 Programmed cell death protein 1 plays an important role in suppressing immune responses and promoting self-tolerance, including regulating the activity of T cells, activating antigen-specific T cell apoptosis programs and inhibiting the apoptosis of conventional T cells .
  • PD-L1 is a transmembrane protein that is considered a common inhibitory factor of the immune response. It can combine with PD-1 to reduce the proliferation of PD-1-positive cells, inhibit their cytokine secretion, and induce cell apoptosis.
  • PD-L1 also plays an important role in the progression of various malignant tumors. It inhibits the immune system's recognition and killing of tumor cells and promotes tumor immune escape. Blocking the PD-1/PD-L1 interaction through monoclonal antibodies has had a huge impact on cancer treatment.
  • Melanoma is a malignant tumor that originates from melanocytes. As an aggressive skin cancer, the incidence of melanoma is increasing worldwide. Many studies have explored the relationship between tumor cells and the tumor microenvironment. However, more than half of melanoma patients do not respond to immune checkpoint inhibitor treatment, which is closely related to the immunosuppressive microenvironment in which tumor cells live. By combining with other drugs, it is important to increase the level of tumor-infiltrating CD8+T cells and the CD8/Treg ratio in the tumor microenvironment, turn immune "cold" tumors into "hot” tumors, and improve the effectiveness of tumor immunotherapy. clinical significance.
  • the present disclosure provides a composition comprising: an anti-tumor immunotherapeutic agent and STM2457 or a derivative thereof.
  • the anti-tumor immunotherapeutic agent includes immune cells or one or more immune checkpoint inhibitors.
  • the immune cells are selected from T cells, macrophages and/or monocytes or T cells containing artificial T cell receptors.
  • the T cells are selected from one or more of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and regulatory T cells.
  • NK natural killer
  • CTL cytotoxic T lymphocytes
  • the T cells are selected from T lymphocytes.
  • the T cells are selected from umbilical cord blood-derived T lymphocytes.
  • the immune checkpoint inhibitor includes a polypeptide, a monoclonal antibody, or a chemically synthesized small molecule inhibitor.
  • the immune checkpoint inhibitor includes a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
  • the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
  • the PD-1 inhibitor is a PD-1 antibody.
  • the anti-tumor immunotherapeutic agent includes an antibody or antibody fragment that targets a tumor-specific antigen.
  • the structural formula of STM2457 is as shown in formula (I):
  • the composition further includes a pharmaceutically acceptable carrier, excipient, or stabilizer.
  • the composition is an anti-tumor composition.
  • the tumors include lung cancer (including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, Ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, kidney cancer, renal cell carcinoma, nephroblastoma, Basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, or human mononuclear leukemia cells.
  • lung cancer including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer
  • gastrointestinal cancer pancreatic cancer
  • glioblastoma glioma
  • cervical cancer Ovarian cancer
  • liver cancer hepatoma
  • bladder cancer breast cancer
  • colon cancer colorectal cancer
  • the inventors have found that PD-1 inhibitors (or PD-1 blockers) or T cells combined with STM2457 have very significant effects in the treatment of melanoma and ovarian cancer, and the effect of the combination group is far better than Single drug group.
  • the combination even produces synergistic therapeutic effects that exceed the expectations of those skilled in the art.
  • Combining anti-CTLA-4 and anti-PD-1 therapies offers the potential for superior efficacy, which may be attributed to each agent acting in a complementary or even synergistic manner. But combination therapy may lead to greater toxicity.
  • drug-related grade 3-4 adverse events occurred in 54% to 55% of patients and in 24% to 27% of patients with concurrent blockade compared with 24% to 27% alone. The incidence was 24% to 27% with ipilimumab and 15% to 16% with nivolumab alone. Therefore, this disclosure finds new anti-tumor drug combination therapy, which is of great significance for drug development and clinical treatment of melanoma.
  • the present disclosure provides a kit comprising a first container, a second container and a package insert; the first container contains an anti-tumor immunotherapeutic agent, the second container contains STM2457 or its A derivative of a drug, and the package insert contains instructions for using the drug to treat cancer in an individual.
  • the anti-tumor immunotherapeutic agent includes immune cells or one or more immune checkpoint inhibitors.
  • the immune cells are selected from T cells, macrophages and/or monocytes or T cells containing artificial T cell receptors.
  • the T cells are selected from one or more of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and regulatory T cells.
  • NK natural killer
  • CTL cytotoxic T lymphocytes
  • the T cells are selected from T lymphocytes.
  • the T cells are selected from umbilical cord blood-derived T lymphocytes.
  • the immune checkpoint inhibitors include polypeptides, monoclonal antibodies, or chemically synthesized small molecule inhibitors.
  • the immune checkpoint inhibitor includes a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
  • the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
  • the PD-1 inhibitor is a PD-1 antibody.
  • the anti-tumor immunotherapeutic agent includes an antibody or antibody fragment targeting a tumor-specific antigen.
  • the structural formula of STM2457 is as shown in formula (I):
  • the present disclosure provides the use of any of the compositions in the preparation of a medicament for the treatment of cancer.
  • the cancer includes lung cancer (including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, Ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, kidney cancer, renal cell carcinoma, nephroblastoma, Basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, or human mononuclear leukemia cells.
  • lung cancer including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer
  • gastrointestinal cancer pancreatic cancer
  • glioblastoma glioma
  • cervical cancer Ovarian cancer
  • liver cancer hepatoma
  • bladder cancer breast cancer
  • colon cancer colorectal cancer
  • the present disclosure provides a composition as described above for treating cancer.
  • the present disclosure provides a method of treating cancer, comprising administering to a patient or subject any of the compositions described above.
  • the present disclosure provides the use of STM2457 or a derivative thereof in the preparation of a medicament for the treatment of melanoma or ovarian cancer.
  • the structural formula of STM2457 is as shown in formula (I):
  • the present disclosure provides a method of treating melanoma or ovarian cancer, comprising administering STM2457 or a derivative thereof to a patient or subject.
  • the present disclosure provides STM2457 or derivatives thereof for the treatment of melanoma or ovarian cancer.
  • Figure 1 shows the volume and mass measurements of mouse tumors in the four groups of regimens, showing that the combination of STM2457 and PD-1 antibodies can effectively inhibit the growth of melanoma in mice.
  • Figure 1A Among the four-group regimens, the STM2457 and PD-1 antibody groups significantly reduced tumor weight compared to the NC control group.
  • Figure 1B Among the four groups of regimens, the STM2457 and PD-1 antibody groups significantly reduced tumor volume compared with the NC control group.
  • Figure 2 shows the results of single-cell CD45 flow cytometry analysis of mouse tumors in the four groups of regimens.
  • STM2457 and PD-1 antibodies can effectively improve the tumor microenvironment, that is, increase the proportion of hematopoietic lineage cells in B16F0 tumors.
  • FIG. 3 Analysis of tumor single cell sequencing data. The results show that the combined use of STM2457 and PD-1 antibodies can effectively promote the mitosis of T cell populations and the expression of genes related to the maintenance of stem cell populations in B16F0 tumors.
  • Figure 4 is a flow chart for the combined administration of STM2457 and PD-1 antibodies.
  • Figure 5 shows the combination of STM2457 and T cells in the treatment of ovarian cancer.
  • Figure 5A Fluorescence photography of A1847 cells (marked with red fluorescence), T cells, and STM2457 treatment.
  • Figure 5B Tumor cell death rate (%) calculated based on the number of A1847 cells detected by flow cytometry, STM2457 group vs NC+T group ***P ⁇ 0.001.
  • Figure 6 shows the comparison of the inhibitory effects of m6A methylase inhibitor STM2457 alone on different tumor cells.
  • Figure 7 shows the combination of STM2457 and T cells to treat B16 melanoma. It is the tumor cell death rate (%) calculated based on the number of B16 cells detected by flow cytometry, STM2457 group vs NC+T group ***P ⁇ 0.001.
  • the ⁇ -cyclodextrin solution used in the following examples was purchased from Aladdin-e Company (https://www.aladdin-e.com/), and the product number is H108813.
  • the PD-1 antibody used was purchased from BioXcell (https://bxcell.com) with the product number BE0146.
  • the PBS buffer used was purchased from HyClone Company, product number SH30028.02.
  • compositions eg, media
  • methods include the recited elements but do not exclude other elements.
  • Consisting essentially of is meant to exclude other elements that are of any importance in combination for the stated purpose.
  • a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure.
  • Consisting of means trace elements and substantial method steps excluding other components. Embodiments defined by each of these transitional terms are within the scope of this disclosure.
  • the components of a "composition” may be present in a mixed form or may be packaged separately.
  • the separately packaged components may also contain their respective adjuvants.
  • the adjuvant refers to a means in medicine that can assist the efficacy of a drug.
  • the separately packaged components may be administered simultaneously or in any sequential order, wherein the patient is first treated with one drug and then the other drug.
  • the patient refers to a mammalian subject, especially a human.
  • Tumor immunotherapy is a treatment method that controls and eliminates tumors by restarting and maintaining the tumor-immune cycle and restoring the body's normal anti-tumor immune response.
  • Tuor immunotherapy agents refer to drugs used for "tumor immunotherapy", including monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors, etc.
  • step (2) Dissolve the STM2457 drug in the ⁇ -cyclodextrin solution described in step (1), shake and mix thoroughly at 42 degrees Celsius to form a homogeneous STM2457- ⁇ -cyclodextrin solution.
  • the final concentration of STM2457 is 6.25mg/mL.
  • the PD-1 antibody was diluted to 2.5mg/mL using PBS buffer.
  • Mouse melanoma B16F0 (or “B16") was inoculated into 6-8 week old C57BL/6J mice, and each mouse was inoculated with 2*10 ⁇ 5 cells. After the tumor mass can be touched, start injecting different drug combinations (a total of four groups, namely: NC, STM2457, PD-1 antibody, STM2457+PD-1 antibody), and regularly detect changes in the mouse's weight and tumor volume. Variety. The results showed that the STM2457+PD-1 antibody group had the most significant effect in inhibiting tumor growth (Figure 1).
  • NC group (or NC+NC):
  • the STM injection dose is 50mg/kg, approximately 1.25mg/mouse, once a day; the PD-1 antibody injection dose is 250ug/mouse, twice a week.
  • a 2-week dosing period started from the time when mice were subcutaneously inoculated with B16F0 tumors and had obvious touch sensation (about 5-7 days later).
  • the flow chart is shown in Figure 4.
  • human ovarian cancer cell A1847 was treated with 1 ⁇ M m6A methylase inhibitor STM2457 and then co-incubated with cord blood-derived T cells.
  • the specific steps are: seed 1,000 A1847 cells in a 96-well plate, treat and culture them at a concentration of 1uM STM2457 for 3 days, then add umbilical cord blood-derived T cells in different combinations (the number of T cells added is based on the ratio of A1847 to T cells). 1:1), a total of four groups (respectively: NC; STM2457; NC+T; STM2457+T). After incubation for 24 hours, the cells were collected. The number of A1847 cells was detected by flow cytometry, and the killing of tumor cells was calculated.
  • the steps of the method for isolating T cells derived from umbilical cord blood include:
  • Umbilical cord blood is separated from mononuclear cells by density gradient centrifugation. The specific steps are: (1) dilute the umbilical cord blood 2 times with PBS and centrifuge it in a clean sterile collection tube at 25°C and 750g for 30 minutes; (2) transfer the white middle layer of MNC into a new 50mL centrifuge tube; (3) Add 30mL PBS to each tube, centrifuge at 350g for 10min at 4°C; (4) Discard the supernatant, add 5mL of red blood cell lysis solution, incubate at 25°C for 10min, fill with PBS to dilute the red blood cells for lysis solution, centrifuge at 300g for 10 minutes at 4°C; (5) Resuspend the cell pellet in 25 mL of PBS, centrifuge at 300g for 10 minutes at 4°C, and repeat once; (6) Resuspend the cells in PBS, count, and the cells obtained are mononuclear cells.
  • biotin-conjugated antibodies (CD14, CD15, CD16, CD19, CD34, CD36, CD56, CD123, CD235a) to the resuspended mononuclear cells and incubate for 5 minutes, followed by incubation with anti-biotin magnetic beads for 10 minutes.
  • the magnetically labeled cells are removed through a magnetic column to isolate high-purity T lymphocytes.
  • 5 ⁇ M m6A methylase inhibitor STM2457 was used to treat mouse melanoma cells B16; human breast cancer cells MDA-MB-231 and MCF7; human monocytic leukemia cells Thp1; mouse lung cancer cells LLC; and human Melanoma cells A375; human lung cancer cells H1299, H23, H460, and H522 were processed.
  • THP-1 and MDA-MB-231 cells are sensitive to STM2457, MCF7, LLC, and H460 have about 20% inhibitory effect, and the other cancer cells are not very sensitive.
  • murine melanoma B16 cells were treated with 1 ⁇ M m6A methylase inhibitor STM2457 and then co-incubated with mouse spleen-derived T cells.
  • the specific steps are: seed 1,000 B16 cells in a 96-well plate, treat and culture them at a concentration of 1 ⁇ M STM2457 for 3 days, then add mouse spleen-derived T cells in different combinations (the number of T cells added is based on the number of B16 and T cells). Ratio 1:2), a total of four groups (respectively: NC; STM2457; NC+T; STM2457+T). After incubation for 24 hours, the cells were collected. The number of B16 cells was detected by flow cytometry, and the killing of tumor cells was calculated.
  • the steps of the method for isolating T cells derived from mouse spleen include:
  • Mononuclear cells were isolated from the spleen obtained by dissection of mice. The specific procedures are as follows: (1) Soak the spleen of the dissected mouse in PBS, use a 1mL syringe to back-grind the spleen to 1mL, and filter with a filter.
  • Centrifuge the filtrate collection tube at 750g for 5 minutes at 25°C; (2) Discard the supernatant, add 5mL of red blood cell lysate, incubate at 25°C for 10 minutes, fill with PBS diluted red blood cell lysate, and centrifuge at 300g for 10 minutes at 4°C; (5) Resuspend with 25mL of PBS Suspend the cells to pellet, centrifuge at 300g for 10 minutes at 4°C, and repeat once; (6) Resuspend the cells in PBS and count. The cells obtained are mononuclear cells.
  • biotin-conjugated antibodies CD11b, CD11c, CD19, CD45R (B220), CD49b (DX5), CD105, MHC class II and Ter-119) to the resuspended mononuclear cells and incubate for 5 minutes, followed by anti- The biotin magnetic beads are incubated for 10 minutes, and the magnetically labeled cells are removed through the magnetic column to isolate high-purity T lymphocytes.

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Abstract

L'invention concerne une combinaison d'un inhibiteur d'ARN méthylase m6A et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs. La polythérapie comprenant la combinaison d'un agent immunothérapeutique tumoral et de STM2457 ou d'un dérivé de celui-ci est utilisée pour traiter des tumeurs comprenant des mélanomes et un cancer de l'ovaire. La nouvelle polythérapie de médicaments antitumoraux présente une grande importance dans le développement de médicaments et le traitement clinique de mélanomes ou de cancer de l'ovaire.
PCT/CN2023/092911 2022-05-13 2023-05-09 Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs WO2023217109A1 (fr)

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