WO2019166667A1 - Détection de la sensibilité d'une tumeur à une thérapie ciblée - Google Patents

Détection de la sensibilité d'une tumeur à une thérapie ciblée Download PDF

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Publication number
WO2019166667A1
WO2019166667A1 PCT/EP2019/055301 EP2019055301W WO2019166667A1 WO 2019166667 A1 WO2019166667 A1 WO 2019166667A1 EP 2019055301 W EP2019055301 W EP 2019055301W WO 2019166667 A1 WO2019166667 A1 WO 2019166667A1
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Prior art keywords
tumor
monocytes
marker
subject
therapy
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PCT/EP2019/055301
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English (en)
Inventor
Ralf SCHIERL
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Zyagnum Ag
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Publication of WO2019166667A1 publication Critical patent/WO2019166667A1/fr

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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
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57496—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving intracellular compounds
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention is in the field of medicine, in particular in tumor therapy, more particular in targeted tumor therapy.
  • Successful tumor therapy is dependent of the time point of the detection of the tumor and the selection of the right therapy.
  • Identification of specific biomarkers in tissue samples of a tumor help to determine both, the stage of malignancy and the presence of cell structures, which can serve as targets for therapy.
  • the detection of tumor-associated biomarkers in the blood is used to detect malignancies.
  • expectations on biomarkers have not been met in many cases, because these are not specific enough or do not have the necessary sensitivity to be able to detect malignancies at an early stage in a reliable way.
  • known biomarkers can often just be applied on specific tumor types. Therefore, biomarkers are increasingly being sought, which allow the general detection of tumors. Such a general tumor test would considerably simplify the diagnosis of a wide variety of tumors and thus significantly improve both, therapy and monitoring.
  • a novel method for detecting biomarkers in specific cells in the blood, which carry tumor material has solved this problem, since the tumor material in these specific cells is not diluted in the whole blood and remains in high concentration inside said cells.
  • This novel method is based on the principle of the immune system to detect, phagocyte and digest undesirable cell structures.
  • Undesirable cell structures comprise intruders from outside like bacteria and parasites or even degenerated body ' s own cells like tumor cells.
  • immune cells such as monocytes, phagocyte these structures and present them.
  • tumor cells are recognized by said immune cells, which then phagocyte and attack them. Therefore, the immune cells migrate from the blood vessels into the tumors to phagocyte tumor cells. Consequently, the immune cells enclose fragments of one or more tumor cells, which are then presented over a period of several days. The aim is to inform other immune cells what the target is.
  • a sort of immune cells which carry tumor material in the cytoplasm are characterized by the fact that they carry the surface markers CD14 and CD16, which can be easily detected in blood samples by flow cytometry. With this method it is possible to detect these immune cells, count them and even further characterize them.
  • biomarkers for apoptosis disorders are of big interest.
  • One of the known biomarkers is based on the DNaseX-enzyme, which normally performs the last step of the apoptosis and has been shown to be overexpressed in tumors. Nevertheless, the enzymatic activity of the DNase-enzyme is inhibited by the increased release of inhibitors by the tumor cells.
  • TKTL1 is a further important biomarker for tumors.
  • the detection of biomarkers ApolO and TKTL1 in immune cells by means of blood test allows early detection of all types of carcinoma examined so far, but also of sarcomas and hematological tumors.
  • targets are specific molecules that are involved in the growth, progression and spread of the cancer.
  • drugs or other substances are administered to the patient, which block the growth or the spread of the cancer by interfering with the targets.
  • a limitation of the targeted tumor therapy is, that the amount of the cells comprising the target can change during the therapy. Cells might become resistant to the therapy, maybe through mutation of the target, so that the targeted drugs or substances no longer interact with it or the tumor finds a new pathway for tumor growth independent on the target. For this reason, it is important to proof, if a special target in the tumor cells is existing before and during the therapy. This is highly important for deciding, which therapy to use and if the therapy already used has to be changed, respectively. For the evaluation if a tumor is susceptible to a special targeted therapy, also the proportion of the tumor cells comprising the target to the whole tumor is important.
  • One approach is the detecting of targets in tumor cells, which have separated from the tumor and are circulating in the blood of the patient.
  • a method for detecting the susceptibility of a tumor to targeted therapy in a subject comprising a. detecting at least one type of monocytes in a sample obtained from said subject and determining a first quantity of monocytes from that monocytes which are TKTL1, ApolO, Epcam and/or other tumor specific marker positive; b. determining a second quantity of said monocytes of a. which are additionally positive for at least one marker of a target used in tumor targeted therapy; and c. calculating the ratio of the first quantity to the second quantity.
  • the invention further relates to a kit for detecting the susceptibility of a tumor to targeted therapy in a subject, the kit comprising instructions for performing the method according to the invention, markers for detecting monocytes, comprising CD14 and CD16 marker, TKTL1, ApolO, Epcam and/or other tumor specific marker, at least one marker of a target used in tumor targeted therapy and reaction agents selected from the group comprising reaction buffer, wash buffer, secondary markers if applicable.
  • markers for detecting monocytes comprising CD14 and CD16 marker, TKTL1, ApolO, Epcam and/or other tumor specific marker, at least one marker of a target used in tumor targeted therapy and reaction agents selected from the group comprising reaction buffer, wash buffer, secondary markers if applicable.
  • the invention also relates to marker for TKTL1, ApolO, Epcam and/or other tumor specific marker and at least one tumor marker for targeted therapy for use in a method for diagnosis, prediction or risk stratification for mortality or disease outcome of a subject that has or is suspected to have a tumor.
  • the invention relates to marker for TKTL1, ApolO, Epcam and/or other tumor specific marker and at least one tumor marker for targeted therapy for use in a method for monitoring a tumor therapy as well as to a method for monitoring, prediction or risk stratification of a tumor targeted treatment of a subject that has or is suspected to have a tumor.
  • the present invention relates to a method for detecting the susceptibility of a tumor to targeted therapy in a subject, the method for detecting the susceptibility of a tumor to targeted therapy in a subject, the method comprising: a. detecting at least one type of monocytes in a sample obtained from said subject b. determining a first quantity of those at least one type of monocytes of step a) which are additionally TKTL1, ApolO, Epcam and/or other tumor specific marker positive; c. determining a second quantity of said monocytes of step b) which are additionally positive for at least one marker of a target used in tumor targeted therapy; and d. calculating the ratio of the first quantity to the second quantity.
  • the inventors surprisingly found that detecting the quantity of monocytes migrating into the tumor tissue and phagocyting tumor tissue and calculating the ratio of the quantity of that monocytes to the quantity of said monocytes, which are additionally positive to a marker of a target for targeted tumor therapy, gives reliable and correct information about the structure of that tumor.
  • tumor is used in the present application and is understood to encompass malignant and non-malignant tumors, including solid tumors and hematological tumors.
  • Solid tumors are exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, lover, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva.
  • endocrine glands e.g. thyroid and adrenal cortex
  • esophagus e.g. endometrium
  • germ cells e.g., head and neck
  • kidney, lover, lung larynx and hypopharynx
  • mesothelioma ovary
  • pancreas rectum
  • Hematological tumors include primary tumors in said organs and corresponding secondary tumors in distant organs (tumor metastases).
  • Hematological tumors are exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes and tumors of unknown primary site.
  • targeted tumor therapy refers to each therapy which targets one or more specific molecules that are involved in the growth, progression and/ or spread of the cancer.
  • drugs or other substances are administered to the patient, which block the growth or the spread of the cancer by interfering with the targets.
  • targeted therapies have been approved for use in cancer treatment. These therapies include, but are not limited to hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery molecules
  • cut off value defines the dividing point on measuring scales where the test results are divided into different categories; typically positive (indicating someone has the condition of interest), or negative (indicating someone does not have the condition of interest).
  • Monocytes are the largest type of white blood cells. They are part of the innate immune system of vertebrates including all mammals (humans included), birds, reptiles, and fish. They are amoeboid in shape, having a granulated cytoplasm. Monocytes constitute 2% to 10% of all leukocytes in the human body. They play multiple roles in immune function. Monocytes are produced by the bone marrow from precursors called monoblasts, which are bipotent cells that differentiated from hematopoietic stem cells. Monocytes typically circulate in the bloodstream for about one to three days and then move into tissues throughout the body. Monocytes in tissues mature to different types of macrophages depending on the anatomical location, i.e. osteoclasts, microglia cells, histiocytes, and Kupfer cells. Monocytes can move quickly to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response.
  • monocytes in human blood There are at least three types of monocytes in human blood:
  • the classical monocyte characterized by high quantity expression of the CD14 cell surface receptor (CD14++ CD16- monocyte)
  • the non-classical monocyte shows low quantity expression CD14 and additional co-expression of the CD16 receptor (CD14+ CD16++ monocyte).
  • the intermediate monocyte with high quantity expression of CD14 and low quantity expression of CD16 (CD14++ CD16+ monocytes).
  • Monocyte markers comprise CD2, CDllb, CD14, CD16, CD31, CD33, CD56, CD62L, CD115, CD163, CD192, CX3CR1, CXCR3, CXC 4, CCR2, CDllb, CD16/CD32, CD31, CD43, CD44, CD45, CD62L, CD115,
  • the combination of surface markers is used to identify monocytes alone in the flow cytometer, for example a combination of the markers CD14 and CD16.
  • Macrophages engulf and digest cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have types of proteins specific to healthy body cells on its surface in a process called phagocytosis.
  • Human macrophages can be identified by using flow cytometry or immunohistochemical staining by their specific expression of proteins such as, but not limited to CDllb, CD14, CD16, CD40, CDllb, CD56, CD64, CD68, and CD163.
  • Macrophages are attracted to a damaged site through chemotaxis, triggered by a range of stimuli (immune response) including pathogens and cytokines released by macrophages already at site. Macrophages phagocyting tumor cells, move away from the tumor and can be found circulating in blood. These macrophages contain debris of tumor cells.
  • subject is used to refer to an animal (e.g. a mammal, a fish, an amphibian, a reptile, a bird and an insect).
  • a subject is a mammal (e.g., a non-human mammal and a human).
  • a subject is a primate (e.g., a chimpanzee and a human).
  • a subject is a human.
  • the subject is a human with one or more tumors.
  • diagnosis refers to the identification of the disease (herein a tumor) at any stage of its development, and also includes the determination of predisposition of a subject to develop the disease. In a preferred embodiment of the invention, diagnosis of a tumor occurs prior to the manifestation of symptoms. Subjects with higher risk of developing a tumor are of particular concern.
  • the diagnostic method of the invention also allows confirmation of the presence of a tumor in a subject suspected to have a tumor.
  • biomarker biological marker
  • markers are used synonymously.
  • the term herein relates to measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, disease diagnosis, etc.
  • a biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or responses to a therapeutic intervention. A biomarker may be measured on a sample.
  • Biomarkers can be classified as antecedent biomarkers (identifying the risk of developing an illness), screening biomarkers (screening for disease), diagnostic biomarkers (recognizing diseases), staging biomarkers (categorizing disease severity), or prognostic biomarkers (predicting future disease course, including recurrence and response to therapy, and monitoring efficacy of therapy).
  • a biomarker may be a protein, peptide or nucleic acid molecule.
  • a biomarker is a biomolecule, more specifically a protein or even more specifically a protein which is expressed on the cell surface or intracellularly of immune cells.
  • a biomarker is a biomolecule used to detect a further biomarker in and/or on immune cells, these comprise primary and/or secondary antibodies.
  • a marker according to this invention is a biomolecule to detect a target for tumor targeted therapy in cells.
  • the term "monitoring” denotes the observation of the state or progression of a subject's medical condition by measuring the level of a certain diagnostic marker or markers for said medical condition at various points of time.
  • the term "beneficial outcome” refers to the outcome a subject may experience after tumor therapy, which leads to an improvement in at least one sign of a tumor, which comprise tumor shrinkage, decrease in growth rate or suppression of tumor growth. Further, a reduction of the number of tumor cells, reduction of tumor size, inhibition of tumor cell infiltration into peripheral organs, retarded, slowed or stopped cell infiltration, inhibition of tumor metastasis or slowed tumor metastasis, prevention or delayed recurrence of tumor. Also, it may mean that the disease is no longer progressive. Further, it refers to the relieve of one, more, or even all symptoms associated with tumors.
  • a "kit” is a packaged combination optionally including instructions for use of the combination and/or other reactions and components for such use.
  • the sample of the subject is obtained before initiation of the therapy. Thereby it can be tested if a tumor is susceptive to targeted tumor therapy.
  • the sample of said subject can also be obtained at one or more further time points during the therapy. Thereby it can be tested if the tumor is still susceptive to the applied targeted tumor therapy.
  • said monocytes are selected from the group comprising monocytes positive for CD14 and CD16, CD2, CDllb, CD14, CD16, CD16/CD32, CD31, CD33, CD40, CD43, CD44, CD45, CD56, CD62L, CD64, CD68, CD115, CD163, CD192, CX3CR1, CXCR3, CXC 4, CCR2, CDllb, CD16/CD32, CD31, CD43, CD44, CD45, CD62L, CD115, CX3CR1, F4/80, Grl, Ly-6C, LFA-1, or VEGF.
  • the monocytes are macrophages.
  • the monocytes are CD 14 and CD 16 positive macrophages.
  • all markers appropriate for detecting a target of tumor targeted therapy can be used.
  • the at least one marker of a target used in tumor targeted therapy is selected from the group of HER2, AFP, Beta-HCG, CEA, PSA, CA 125, CA 15-3, CA 19-9, CA 72-4, Calcitonin, CgA, CYFRA 21-1, NSE-Tumormarker, Protein S100, PD-L1, PSMA-Ligand and SCC- Tumormarker.
  • the first quantity of the monocytes is set to 100%.
  • the percentage of monocytes in the tumor that are susceptible to targeted tumor therapy can be obtained.
  • a beneficial outcome is associated to the targeted therapy using the detected target, if the ratio of the first quantity to the second quantity is beyond a determined cut off value.
  • methods for direct and indirect cell counting are used. Especially preferred is the method of flowcytometry.
  • the first quantity of monocytes and the second quantity of monocytes are determined by flowcytometry.
  • the method according to the invention is for use in medical decision making for individual targeted tumor therapy in a subject.
  • kits for detecting the susceptibility of a tumor to targeted therapy in a subject comprising: a) instructions for performing the method of any of the claims 1 to 8 b) markers for detecting monocytes, comprising CD14 and CD16 marker c) marker for TKTL1, ApolO, Epcam and/or other tumor specific marker, d) at least one marker of a target used in tumor targeted therapy e) reaction agents selected from the group comprising reaction buffer, wash buffer, secondary markers if applicable
  • the invention also relates to TKTL1, ApolO, Epcam and/or other tumor specific marker and at least one tumor marker for targeted therapy for use in a method for diagnosis, prediction or risk stratification for mortality or disease outcome of a subject that has or is suspected to have a tumor.
  • the invention further relates to TKTL1, ApolO, Epcam and/or other tumor specific marker and at least one tumor marker for targeted therapy for use in a method for monitoring a tumor therapy.
  • the invention also relates to a method for monitoring, prediction or risk stratification of a tumor targeted treatment of a subject that has or is suspected to have a tumor, the method comprising: a) detecting at least one type of monocytes in a sample obtained from said subject b) determining a first quantity of those at least one type of monocytes of step a) which are additionally TKTL1, ApolO, Epcam and/or other tumor specific marker positive; c) determining a second quantity of said monocytes of step b) which are additionally positive for at least one marker of a target used in tumor targeted therapy; and d) calculating the ratio of the first quantity to the second quantity.
  • the invention relates to a method of treating a tumor patient in need thereof, wherein the tumor therapy is initiated or altered depending on the outcome of the method of monitoring according to the invention.

Abstract

L'invention concerne un procédé de détection de la sensibilité d'une tumeur à une thérapie ciblée chez un sujet, le procédé consistant à a. détecter au moins un type de monocytes dans un échantillon obtenu à partir dudit sujet et déterminer une première quantité de monocytes à partir de ces monocytes qui sont positifs à TKTL1, Apo10, Epcam et/ou un autre marqueur spécifique à une tumeur ; b. déterminer une seconde quantité desdits monocytes de a. qui sont en outre positifs pour au moins un marqueur d'une cible utilisée dans une thérapie ciblée contre une tumeur ; et c. calculer le rapport de la première quantité sur la seconde quantité. L'invention concerne en outre un kit pour détecter la sensibilité d'une tumeur à une thérapie ciblée chez un sujet. L'invention concerne également TKTL1, Apo10, Epcam et/ou un autre marqueur spécifique à une tumeur et au moins un marqueur tumoral pour une thérapie ciblée destinée à être utilisée dans un procédé de diagnostic, de prédiction ou de stratification des risques pour la mortalité ou l'issue d'une maladie d'un sujet qui présente ou est suspecté de présenter une tumeur et pour l'utilisation dans un procédé de surveillance d'une thérapie tumorale, ainsi qu'un procédé de surveillance, de prédiction ou de stratification des risques d'une traitement ciblant une tumeur d'un sujet qui présente ou est suspecté de présenter une tumeur.
PCT/EP2019/055301 2018-03-02 2019-03-04 Détection de la sensibilité d'une tumeur à une thérapie ciblée WO2019166667A1 (fr)

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