WO2020187975A1 - Sélection de patients pour un traitement avec vaccination à base de cellules dendritiques - Google Patents

Sélection de patients pour un traitement avec vaccination à base de cellules dendritiques Download PDF

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WO2020187975A1
WO2020187975A1 PCT/EP2020/057415 EP2020057415W WO2020187975A1 WO 2020187975 A1 WO2020187975 A1 WO 2020187975A1 EP 2020057415 W EP2020057415 W EP 2020057415W WO 2020187975 A1 WO2020187975 A1 WO 2020187975A1
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cells
patient
dendritic cell
platelets
vaccine
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Jirina Bartunková
Ladislav PECEN
Hariz Iskandar Bin HASSAN
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SOTIO a.s.
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5094—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for blood cell populations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/59—Reproductive system, e.g. uterus, ovaries, cervix or testes
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/22—Colony stimulating factors (G-CSF, GM-CSF)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]
    • C12N2501/2304—Interleukin-4 (IL-4)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/50—Cell markers; Cell surface determinants
    • C12N2501/599—Cell markers; Cell surface determinants with CD designations not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the immune system is a powerful tool that, if better harnessed, could enhance the efficacy of cytotoxic agents and improve outcomes for cancer sufferers.
  • Vaccination is hoped to be an effective method of harnessing the immune system to eliminate cancer cells. Its activity is mostly dependent on antigen-specific CD8 + T cells that generate cytotoxic T lymphocytes (CTLs) to reject cancer (Palucka and Banchereau 2013).
  • CTLs cytotoxic T lymphocytes
  • the immune system components necessary for the induction of such CD8 + T cells include the presentation of antigens by appropriate antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • DCs Dendritic cells
  • a newly developed DC vaccine based on dendritic cell obtained from patient-derived (autologous) monocytes loaded with tumor cell undergoing immunogenic cell death (ICD) and matured with Toll-like receptor (TLR) agonists binding TLR3 or TLR4 has been shown to be more beneficial for the overall survival (OS) and progression free survival (PFS) of ovarian cancer patients than standard of care chemotherapy alone (Cibula et al. 2018; Rob et al. 2018).
  • ICD immunogenic cell death
  • TLR Toll-like receptor
  • Efficacy of such a DC vaccine treatment may further be improved by identifying, prior to treatment, patients who would benefit from such treatment.
  • blood tests are routinely used in health care to determine physiological and biochemical states of patients, and are often preceding the initiation of many existing cancer treatments, such blood tests may thus also be an appropriate pre-treatment evaluation of patients eligible for a DC vaccine treatment.
  • the inventors have now surprisingly identified blood biomarkers, namely levels of NK cells and levels of platelets in blood, enabling to identify, prior to treatment, patients suffering from ovarian cancer who would benefit the most from such a DC vaccine treatment. Definitions
  • DC vaccine refers to human DCs for therapeutic use that may be administered, being prepared without an antigen source or with an antigen source.
  • the DCs have been prepared by loading the DCs with an antigen sourced from tumor associated peptide(s), whole antigens from DNA or RNA, whole antigen-protein, idiotype protein, tumor lysate, whole tumor cells or viral vector-delivered whole antigen and subsequently optionally matured with toll-like receptor agonists. More preferably, the DCs have been loaded with whole tumor cells undergoing immunogenic cell death as described for example by Fucikova et al. (2014). Further, the loaded DCs may be further matured. Maturation occurs e.g. by culturing the loaded DCs in the presence of maturation factors such as Toll-like receptor agonists (e.g., poly[I:C] or LPS).
  • maturation factors such as Toll-like receptor agonists (e.g., poly[I:C] or LPS).
  • Toll-like receptor agonists refers to molecules binding toll-like receptors (TLR), e.g. lipopolysaccharides binding to TLR4, double-stranded RNA or polyinosinic:polycytidylic acid (poly[I:C]) binding to TLR3. Further, TLR1, TLR2, TLR5 and TLR8 agonists are suitable for maturation. TLR expression and function in DCs is reviewed by Schreibelt et al. (2010), see table 1 for monocyte derived DCs (moDC).
  • Chemotherapy is a treatment that uses drugs or agents to stop the growth of cancer cells, either by killing the cells (cytotoxic agents) or by stopping them from dividing (cytostatic agents).
  • Chemotherapy drugs may include alkylating agents or alkylating-like agents such as carboplatin or cisplatin, antimetabolites such as gemcitabine, pemetrexed, methotrexate, anti-tumor antibiotics such as doxorubicin, topoisomerase inhibitors such as topotecan, irinotecan or etoposide, mitotic inhibitors such as docetaxel, paclitaxel, vinblastine, or vinorelbine.
  • Chemotherapy drugs are provided by the American Cancer Society and can be found here: Cancer Society - How Chemotherapy Drugs Work' 2016). Such drugs may typically be small molecule drugs (organic compounds of low molecular weight, e.g. ⁇ 900 Dalton). Chemotherapy may also include other treatments such as hormones and hormone analogous, small molecules drugs (e.g. kinase inhibitors, PARP inhibitors), vaccines other than DC vaccines, or biologies (e.g. antibodies), or combinations thereof. Chemotherapy may be given orally, by injection, or infusion, or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy.
  • hormones and hormone analogous, small molecules drugs e.g. kinase inhibitors, PARP inhibitors
  • vaccines other than DC vaccines e.g. antibodies
  • biologies e.g. antibodies
  • chemotherapy also covers“neoadjuvant chemotherapy”, which is a chemotherapy treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery.
  • chemotherapy also covers“adjuvant chemotherapy”, which is a chemotherapy treatment given after the primary treatment (for example surgery or radiation) to treat residual tumor and/or to prevent or treat metastasis.
  • adjuvant chemotherapy is a chemotherapy treatment given after the primary treatment (for example surgery or radiation) to treat residual tumor and/or to prevent or treat metastasis.
  • dendritic cell vaccines are considered not to be adjuvant chemotherapy.
  • First-line therapy is a first treatment given for a disease. It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used by itself, first- line therapy is typically the one accepted as the best treatment for a disease. If it does not cure the disease or if it causes severe side effects, other treatment options may be added or used instead.
  • the first-line therapy can also be called induction therapy, primary therapy, or primary treatment.
  • First-line chemotherapy is a therapy with at least one chemotherapeutic agent as part of a first- line therapy. It is understood that the term“first-line chemotherapy” does not comprise a parallel use of a dendritic cell vaccine therapy.
  • “Second-line chemotherapy” is a chemotherapy that is given when the patient does not respond to the initial treatment (first-line therapy), or if the first-line therapy stops being effective.“Third-line chemotherapy” is the chemotherapy that is given when both initial treatment (first-line therapy) and subsequent treatment (second-line therapy) were not effective or stopped being effective.
  • a treated cancer may“relapse” or be“recurrent” when the cancer or signs and symptoms of the cancer return after a period of improvement.
  • “Overall survival” is the length of time from either the date of diagnosis, date of randomization or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the overall survival is one way to measure the efficacy of a new treatment. Randomization into a clinical trial is the process by which subjects are assigned by chance to separate groups that compare different treatments or other interventions. Randomization gives each participant an equal chance of being assigned to any of the groups.
  • “Overall survival rate” is the percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with a disease, randomized or started treatment for a disease, such as cancer.
  • the overall survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after their diagnosis or the start of treatment.
  • SOC Standard of care
  • A“blood test” helps doctors to check for certain diseases and conditions.
  • the Complete Blood Count (CBC) is the most common blood test. This test measures the count of erythrocyte (or red blood cells), of leucocytes (or white blood cells), of platelets, hemoglobin, hematocrit and mean corpuscular volume. Methods to practice blood tests can be found in guides or textbooks for use in diagnostic hematology laboratories (Bain 2015) (see especially Chapter 2“Performing a blood count”, p 17- 66).
  • The“platelet count” in blood can be measured during the blood test. Platelets (or thrombocytes) can be counted in a hemocytometer using either diluted whole blood or platelets-rich plasma prepared by sedimentation or centrifugation. In this method, platelets are visualized by light or phase-contrast microscopy. Platelets can also be counted by semi-automated or fully automated methods using flow cytometry based on impedance counters. The most accurate way to perform a platelet count require fully automated blood cell counters, where platelets are either counted using impedance, light-scattering or optical fluorescence technology. When direct current (DC) impedance is used to count platelets, it can be combined with hydrodynamic focusing.
  • DC direct current
  • DC impedance technology is based on the principle that an electrical field, created between two electrodes of opposite charge, can be used to count and determine the size of cells.
  • Blood cells are poor conductors of electricity.
  • the diluent (reagent) in which they are suspended during counting is an isotonic solution which is a good conductor of electricity. Consequently, when the cells suspended in the diluent pass through an aperture (a narrowing) between the electrodes, each individual cell will momentarily increase the impedance (resistance) of the electrical path between the electrodes. Each cell generates an electrical pulse in proportion to its size (volume).
  • Cell/particle counting can be optimized by hydrostatic focusing, where by means of a sheath flow, the cells or particles are separated and aligned upon entering the flow cell or detection unit to effectively prevent coinciding or recirculation of cells/particles (Sun and Morgan 2010; Briggs, Harrison, and Machin 2007).
  • fluorescence technologies fluorochrome-labelled monoclonal antibodies raised against a platelet glycoprotein or against proteins expressed by platelets such as CD41, CD42a or CD61, can be incorporated so that platelets are reliably distinguished from other small particles.
  • platelets can also be counted by fluorescence technologies using fluorescent dyes selectively labelling platelets, such as the PLT-F dye (Wada et al. 2015).
  • NK cells are a type of cytotoxic lymphocytes critical to the innate immune system.
  • the population of NK cells is heterogeneous.
  • NK cells can be sorted and counted by flow cytometry as cells being CD45 + CD56 ⁇ (or bn s ht) CD16 and CD45 ⁇ CD56 -(or dim) CD16 + (Caligiuri 2008).
  • the average count of NK cells in healthy human patients is about 250 cells/m ⁇ of blood (absolute count) or about 12% of all blood lymphocytes (relative count) ( aceal et al. 2017; Pascal et al. 2004).
  • the invention relates to a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the amount of NK cells and comparing it to a threshold level. Determining the amount of NK cells may be part of the routine blood test during physical examination prior to treatment or prescription of the dendritic cell vaccine.
  • NK cells are understood to be CD45 + CD56 + (or bn s ht) CD 16 and CD45 + CD56 (or dim) CD16 + and may be counted by flow cytometry or other means known to a person skilled in the art. Blood tests a routinely performed by specialized hematology laboratories according to guidelines.
  • Blood sampling may be performed by trained laboratory personnel at the practicing doctor’s office.
  • the blood sample may be obtained the most easily from a vein in the antecubital fossa using needles and either syringes or evacuated tubes (such as a vacutainer tubes).
  • Blood collection tube may additionally contain additives such as anticoagulants (EDTA, sodium citrate, or heparin) or gels to separate blood cells from plasma (Bain 2015) (see Chapter 1“Blood sampling and blood film preparation and examination”, p 1-16).
  • the inventors have now surprisingly found that tumor patients can retrospectively be stratified with respect to their levels of NK cells in blood, and the resulting two groups had a significant difference in survival when treated with a dendritic cell vaccine (see Example 4. Clinical data in first recurrence of ovarian cancer).
  • the invention in another aspect, relates to a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the count of platelets and comparing it to a threshold level. Determining the count of platelets in a blood sample may be part of the routine blood test during physical examination prior to treatment or prescription of the dendritic cell vaccine. Multiple methods have been developed to count platelets (Bain 2015) (see p. 22-23). Platelets may be measured by flow cytometry using DC impedance method with hydrodynamic focusing (Briggs, Harrison, and Machin 2007; Sun and Morgan 2010).
  • Platelets may also be accurately measured by fluorescent flow cytometry as CD41 + , CD42a + or CD61 + cells, or using fluorescent dyes selectively labelling platelets, such as the PLT-F dye (Wada et al. 2015).
  • the platelets count is usually part of a complete blood count (CBC) and can be measured using automated hematology analyzer in specialized hematology laboratories according to guidelines.
  • CBC complete blood count
  • tumor patients can retrospectively be stratified with respect to their levels of platelets in blood, and the resulting two groups had a significant difference in survival when treated with a dendritic cell vaccine (see Example 4. Clinical data in first recurrence of ovarian cancer).
  • the invention relates to a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the amount of NK cells and comparing it to a threshold level and by determining in a blood sample from the patient the count of platelets and comparing it to a threshold level. Blood from the same sample may be used to determine the amount of NK cells and the count of platelets.
  • both NK cell levels and platelet levels were correlating together with the survival of the treated tumor patients (see Example 4. Clinical data in first recurrence of ovarian cancer).
  • the amount of NK cells measured for the patient selection may be expressed as the relative level of NK cells of total lymphocytes.
  • the total amount of lymphocytes may be determined from a blood sample by fluorescent flow cytometry as the count of all CD45 + blood cells in the blood sample.
  • the relative level of NK cells of total lymphocytes is the percentage of CD45 + CD56 + ⁇ or bri s ht > CD 16 and CD45 + CD56 ⁇ or dim) CD 16 + cells among all CD45 + cells.
  • the amount of NK cells measured for the patient selection may be expressed as the absolute count of NK cells per microliter (m ⁇ ) of blood. Such measurement may also require measurements by fluorescent flow cytometry.
  • the relative level of NK cells of total lymphocytes measured for the selection of patient to be treated with a DC vaccine is compared to a threshold level between 1 1% and 16% of total lymphocytes.
  • the relative level of NK cells of total lymphocytes measured for the selection of patient to be treated with a DC vaccine is compared to a threshold level between 12% and 15% of total lymphocytes.
  • the relative level of NK cells of total lymphocytes measured for the selection of patient to be treated with a DC vaccine is compared to a threshold level of 13% of total lymphocytes.
  • the absolute count of NK cells measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 150 and 250 cells/m ⁇ of blood. In a preferred embodiment, the absolute count of NK cells measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 160 and 200 cells/m ⁇ of blood. In yet a more preferred embodiment, the absolute count of NK cells measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level of about 177 cells/m ⁇ of blood. The inventors stratified the patients the patients into two groups using the median number of NK cells of this cohort, being 177 cells/m ⁇ of blood thereby defining two separate group of patients with a significantly different survival outcome of the DC vaccination.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 250 x 10 9 and 310 x 10 9 platelets/1.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 260 x 10 9 and 300 x 10 9 platelets/1.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level of about 279 x 10 9 platelets/1.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 270 x 10 9 and 330 x 10 9 platelets/1.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level between 280 x 10 9 and 310 x 10 9 platelets/1.
  • the platelet count measured for the selection of patients to be treated with a DC vaccine is compared to a threshold level of about 300 x 10 9 platelets/1.
  • the invention in another embodiment, relates to a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine if the amount of NK cells and/or the amount of platelets is equal or above the threshold level.
  • patients selected with a NK cells level equal or above the threshold level for a treatment with the DC vaccine in combination with standard of care chemotherapy will have a higher chance of survival to cancer than patients with a NK cells level below this threshold.
  • patients selected with a platelet count equal or above the threshold for a treatment with the DC vaccine in combination with standard of care chemotherapy will have a higher chance of survival to cancer than patients with a platelet count below this threshold.
  • NK cells have been previously described as prognostic factors, but mainly based on tumor infiltrating NK cells (Lundgren et al. 2016; Takanami, Takeuchi, and Giga 2001; Drakes and Stiff 2018) and more rarely based on the level of NK cells in circulating blood (Kondo et al. 2003; Terme et al. 2016).
  • prognostic factor based on the level of NK cells was never described in relation to a DC vaccination alone or DC vaccination in combination with chemotherapy.
  • the artisan would expect that rather CD8 + cytotoxic T cells are important to mount an effective immune response in a vaccination approach.
  • the presence of absence of CD8 + cytotoxic T cells did not correlate with the outcome of the study.
  • the invention in another embodiment, relates to a dendritic cells vaccine for use in a method of treating cancer in a patient, wherein the treatment comprises a step of determining in a blood sample of the patient whether or not the patient has a relative level of NK cells that is equal or above said threshold level.
  • the invention also relates to a dendritic cells vaccine for use in a method of treating cancer in a patient wherein the treatment comprises a step of determining in a blood sample of the patient whether or not the patient has an absolute count of NK cells that is equal or above said threshold level.
  • the invention relates to a dendritic cells vaccine for use in a method of treating cancer in a patient wherein the treatment comprises a step of determining in a blood sample of the patient whether the patient has a level of platelets that is equal or above said threshold level.
  • the selected patients are treated for cancer with a DC vaccine and standard of care chemotherapy, preferably wherein the cancer to be treated is ovarian, lung or prostate cancer.
  • Ovarian cancer includes epithelial ovarian, fallopian tube, or primary peritoneal cancer and may be stage I to IV according to the International Federation of Gynecology and Obstetrics (FIGO).
  • the cancer to be treated is prostate cancer.
  • Prostate cancer includes acinar adenocarcinoma, ductal adenocarcinoma, transitional cell cancer, squamous cell cancer and small cell cancer and may be graded using the Gleason scoring system.
  • the cancer to be treated is lung cancer.
  • Lung cancer is preferentially non-small cell lung cancer and includes lung adenocarcinoma, squamous cell lung carcinoma and large-cell lung carcinoma.
  • the cancer to be treated is ovarian cancer.
  • the cancer is recurrent.
  • the cancer is recurrent when a previous chemotherapy treatment failed to cure the patient from cancer.
  • a previous chemotherapy may have failed to cure the patient because the patient relapsed after completion or termination of the previous chemotherapy or because the patient was refractory to the chemotherapy.
  • the first DC vaccine dose administration starts after the 2 nd cycle of chemotherapy and continues after completion/termination of the chemotherapy.
  • the cancer is recurrent advanced ovarian cancer or relapsed platinum- sensitive epithelial ovarian carcinoma.
  • DC vaccines are well known in the art and can be divided into different groups according to the method how the DCs are loaded or pulsed with tumor antigens (Tumis and Rooney 2010; Elster, Krishnadas, and Lucas 2016), incorporated herein by reference.
  • the DC vaccine for use in the treatment of cancer administered to a patient in parallel to chemotherapy is a DC vaccine loaded ex-vivo with an antigen source, which is preferably selected from tumor associated peptide(s), whole antigens from DNA or RNA, whole antigen-protein, idiotype protein, tumor lysate, whole tumor cells or viral vector-delivered whole antigen.
  • the DC vaccine may optionally be matured with toll-like receptor (TLR) agonists (e.g. poly[I:C] or LPS). Preferentially, the DC vaccine is matured with the TLR3 agonist poly[I:C].
  • TLR toll-like receptor
  • the tumor lysate may be autologous or allogeneic/heterologous. Likewise, whole tumor cells may be autologous or allogeneic/heterologous. Whole tumor cells and tumor lysate may originate from one or multiple tumor cell lines, and may be selected for a specific presence of antigens matching the patient’s tumor to be treated. The source of antigens may be selected and DCs may be loaded by techniques known to one of skill in the art (Tumis and Rooney 2010; Elster, Krishnadas, and Lucas 2016).
  • the whole tumor cells loaded upon the DC vaccine are allogeneic to the patient.
  • allogeneic tumor cells e.g. tumor cell lines, which have an overlap of expressed tumor antigens with the typical tumor antigens of the tumor disease to be treated.
  • the DC vaccine may be formulated for intravenous, intradermal or subcutaneous administrations, preferably for subcutaneous administration.
  • the DC vaccine can be formulated for example for infusion or bolus injection, and may be administered together with an adjuvant (Elster, Krishnadas, and Lucas 2016).
  • Administration can be systemic, loco-regional or local.
  • the dose can be administered in one or multiple injections, preferably in two injections.
  • the DC vaccine may be administered to the patient subcutaneously into lymph-node regions close to the region where the cancer to be treated is developing.
  • Various delivery systems are known and can be used to deliver the DC vaccine.
  • the mode of administration may be left to the discretion of the practitioner.
  • the blood to be analyzed for patient selection is obtained prior to the treatment of the patient with the dendritic cell vaccine and an optional concomitant chemotherapy.
  • the blood sample may be obtained within one week, two weeks, three weeks, four weeks or within one month or two month of the start of the treatment.
  • the optional concomitant chemotherapy may be the standard of care chemotherapy.
  • the chemotherapeutic agent or agents to be used may be determined by the qualified practitioner, and may be part of the standard of care recommended for the type of cancer to be treated.
  • the chemotherapeutic agent/s may be administered in one or multiple cycles. The duration, frequency and number of cycles will depend on the cancer to be treated and on the agent/s used.
  • the chemotherapeutic agent/s may all be given on a single day, several consecutive days, or continuously, to an outpatient or to an inpatient. Treatment could last minutes, hours, or days, depending on the specific protocol.
  • Chemotherapy may be repeated weekly, bi weekly, or monthly. Usually, a cycle is defined in monthly intervals.
  • NK cells in blood is measured by flow cytometry/FACS.
  • NK cells are understood to be CD45 + CD56 + ( ° rbnght) CD16 and CD45 + CD56 ( ° r dim) CD16 + cells, and further CD3 cells. Any fluorophore-coupled antibodies against CD45, CD3, CD16 and CD56 may be used to measure the amount of NK cells by flow cytometry.
  • FACS Fluorescence-activated cell sorting. Flow cytometry may be performed as described in Adan A. et al. (2017) and Jevremovic & Olteanu (2019). Blood samples for flow cytometry analysis may be prepared according to McCoy (2001).
  • the level of platelets in blood is measured by flow cytometry.
  • platelets may be measured by DC impedance method with hydrodynamic focusing (Briggs, Harrison, and Machin 2007). Platelets may also be measured by fluorescent flow cytometry.
  • fluorescent flow cytometry platelets may be stained with fluorochrome-labelled monoclonal antibodies raised against a platelet glycoprotein or against proteins expressed by platelets such as GPIIb/IIIa, CD41, CD42a or CD61.
  • flow cytometry is performed using antibodies to stain platelets, it may be performed as described in Karolczak et al. (2019).
  • platelets can also be labelled with fluorescent dyes selectively labelling platelets, such as the PLT-F dye (Wada et al. 2015).
  • fluorescent dyes selectively labelling platelets, such as the PLT-F dye (Wada et al. 2015).
  • Automated blood cell counters have been optimized to count by flow cytometry platelets using PLT-F or similar dyes (Wada et al. 2015; Lim et al. 2018; Bain 2015).
  • the levels of NK cells and platelets is determined in blood obtained from the patient prior to leukapheresis.
  • the blood sample may be obtained prior to prescription of the DC vaccine treatment.
  • Leukapheresis will only be performed once the DC vaccine treatment is prescribed.
  • Leukapheresis is a laboratory procedure in which leukocyte are separated from a sample of blood. Therefore, an NK cells or platelet count may not be accurate, if performed after leukapheresis.
  • the DCs may be derived from monocytes that are autologous to the patient being treated.
  • the term“monocytes” refers to leukocytes circulating in the blood characterized by a bean-shaped nucleus and by the absence of granules. Monocytes can give rise to dendritic cells.
  • the monocytes can be isolated from a patient’s blood by any technique known to one of skill in the art, the preferred method being leukapheresis. Leukapheresis allows to collect monocytes that are autologous to the patient being treated, to be used for the preparation of the DC vaccine. Leukapheresis may be performed by any technique known to one of skill in the art.
  • dendritic cells are derived from monocytes obtained by leukapheresis prior to chemotherapy, which is combined with the DC vaccination. As many chemotherapies induce neutropenia, a leukapheresis after initiation of chemotherapy may lead to less viable cells and therefore to a lower quantity and/or quality of the DC vaccine.
  • the immature dendritic cells derived from monocytes are in a first step loaded with tumor cells undergoing immunogenic cell death (ICD).
  • ICD immunogenic cell death
  • a specific type of apoptosis may be characterized by expression of immunogenic molecules on the cell surface such as HSP70, HSP90 and calreticulin and the release of late apoptotic markers HMGB 1 and ATP and thus increases the uptake of these cells by DCs, resulting in loaded DCs presenting the multiple tumor antigens.
  • the antigen source is whole tumor cells and wherein preferably the tumor cells were killed by high hydrostatic pressure (HHP), e.g.
  • WO 2013/004708 and WO 2015/097037 are treated by HHP between 200 and 300 MPa for 10 min to 2 hours. Such a treatment will induce ICD.
  • Other methods to introduce ICD are the treatment with anthracyclines (Casares et al. 2005) or heat - preferably severe heat above 45°C (Adkins et al. 2017).
  • the apoptotic tumor cells Prior to being loaded on DCs, the apoptotic tumor cells may be cryopreserved (see WO 2015/097037).
  • the whole tumor cells loaded upon the DC vaccine are allogeneic to the patient.
  • autologous tumor cells purportedly have a better match with the patient’s tumor antigens
  • the collected autologous monocytes are cultivated in the presence of cytokines to obtain immature DCs.
  • cytokines are GM-CSF and IL-4.
  • the DC vaccine is obtained by loading the immature DCs with tumor cells undergoing ICD, preferably from HHP treated allogeneic tumor cell lines of the same tumor origin as the one to be treated.
  • loaded DCs are further matured with TLR agonists.
  • TLR agonists may be TLR 3 or TLR4 agonists, preferably the TLR3 agonist poly[I:C].
  • Resulting DC vaccines may be fractioned and stored in individual doses of approximately lxlO 7 DCs per dose.
  • Mature DCs generated as described herein may be characterized as displaying significantly higher expression of maturation markers, such as CD80, CD83, HLA-DR and CD86, than immature DCs and DCs loaded with tumor cells killed by other modalities, such as UV irradiation, as shown by Hradilova et al. and Fucikova et al. (Hradilova et al. 2017; Fucikova et al. 2014). Furthermore, Fucikova et al. and Hradilova et al.
  • DCs generated as described herein induced a greater number of tumor-specific CD4 + and CD8 + IFN-y-producing T cells and decreases the number of CD4 + CD25 + Foxp3 + T regulatory cells compared to DCs pulsed with UV-B light- exposed cells.
  • the dendritic cell vaccine is administered to a patient in combination with a different treatment modality selected from the group of chemotherapy, targeted therapy and biologies.
  • chemotherapy is understood to relate to the class of compounds used as cytostatic or cytotoxic agents.
  • the at least one chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, olaparib, rucaparib, trabectedin, niraparib, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, vinblastine, and albumin-bound paclitaxel.
  • the specific regimen of chemotherapy may be dictated by the established standard of care of the specific cancer to be treated, and may be at the discretion of the practitioner.
  • cyclophosphamide is not a chemotherapeutic agent.
  • a low dose cyclophosphamide is not a chemotherapeutic agent according to the present invention; it is used to reduce the function of regulatory T cells (Berd and Mastrangelo 1987; Fucikova et al. 2017) and has been used prior to DC vaccination in the prior art (Dong et al. 2016).
  • Chemotherapy may include drugs prescribed as maintenance therapies or prescribed until progression of the cancer such as hormonal therapies (e.g. enzalutamide, abiraterone, tamoxifen, LHRH agonists and antagonists), targeted therapies (e.g.
  • chemotherapy in the meaning of this invention does not include drugs prescribed to treat co- morbidities, to avoid or treat side-effects or help the patient to recover from side-effects (e.g. erythropoietin).
  • the first dose of DC vaccine is administered in parallel to each chemotherapy cycle, and may be further administered after completion/termination of the chemotherapy.
  • the first DC vaccine administration may start with the first cycle of chemotherapy, with the second chemotherapy cycle, with the third chemotherapy cycle, or with later chemotherapy cycles.
  • the first DC vaccine dose administration starts after the 2 nd cycle of chemotherapy and continues after completion/termination of the chemotherapy.
  • the patient received at least 6 cycles of chemotherapy.
  • DC vaccine is administered to a patient in parallel to chemotherapy with at least one chemotherapeutic agent.
  • the invention relates to a DC vaccine treatment administered to a patient in parallel to chemotherapy, where a previous chemotherapy treatment failed to cure the patient from cancer.
  • a previous chemotherapy may have failed to cure the patient because the patient relapsed after completion or termination of the previous chemotherapy or because the patient was refractory to the chemotherapy.
  • the first DC vaccine dose administration starts after the 2 nd cycle of chemotherapy and continues after completion/termination of the chemotherapy.
  • the dendritic cell vaccine is administered to a patient after completion of chemotherapy with at least one chemotherapeutic agent.
  • the first dose of the DC vaccine is administered to the patient preferably within two months after completion of the last cycle of the chemotherapy, preferably within one month after completion of the last cycle of the chemotherapy, more preferably within two weeks after completion of the last cycle of the chemotherapy, most preferably immediately after the completion of the last cycle of the chemotherapy.
  • the timing between completion of the last cycle of chemotherapy and administration of the DC vaccine may depend on the chemotherapeutic agent/s, on the cancer to be treated, on the reaction of the patient regarding toxicity of the chemotherapeutic agent/s.
  • the patient received at least 3 cycles of chemotherapy and preferably at least 6 cycles of chemotherapy.
  • the first dose of the DC vaccine is administered to the patient within two months after administration of the last dose of the chemotherapy, preferably within one month after administration of the last dose of the chemotherapy, more preferably within two weeks after administration of the last dose of the chemotherapy.
  • the last dose may be given within the last cycle of chemotherapy, i.e. before completion of the last chemotherapy cycle.
  • a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the amount of NK cells and comparing it to a threshold level.
  • a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the count of platelets and comparing it to a threshold level.
  • a dendritic cell vaccine for use in a method of treating cancer in a patient, wherein the patient is selected for treatment with said dendritic cell vaccine by determining in a blood sample from the patient the amount of NK cells and comparing it to a threshold level and by determining in a blood sample from the patient the count of platelets and comparing it to a threshold level.
  • the dendritic cell vaccine for use of item 1 or item 3, wherein the threshold level is a relative level of NK cells of the total lymphocytes.
  • the dendritic cell vaccine for use of item 1 or item 3, wherein the threshold level is an absolute count of NK cells.
  • the threshold level is a count of platelets between 250 x 10 9 and 310 x 10 9 platelets/1, between 260 x 10 9 and 300 x 10 9 platelets/1 and preferably of 279 x 10 9 platelets/1.
  • dendritic cells vaccine for use of items 1 to 9, wherein the treatment comprises a step of determining in a blood sample of the patient,
  • the dendritic cell vaccine for use of items 1 to 10, wherein the cancer is ovarian, lung or prostate cancer, preferably ovarian cancer.
  • the dendritic cell vaccine for use of items 1 to 11 wherein the cancer is recurrent.
  • the dendritic cell vaccine for use of items 1 and 12, wherein the blood sample is obtained prior to the treatment of the patient with the dendritic cell vaccine and an optional concomitant chemotherapy.
  • the dendritic cell vaccine for use of items 1 and 13, wherein the levels of CD16 + CD56 + NK cells and platelets are determined in blood obtained from the patient prior to leukapheresis.
  • the dendritic cell vaccine for use of items 1, 3-7 and 9-14, wherein the level of NK cells in blood is measured by flow cytometry/FACS.
  • the dendritic cell vaccine for use of items 1, 2 and 8-14, wherein the level of platelets in blood is measured by flow cytometry.
  • dendritic cell vaccine for use of items 1 to 16, wherein the dendritic cells are derived from monocytes that are autologous to the patient to be treated.
  • dendritic cell vaccine for use of items 1 to 18, wherein immature dendritic cells are in a first step loaded with tumor cells undergoing immunogenic cell death.
  • the dendritic cell vaccine for use of items 1 to 19, wherein the loaded dendritic cells are thereafter matured with Toll-like receptor 3 agonists or Toll-like receptor 4 agonists.
  • the dendritic cell vaccine for use of items 1 to 21, wherein the dendritic cell vaccine is administered to a patient in parallel to chemotherapy with at least one chemotherapeutic agent.
  • the dendritic cell vaccine for use of items 1 to 22, wherein the dendritic cell vaccine is administered to a patient after completion of chemotherapy with at least one chemotherapeutic agent.
  • FIG. 1 Schematic diagram of the clinical study on patients with 1 st recurrence of ovarian cancer, comparing the standard of care chemotherapy treatment to the DC vaccine treatment administered in parallel to chemotherapy.
  • DCVAC OvCa stands for a dendritic cell vaccine wherein dendritic cells have been loaded with ovarian cancer cells undergoing immunogenic cell death and matured by a Toll-like receptor ligand.
  • a day 1/8 regimen means that gemcitabine is given on day 1 and 8 of each cycle and carboplatin is given on the first day of every cycle. The length of a cycle is 21 days.
  • Figure 2 Analysis of OS in the clinical study for the ITT population with 1 st recurrence of ovarian cancer.“Standard of care” stands for chemotherapy treatment alone.
  • Figure 3 Analysis of OS in the clinical study for the ITT population with 1 st recurrence of ovarian cancer stratified for the absolute count of NK cells.
  • Figure 4 Analysis of OS in the clinical study for the ITT population with 1 st recurrence of ovarian cancer stratified for the relative amount of NK cells.
  • Figure 5 Analysis of OS in the clinical study for the ITT population with 1 st recurrence of ovarian cancer stratified for the level of platelets.
  • Figure 6 Analysis of OS in the clinical study for the ITT population with 1 st recurrence of ovarian cancer stratified for the level of platelets.
  • Figure 7 Graph representing the distribution of absolute NK cells counts over the patient population treated with DCVAC (left graph) and patient population treated with standard of care (right graph).
  • X axis count of NK cells/m ⁇ of blood;
  • Y axis frequency of patients.
  • Figure 8 Graph representing the distribution of platelet counts over the patient population treated with DCVAC (left graph) and patient population treated with standard of care (right graph).
  • X axis platelet count in 10 9 platelets/1 of blood; Y axis: frequency of patients.
  • the DC vaccine consisted of autologous DCs loaded ex vivo with killed ovarian cancer cells and matured by a Toll-like receptor 3 (TLR-3) ligand.
  • DCs were derived from autologous monocytes that were obtained by leukapheresis. Monocytes isolated from the leukapheresis product were cultured in the presence of granulocyte macrophage colony-stimulating factor and interleukin 4 to obtain immature DCs.
  • Immature DCs were loaded with cells of the ovarian cancer cell lines OV- 90 and SK-OV-3 (in a ratio of 2: 1).
  • OV-90 and SK-OV-3 cells were treated with high hydrostatic pressure (HHP) (as described in WO 2013/004708, examples 1-4), which induces immunogenic cell death (Fucikova et al. 2014).
  • HP high hydrostatic pressure
  • the tumor cell- loaded DCs were matured by polyinosinic:polycytidylic acid (poly[I:C]), a TLR-3 ligand.
  • the final product was cryopreserved in doses of approximately lxlO 7 DCs per vial in 1 mL of CryoStor CS10 freezing medium containing 10% dimethyl sulfoxide.
  • DC vaccine aliquots were transported to the study sites on dry ice at a temperature below -50°C. Each DC vaccine dose was then thawed and diluted in saline to a final volume of 5 mL. The diluted dose was administered to the patient subcutaneously in two applications: one into the inguinal area and one into the contralateral axillary area (2.5 mL to each of the application sites).
  • Platelets count in a blood sample
  • Venous blood samples of patients to be screened have been collected in BD Vacutainer® EDTA tubes (BC Biosciences, Heidelberg, DE) according to approved protocol and stored at 2 to 8°C until analysis. Prior to analysis, samples were brought back to room temperature.
  • Platelets count was measured by flow cytometry with a Sysmex XN1000 hematology analyzer (Sysmex Europe GmbH, Norderstedt, DE) according to the manufacturer’s instruction ("Automated Hematology Analyzer XN series (XN-1000) Instructions for Use” 2014).
  • the platelets (as well as the erythrocytes) were analyzed using the DC impedance method with hydrodynamic focusing.
  • the electrical signals of the cells are analyzed as they pass through an aperture in the device. From these primary signals, the device can identify the cell type by determination of the particle size.
  • the device automatically evaluates the particle distribution in a range from 2-6 fL (low discriminator) to 12-30 fL (high discriminator). For comparison, the size limits (discriminators) for erythrocytes are 25-75 fL and 200-250 fL, respectively. If any irregularities were detected (e.g. abnormal distribution width, multiple peaks), the measurement would have to be repeated using an optical readout (same method as for reticulocytes) according to the programming of the device. The platelet count is given in number of cells x 10 9 /l.
  • NK cells count in a blood sample
  • Venous blood samples of patients to be screened have been collected in BD Vacutainer® EDTA tubes (BC Biosciences, Heidelberg, DE) according to approved protocol.
  • NK cells count was measured by flow cytometry/FACS using a Coulter Epics XL flow cytometer (Beckman Coulter, Krefeld, DE).
  • a fraction of the blood sample was treated for red blood lysis with a red blood lysis buffer (RBC Lysis Buffer (10X), Beckman Coulter, Krefeld) according to the manufacturer’s instructions.
  • RBC Lysis Buffer (10X) red blood lysis buffer
  • the cells were stained with CD3, CD 16 and CD56 (anti-human FITC CD3, clone UCHT1, Beckman Coulter; anti-human CD16 PE clone 3G8, Beckman Coulter; anti-human CD56PE clone N901, Beckman Coulter).
  • the lymphocytes were live gated during acquisition using the side and forward scatter dot plot display.
  • the NK cell population was further identified and differentiated into cytotoxic NK cells (CD3 , CD16 + , CD56 + ) on the basis of the expression of CD56 and CD16.
  • the count of NK cells is expressed either as absolute count of cell/ m ⁇ of blood or as relative count of % of NK cell/total lymphocytes.
  • Second-line therapy taxane in combination with a platinum compound (platinum doublet) is considered valuable, with other agent combinations tested in clinical trials, including gemcitabine, trabectedin and pegylated liposomal doxorubicin. The choice should be based on the toxicity profile and convenience of administration.
  • Targeted therapy bevacizumab in combination with carboplatin and gemcitabine has been approved and is recommended in platinum-sensitive relapsed disease in patients not previously treated with bevacizumab.
  • olaparib a PARP inhibitor
  • olaparib a PARP inhibitor
  • the study was a randomized, open-label, parallel group, multicenter, phase II clinical trial evaluating the effect of addition of a DC vaccine to standard of care chemotherapy (carboplatin and gemcitabine) in women with relapsed platinum-sensitive epithelial ovarian cancer.
  • the aim of this study was to explore the efficacy and safety of a DC vaccine administered in parallel to chemotherapy, as an add-on to standard of care chemotherapy with carboplatin and gemcitabine as compared to chemotherapy alone.
  • a total of 71 patients were centrally randomized in a ratio of 1 : 1 to treatment group A (39 patients) to receive the DC vaccine in parallel with standard of care chemotherapy or to treatment group B (32 patients) to receive standard of care chemotherapy alone.
  • the DC vaccine was administered to the patients in treatment group A in up to 10 doses.
  • a total of 6, 8, or 10 cycles of standard of care chemotherapy were to be completed by patients in both treatment groups as per investigators’ decision ( Figure 1).
  • the intent-to-treat (ITT) population included all randomized patients regardless of whether they received treatment or not; however, patients randomized to treatment group A had to receive at least 1 dose of DC vaccine to be included into the ITT population (32 patients in treatment group A (parallel DC vaccine) and 32 patients in treatment group B (standard of care).
  • OS was analyzed upon stratification of the patients based on their platelet count (see Figure 8 for the distribution of platelet counts over the treated population).
  • Cibula D., P. Mallmann, P. Knapp, B. Melichar, J. Klat, L. Minar, Z. Novotny, P. Wimberger, A. Hein, R.
  • DCVAC 'Dendritic cell vaccine
  • EOC epithelial ovarian carcinoma
  • PDS primary debulking surgery
  • 'Peripheral natural killer cells are a prognostic factor in advanced oesogastric adenocarcinoma and are associated with intestinal types in the randomized trial PRODIGE17- ACCORD20 (UNICANCER Gl) 1 , Journal of Clinical Oncology, 34: 4061-61.

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Abstract

La présente invention concerne un vaccin à base de cellules dendritiques destiné à être utilisé dans une méthode de traitement d'un cancer chez un patient, le patient étant sélectionné pour le traitement avec ledit vaccin à base de cellules dendritiques en déterminant, dans un échantillon de sang prélevé sur le patient, la quantité de cellules NK et en la comparant à un niveau seuil.
PCT/EP2020/057415 2019-03-19 2020-03-18 Sélection de patients pour un traitement avec vaccination à base de cellules dendritiques WO2020187975A1 (fr)

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