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WO2019043138A1 - Procédé de prédiction de l'issue d'un cancer - Google Patents

Procédé de prédiction de l'issue d'un cancer Download PDF

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Publication number
WO2019043138A1
WO2019043138A1 PCT/EP2018/073429 EP2018073429W WO2019043138A1 WO 2019043138 A1 WO2019043138 A1 WO 2019043138A1 EP 2018073429 W EP2018073429 W EP 2018073429W WO 2019043138 A1 WO2019043138 A1 WO 2019043138A1
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Prior art keywords
cancer
clq
cells
expression level
cell
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PCT/EP2018/073429
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English (en)
Inventor
Wolf Herman Fridman
Catherine SAUTES-FRIDMAN
Lubka ROUMENINA
Rémi NOE
Marie DAUGAN
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
Institut Mutualiste Montsouris
Sorbonne Universite
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
Institut Mutualiste Montsouris
Sorbonne Universite
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Publication of WO2019043138A1 publication Critical patent/WO2019043138A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention is in the field of cancer. More particularly, the invention relates to a method for predicting the survival time of a patient suffering from a cancer.
  • Renal cell cancer is responsible for over 140 000 deaths per year.
  • RCC encompasses different histological subtypes, the far most frequent being the clear cell RCC (ccRCC), representing 75% of RCC.
  • ccRCC still represents an unmet medical need, particularly at the metastatic stage when surgery is inappropriate or inefficient.
  • Progress has, however, been made based on better knowledge of the histology of ccRCC.
  • Mutations of the VHL gene, responsible for the Von Hippel-Lindau Syndrome are found in 80% of ccRCC. Such mutations result in the activation of the transcription factor HIF (hypoxia inducible factor), which regulates genes involved in the angiogenesis, cell proliferation and survival.
  • HIF hyperoxia inducible factor
  • ccRCC is particular in terms of its microenvironment and of how it impacts patients' clinical outcome.
  • many ccRCC tumors present with a strong and inflammatory cell infiltration.
  • Precise analyses of ccRCC tumors revealed particular behaviors and clinical impact of the immune and inflammatory tumor microenvironment (TME).
  • TEM immune and inflammatory tumor microenvironment
  • tumors present with a structured immune landscape with mature dendritic cells (DC) within tertiary lymphoid structures (TLS) allowing T cell differentiation and regulation.
  • DC dendritic cells
  • TLS tertiary lymphoid structures
  • CD8+ T cells in the TME correlates with longer progression free survival (PFS) and OS.
  • PFS progression free survival
  • OS OS
  • CD8+ T cells in these tumors show an exhausted phenotype, with expression of PD-1, LAG3 (CD223, Lymphocyte-activation gene 3) and TIM-3 (T-cell immunoglobulin and mucin- domain containing-3, HAVCR2), accompanied by expression of PD-1 ligands (PDL-1 and PDL-2) on tumor cells.
  • CD8+ T cells do not produce perforin and exhibit a very diverse inflammatory type T cell repertoire.
  • a major characteristic of these tumors is a strong infiltration with inflammatory cells, particularly macrophages.
  • This chronic inflammatory context via factors locally produced by the inflammatory cells, may modulate the T cells content of the TME, making it deleterious for the patient.
  • Macrophages represent a major component of the TME and in most tumors, including ccRCC, are considered to be predominantly of M2 phenotype, favoring cancer growth, neovascularization and invasion (8, 9).
  • Complement system is one of the key factors for tissue inflammation (12) and the kidney is capable to produce the whole spectrum of complement components. (13, 14) Nevertheless, the role of complement activation for the progression of ccRCC remains poorly understood. In the present work we address the capacity of the components of the complement system to modulate the TME and to impact the clinical outcome. Complement is a major player in the anti-infections responses and also entertains chronic inflammation through the anaphylatoxins C3a and C5a, which are generated upon complement activation. (12) Complement activation can be induced by three different pathways - classical, lectin and alternative, depending on the context and the presence of distinct activator molecules.
  • the inventors have investigated the presence and impact of Clq, produced by the macrophages, in the ccRCC TME and showed that it is associated with poor prognosis, particularly in patients with advanced and metastatic tumors. They propose that this is due to the activation of at least the early steps of the complement. Their data provide a novel mechanism of immune modulation of TME in ccRCC that may explain the particularly poor clinical impact of the TME in these tumors.
  • the present invention relates to a method for predicting the survival time of a patient suffering from a cancer comprising i) determining in a sample obtained from the patient the expression level of Clq ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • the invention is defined by its claims.
  • a first aspect of the invention relates to a method for predicting the survival time of a patient suffering from a cancer comprising i) determining in a sample obtained from the patient the expression level of Clq ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • cancer has its general meaning in the art and includes, but is not limited to, solid tumors and blood borne tumors.
  • the term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels.
  • the term “cancer” further encompasses both primary and metastatic cancers. Examples of cancers that may be treated by methods and compositions of the present invention include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lympho epithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acid
  • the subject suffers from a cancer selected from the group consisting of pancreatic cancer, breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, rectal cancer, gastric cancer, esophageal cancer, sarcomas, tracheal cancer, head and neck cancer, liver cancer, ovarian cancer, lymphoid cancer, cervical cancer, vulvar cancer, melanoma, mesothelioma, bladder cancer, thyroid cancer, bone cancers, carcinomas, sarcomas, and soft tissue cancers.
  • a cancer selected from the group consisting of pancreatic cancer, breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, rectal cancer, gastric cancer, esophageal cancer, sarcomas, tracheal cancer, head and neck cancer, liver cancer, ovarian cancer, lymphoid cancer, cervical cancer, vulvar cancer, melanoma, mesothelioma, bladder cancer,
  • the cancer is a renal cancer and more particularly a renal cell cancer (RCC) or clear cell renal cell cancer ccRCC).
  • RRC renal cell cancer
  • ccRCC clear cell renal cell cancer
  • the renal cancer is a renal cancer of stages I, II, III or IV. In another embodiment, the renal cancer is a metastatic renal cancer.
  • the cancer is a cancer in which complement activation occur, especially in cancers in which infiltrating macrophages produce Clq and the tumor cells produce Clr and Cls, allowing formation of the CI complex like renal cancer.
  • Another aspect of the invention relates to a method for predicting the overall survival
  • (OS) of a patient suffering from a cancer comprising i) determining in a sample obtained from the patient the expression level of Clq ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • Another aspect of the invention relates to a method for predicting the progression free survival (PFS) of a patient suffering from a cancer comprising i) determining in a sample obtained from the patient the expression level of Clq ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • PFS progression free survival
  • OS Overall survival
  • progression free survival denotes the length of time after primary treatment for a cancer ends that the patient remains free of certain complications or events that the treatment was intended to prevent or delay. These events may include the return of the cancer or the onset of certain symptoms.
  • the term "Good Prognosis” denotes a patient with more than 50% chance of survival for the next 5 years after the treatment.
  • Another aspect of the invention relates to a method for predicting the responsiveness of a patient affected with a cancer to an anti-cancer treatment comprising i) determining in a sample obtained from the patient the expression level of Clq ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • Clq has its general meaning in the art and refers to a protein involved in the complement system. Clq is part of the CI -complex. Clq can bind to the antibodies IgM and IgG (all but IgG4) when the antibody is bound to an antigen. When Clq binds to IgM or IgG complexed with antigen, the CI -complex is activated. Activation of the CI -complex initiates the classical complement pathway. Clq is a 400 kDa protein formed from 18 peptide chains in 3 subunits of 6.
  • Each 6 peptide subunit consists of a Y-shaped pair of triple peptide helices joined at the stem and ending in a globular non- helical head.
  • Clq also denotes the different chains ClqA, ClqB and ClqC (NCBI Reference Sequence: NP 001334395.1; NP 000482.3; AAH09016.1).
  • CI complex denotes a protein complex involved in the complement system, which is part of the innate immune system.
  • the CI -complex is composed of 1 molecule of Clq, 2 molecules of Clr and 2 molecules of Cls, or Clqrs.
  • sample denotes surgical tumor specimen, tumor biopsy, bone marrow, peripheral blood mononuclear cell (PBMC), macrophages, blood, serum or plasma.
  • PBMC peripheral blood mononuclear cell
  • Measuring the expression level of the biomarker of the invention may be obtained by determining the expression level of the genes or of the proteins corresponding of the biomarker of the invention (Clq and others biomarkers of the invention) in a sample. Measuring the expression level of the biomarkers may be also obtained by using in situ labelling technique. In this case, the expression level of the biomarkers will be quantify thank to the staining coverage and/or the amount of present positive cells labelled with the antibody anti-Clq.
  • measuring the expression level of the biomarker Clq can be done by measuring the expression level of the different chains ClqA, ClqB and ClqC or of the different genes coding for the chains ClqA, ClqB and ClqC.
  • the expression level of a gene may be determined by determining the quantity of mRNA (Clq gene or the genes coding for the chains ClqA, ClqB and ClqC).
  • Methods for determining the quantity of mRNA are well known in the art.
  • the nucleic acid contained in the samples e.g., cell or tissue prepared from the patient
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR).
  • LCR ligase chain reaction
  • TMA transcription- mediated amplification
  • SDA strand displacement amplification
  • NASBA nucleic acid sequence based amplification
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization.
  • the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes.
  • a nucleic acid probe includes a label (e.g., a detectable label).
  • a "detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample.
  • a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample.
  • a label associated with one or more nucleic acid molecules can be detected either directly or indirectly.
  • a label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons).
  • Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials.
  • detectable labels include fluorescent molecules (or fluorochromes).
  • fluorescent molecules or fluorochromes
  • Numerous fluorochromes are known to those of skill in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies).
  • fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U.S. Pat. No.
  • fluorophores include thiol-reactive europium chelates which emit at approximately 617 mn (Heyduk and Heyduk, Analyt. Biochem. 248:216-27, 1997; J. Biol. Chem. 274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphtho fluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof.
  • fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrrometheneboron difiuoride dyes, for example as described in U.S. Pat. Nos.
  • a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOTTM (obtained, for example, from Life Technologies (QuantumDot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat. Nos. 6,815,064; 6,682,596; and 6,649, 138).
  • Semiconductor nanocrystals are microscopic particles having size-dependent optical and/or electrical properties.
  • a secondary emission of energy occurs of a frequency that corresponds to the handgap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence.
  • Semiconductor nanocrystals with different spectral characteristics are described in e.g., U.S. Pat. No. 6,602,671.
  • semiconductor nanocrystals can he produced that are identifiable based on their different spectral characteristics.
  • semiconductor nanocrystals can he produced that emit light of different colors hased on their composition, size or size and composition.
  • quantum dots that emit light at different wavelengths based on size (565 mn, 655 mn, 705 mn, or 800 mn emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlshad, Calif).
  • Additional labels include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes.
  • radioisotopes such as 3 H
  • metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+
  • liposomes include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes.
  • Detectable labels that can he used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • enzymes for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • an enzyme can be used in a metallographic detection scheme.
  • SISH silver in situ hyhridization
  • Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate.
  • Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate.
  • an oxido-reductase enzyme such as horseradish peroxidase
  • Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH).
  • ISH procedures for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)
  • CGH comparative genomic hybridization
  • ISH In situ hybridization
  • a sample containing target nucleic acid sequence e.g., genomic target nucleic acid sequence
  • a metaphase or interphase chromosome preparation such as a cell or tissue sample mounted on a slide
  • a labeled probe specifically hybridizable or specific for the target nucleic acid sequence (e.g., genomic target nucleic acid sequence).
  • the slides are optionally pretreated, e.g., to remove paraffin or other materials that can interfere with uniform hybridization.
  • the sample and the probe are both treated, for example by heating to denature the double stranded nucleic acids.
  • the probe (formulated in a suitable hybridization buffer) and the sample are combined, under conditions and for sufficient time to permit hybridization to occur (typically to reach equilibrium).
  • the chromosome preparation is washed to remove excess probe, and detection of specific labeling of the chromosome target is performed using standard techniques.
  • a biotinylated probe can be detected using fluorescein-labeled avidin or avidin-alkaline phosphatase.
  • fluorescein-labeled avidin or avidin-alkaline phosphatase For fluorochrome detection, the fluorochrome can be detected directly, or the samples can be incubated, for example, with fluorescein isothiocyanate (FITC)- conjugated avidin. Amplification of the FITC signal can be effected, if necessary, by incubation with biotin-conjugated goat antiavidin antibodies, washing and a second incubation with FITC- conjugated avidin.
  • FITC fluorescein isothiocyanate
  • samples can be incubated, for example, with streptavidin, washed, incubated with biotin-conjugated alkaline phosphatase, washed again and pre-equilibrated (e.g., in alkaline phosphatase (AP) buffer).
  • AP alkaline phosphatase
  • in situ hybridization procedures see, e.g., U.S. Pat. No. 4,888,278.
  • Numerous procedures for FISH, CISH, and SISH are known in the art.
  • procedures for performing FISH are described in U.S. Pat. Nos. 5,447,841; 5,472,842; and 5,427,932; and for example, in Pirlkel et al, Proc. Natl.
  • CISH is described in, e.g., Tanner et al, Am. .1. Pathol. 157: 1467-1472, 2000 and U.S. Pat. No. 6,942,970. Additional detection methods are provided in U.S. Pat. No. 6,280,929.
  • Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties.
  • probes labeled with fluorophores including fluorescent dyes and QUANTUM DOTS®
  • fluorophores including fluorescent dyes and QUANTUM DOTS®
  • the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety.
  • a hapten such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin,
  • Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • a labeled detection reagent such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • the detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore.
  • the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH).
  • the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos. 2006/0246524; 2006/0246523, and 2007/ 01 17153.
  • multiplex detection schemes can he produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample).
  • a first probe that corresponds to a first target sequence can he labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP.
  • the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn) and a second specific binding agent (in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 mn).
  • a first specific binding agent in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn
  • a second specific binding agent in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®,
  • Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a preferred kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the methods of the invention comprise the steps of providing total RNAs extracted from cumulus cells and subjecting the RNAs to amplification and hybridization to specific probes, more particularly by means of a quantitative or semi- quantitative RT-PCR.
  • the expression level is determined by DNA chip analysis.
  • DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere-sized bead.
  • a microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.
  • Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs.
  • a sample from a test subject optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface.
  • the labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling.
  • Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210).
  • Expression level of a gene may be expressed as absolute expression level or normalized expression level.
  • expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the patient, e.g., a housekeeping gene that is constitutively expressed.
  • Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1 and TFRC. According to the invention the housekeeping genes used were GAPDH, GUSB, TBP and ABL1. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources.
  • ClqC can be performed by a variety of techniques well known in the art.
  • protein concentration may be measured for example by capillary electrophoresis-mass spectroscopy technique (CE-MS) or ELISA performed on the sample.
  • CE-MS capillary electrophoresis-mass spectroscopy technique
  • ELISA ELISA
  • Detection of protein concentration in the sample may also be performed by measuring the level of protein (Clq).
  • the "level of proteins” means the quantity or concentration of said proteins.
  • the "level of proteins” means the level of proteins fragments (Clq fragments for example).
  • Such methods comprise contacting a sample with a binding partner capable of selectively interacting with proteins present in the sample.
  • the binding partner is generally an antibody that may be polyclonal or monoclonal, preferably monoclonal.
  • the presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
  • immunoassays such as competition, direct reaction, or sandwich type assays.
  • assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation, capillary electrophoresis- mass spectroscopy technique (CE-MS).etc.
  • the reactions generally include revealing labels such as fluorescent, chemiluminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith.
  • the aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art.
  • Methods of the invention may comprise a step consisting of comparing the protein and fragments concentration in circulating cells with a control value.
  • concentration of proteins refers to an amount or a concentration of a transcription product, for instance the protein Clq.
  • a level of a protein can be expressed as nanograms per microgram of tissue or nanograms per milliliter of a culture medium, for example.
  • relative units can be employed to describe a concentration.
  • concentration of proteins may refer to fragments of the proteins (Clq).
  • fragments of Clq may also be measured.
  • Measuring the expression level of the biomarker Clq may be also obtained by using in situ labelling techniques. Method like Immunohistochemistry (IHC) and immunofluorescence (IF) are particularly useful to detect the presence of the biomarkers. In this case, the expression level of the biomarkers will be quantify thank to the staining coverage and/or the amount of present positive cells labelled with the antibody. More the biomarker will be present in a sample more the positive area will be high.
  • IHC Immunohistochemistry
  • IF immunofluorescence
  • Immunohistochemistry typically includes the following steps i) fixing the tumor tissue sample with formalin, ii) embedding said tumor tissue sample in paraffin, iii) cutting said tumor tissue sample into sections for staining, iv) incubating said sections with the binding partner specific for the marker, v) rinsing said sections, vi) incubating said section with a secondary antibody typically biotinylated and vii) revealing the antigen-antibody complex typically with avidin-biotin-peroxidase complex.
  • the tumor tissue sample is firstly incubated the binding partners. After washing, the labeled antibodies that are bound to marker of interest are revealed by the appropriate technique, depending of the kind of label is borne by the labeled antibody, e.g.
  • the method of the present invention may use a secondary antibody coupled to an amplification system (to intensify staining signal) and enzymatic molecules.
  • a secondary antibody coupled to an amplification system (to intensify staining signal) and enzymatic molecules.
  • Such coupled secondary antibodies are commercially available, e.g. from Dako, En Vision system.
  • Counterstaining may be used, e.g. Hematoxylin & Eosin, DAPI, Hoechst.
  • Other staining methods may be accomplished using any suitable method or system as would be apparent to one of skill in the art, including automated, semi-automated or manual systems.
  • one or more labels can be attached to the antibody, thereby permitting detection of the target protein (i.e the marker).
  • Exemplary labels include radioactive isotopes, fluorophores, ligands, chemiluminescent agents, enzymes, and combinations thereof.
  • the label is a quantum dot.
  • Non- limiting examples of labels that can be conjugated to primary and/or secondary affinity ligands include fluorescent dyes or metals (e.g. fluorescein, rhodamine, phycoerythrin, fluorescamine), chromophoric dyes (e.g. rhodopsin), chemiluminescent compounds (e.g. luminal, imidazole) and bio luminescent proteins (e.g. luciferin, luciferase), haptens (e.g. biotin).
  • fluorescent dyes or metals e.g. fluorescein, rhodamine, phycoerythrin, fluorescamine
  • chromophoric dyes e.g. rhodopsin
  • Affinity ligands can also be labeled with enzymes (e.g. horseradish peroxidase, alkaline phosphatase, beta-lactamase), radioisotopes (e.g. 3H, 14C, 32P, 35S or 1251) and particles (e.g. gold).
  • enzymes e.g. horseradish peroxidase, alkaline phosphatase, beta-lactamase
  • radioisotopes e.g. 3H, 14C, 32P, 35S or 1251
  • particles e.g. gold
  • the different types of labels can be conjugated to an affinity ligand using various chemistries, e.g. the amine reaction or the thiol reaction.
  • amines and thiols can be used, e.g. aldehydes, carboxylic acids and glutamine.
  • Various enzymatic staining methods are known in the art for detecting a protein of interest. For example, enzymatic interactions can be visualized using different enzymes such as peroxidase, alkaline phosphatase, or different chromogens such as DAB, AEC or Fast Red.
  • the antibody can be conjugated to peptides or proteins that can be detected via a labeled binding partner or antibody. In an indirect IHC assay, a secondary antibody or second binding partner is necessary to detect the binding of the first binding partner, as it is not labeled.
  • the resulting stained specimens are each imaged using a system for viewing the detectable signal and acquiring an image, such as a digital image of the staining.
  • Methods for image acquisition are well known to one of skill in the art.
  • any optical or non-optical imaging device can be used to detect the stain or biomarker label, such as, for example, upright or inverted optical microscopes, scanning confocal microscopes, cameras, scanning or tunneling electron microscopes, canning probe microscopes and imaging infrared detectors.
  • the image can be captured digitally.
  • the obtained images can then be used for quantitatively or semi-quantitatively determining the amount of the marker in the sample, or the absolute number of cells positive for the maker of interest, or the surface of cells positive for the maker of interest.
  • Various automated sample processing, scanning and analysis systems suitable for use with IHC are available in the art. Such systems can include automated staining and microscopic scanning, computerized image analysis, serial section comparison (to control for variation in the orientation and size of a sample), digital report generation, and archiving and tracking of samples (such as slides on which tissue sections are placed).
  • Cellular imaging systems are commercially available that combine conventional light microscopes with digital image processing systems to perform quantitative analysis on cells and tissues, including immunostained samples.
  • detection can be made manually or by image processing techniques involving computer processors and software.
  • the images can be configured, calibrated, standardized and/or validated based on factors including, for example, stain quality or stain intensity, using procedures known to one of skill in the art (see e.g., published U.S. Patent Publication No. US20100136549).
  • the image can be quantitatively or semi-quantitatively analyzed and scored based on staining intensity of the sample.
  • Quantitative or semi-quantitative histochemistry refers to method of scanning and scoring samples that have undergone histochemistry, to identify and quantitate the presence of the specified biomarker (i.e. the marker).
  • Quantitative or semi-quantitative methods can employ imaging software to detect staining densities or amount of staining or methods of detecting staining by the human eye, where a trained operator ranks results numerically. For example, images can be quantitatively analyzed using a pixel count algorithms and tissue recognition pattern (e.g.
  • a ratio of strong positive stain (such as brown stain) to the sum of total stained area can be calculated and scored.
  • the amount of the detected biomarker i.e. the marker
  • the amount is quantified and given as a percentage of positive pixels and/or a score.
  • the amount can be quantified as a percentage of positive pixels.
  • the amount is quantified as the percentage of area stained, e.g., the percentage of positive pixels.
  • a sample can have at least or about at least or about 0, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more positive pixels as compared to the total staining area.
  • the amount can be quantified as an absolute number of cells positive for the maker of interest.
  • a score is given to the sample that is a numerical representation of the intensity or amount of the histochemical staining of the sample, and represents the amount of target biomarker (e.g., the marker) present in the sample.
  • Optical density or percentage area values can be given a scaled score, for example on an integer scale.
  • the method of the present invention comprises the steps consisting in i) providing one or more immunostained slices of tissue section obtained by an automated slide-staining system by using a binding partner capable of selectively interacting with the marker (e.g.
  • step i) proceeding to digitalisation of the slides of step i).by high resolution scan capture, iii) detecting the slice of tissue section on the digital picture iv) providing a size reference grid with uniformly distributed units having a same surface, said grid being adapted to the size of the tissue section to be analyzed, and v) detecting, quantifying and measuring intensity or the absolute number of stained cells in each unit whereby the number or the density of cells stained of each unit is assessed.
  • Immunofluorescence staining methods are widely used in research and diagnostics to demonstrate the presence of specific antigenic determinants on cells or tissues and to quantify the numbers of cells bearing particular determinants in a heterogeneous population.
  • Immunofluorescence staining methods can be divided into two categories, direct and indirect methods.
  • a fluorophore is conjugated to an antibody (hereinafter called "the primary antibody") which is capable of binding directly to the cell surface antigen of interest.
  • the primary antibody is not fluorescently labeled; its binding is visualized instead by the binding of a fluorescently labeled second- step antibody, which second- step antibody is capable of binding to the primary antibody.
  • the second-step antibody is an anti-immunoglobulin antibody.
  • TMIndirect immunofluorescence is advantageous in that it is more sensitive than direct immunofluorescence because for each molecule of the primary antibody which is bound, several molecules of the labeled second-step.
  • Predetermined reference values used for comparison may comprise "cut-off or "threshold” values that may be determined as described herein.
  • Each reference (“cut-off) value for each bio markers of interest may be predetermined by carrying out a method comprising the steps of
  • e) providing, for each sample provided at step a), information relating to the responsiveness of the patient or the actual clinical outcome for the corresponding cancer patient (i.e. the duration of the overall survival (OS), the progression-free survival (PFS) or both); f) for each pair of subsets of samples, obtaining a Kaplan Meier percentage of survival curve;
  • OS overall survival
  • PFS progression-free survival
  • the expression level of a biomarker X has been assessed for 100 cancer samples of 100 patients.
  • the 100 samples are ranked according to their expression level.
  • Sample 1 has the best expression level and sample 100 has the worst expression level.
  • a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
  • the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
  • Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated.
  • the reference value is selected such as the discrimination based on the criterion of the minimum p value is the strongest.
  • the expression level corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of expression levels.
  • the reference value (cut-off value) may be used in the present method to discriminate cancer samples and therefore the corresponding patients.
  • Kaplan-Meier curves of percentage of survival as a function of time are commonly to measure the fraction of patients living for a certain amount of time after treatment and are well known by the man skilled in the art.
  • Such predetermined reference values of expression level may be determined for any biomarker defined above.
  • the method may comprise another biomarker like LAG3 and PD1.
  • the invention may also relates to a method for predicting the survival time of a patient suffering from a cancer comprising i) determining in a sample obtained from the patient the expression level of at least 1 biomarker selected from the group consisting of Clq, LAG3 and PD1 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than its predetermined reference value.
  • LAG3 for "Lymphocyte-activation gene 3” also known as “CD223” has its general meaning in the art and denotes a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
  • PD1 for "Programmed cell death 1” has its general meaning in the art and denotes a cell surface receptor that plays an important role in down-regulating the immune system and promoting self tolerance by suppressing T cell inflammatory activity.
  • PD- 1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti- inflammatory, suppressive T cells).
  • kits for performing the methods of the invention comprise means for measuring the expression level or the staining pattern of the biomarkers of the invention in the sample obtained from the patient.
  • kits may include probes, primers macroarrays or microarrays as above described.
  • the kit may comprise a set of probes as above defined, usually made of DNA, and that may be pre-labelled.
  • probes may be unlabelled and the ingredients for labelling may be included in the kit in separate containers.
  • the kit may further comprise hybridization reagents or other suitably packaged reagents and materials needed for the particular hybridization protocol, including solid-phase matrices, if applicable, and standards.
  • the kit of the invention may comprise amplification primers that may be pre- labelled or may contain an affinity purification or attachment moiety.
  • the kit may further comprise amplification reagents and also other suitably packaged reagents and materials needed for the particular amplification protocol.
  • the kit may comprise a selected set of antibodies, staining protocols and data interpretation algorithm and standards, allowing to perform IHC or IF on the patient's surgical tumor specimen.
  • the invention also relates to an anti-cancer compound for use in the treatment of a cancer in patient with a bad prognosis as described above.
  • the invention also relates to a method for treating a cancer in a patient with a bad prognosis as described above comprising administering to said patient an anti-cancer compound.
  • the patient has a renal cell cancer with a bad prognosis.
  • patients with a higher expression level for Clq than their predetermined reference values as described above are eligible for a treatment using an anticancer compound according to the invention.
  • the methods of the invention may be used as a companion diagnostic under a treatment of patient affected with a cancer and particularly a renal cell cancer.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • anti-cancer compounds denote all compounds use in chemotherapy and immunotherapy.
  • chemotherapy denotes all treatment with a chemotherapeutic agent.
  • chemotherapeutic agent refers to chemical compounds that are effective in inhibiting tumor growth.
  • examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin;
  • calicheamicin especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolin
  • paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisp latin and carbop latin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • radiotherapy denotes all treatment with a radiotherapeutic agent.
  • radiotherapeutic agent as used herein, is intended to refer to any radiotherapeutic agent known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation.
  • the radiotherapeutic agent can be an agent such as those administered in brachytherapy or radionuclide therapy.
  • Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies, and/or another radiotherapy.
  • immunotherapy denotes all treatment with an immunotherapeutic agent.
  • immunotherapeutic agent refers to a compound, composition or treatment that indirectly or directly enhances, stimulates or increases the body's immune response against cancer cells and/orthat decreases the side effects of other anticancer therapies. Immunotherapy is thus a therapy that directly or indirectly stimulates or enhances the immune system's responses to cancer cells and/or lessens the side effects that may have been caused by other anti-cancer agents. Immunotherapy is also referred to in the art as immunologic therapy, biological therapy biological response modifier therapy and biotherapy.
  • immunotherapeutic agents examples include, but are not limited to, cytokines, cancer vaccines, monoclonal antibodies and non-cytokine adjuvants.
  • the immunotherapeutic treatment may consist of administering the subject with an amount of immune cells (T cells, NK, cells, dendritic cells, B cells).
  • Immunotherapeutic agents can be non-specific, i.e. boost the immune system generally so that the human body becomes more effective in fighting the growth and/or spread of cancer cells, or they can be specific, i.e. targeted to the cancer cells themselves immunotherapy regimens may combine the use of nonspecific and specific immunotherapeutic agents.
  • Non-specific immunotherapeutic agents are substances that stimulate or indirectly improve the immune system.
  • Non-specific immunotherapeutic agents have been used alone as a main therapy for the treatment of cancer, as well as in addition to a main therapy, in which case the non-specific immunotherapeutic agent functions as an adjuvant to enhance the effectiveness of other therapies (e.g. cancer vaccines).
  • Non-specific immunotherapeutic agents can also function in this latter context to reduce the side effects of other therapies, for example, bone marrow suppression induced by certain chemotherapeutic agents.
  • Non-specific immunotherapeutic agents can act on key immune system cells and cause secondary responses, such as increased production of cytokines and immunoglobulins. Alternatively, the agents can themselves comprise cytokines.
  • Nonspecific immunotherapeutic agents are generally classified as cytokines or non-cytokine adjuvants.
  • cytokines have found application in the treatment of cancer either as general non-specific immunotherapies designed to boost the immune system, or as adjuvants provided with other therapies.
  • Suitable cytokines include, but are not limited to, interferons, interleukins and colony- stimulating factors.
  • Interferons (IFNs) contemplated by the present invention include the common types of IFNs, IFN-alpha (IFN-a), IFN-beta (IFN- ⁇ ) and IFN- gamma (IFN- ⁇ ).
  • IFNs can act directly on cancer cells, for example, by slowing their growth, promoting their development into cells with more normal behaviour and/or increasing their production of antigens thus making the cancer cells easier for the immune system to recognise and destroy.
  • IFNs can also act indirectly on cancer cells, for example, by slowing down angiogenesis, boosting the immune system and/or stimulating natural killer (NK) cells, T cells and macrophages.
  • Recombinant IFN-alpha is available commercially as Roferon (Roche Pharmaceuticals) and Intron A (Schering Corporation).
  • Interleukins contemplated by the present invention include IL-2, IL-4, IL-11 and IL-12. Examples of commercially available recombinant interleukins include Proleukin® (IL-2; Chiron Corporation) and Neumega® (IL- 12; Wyeth Pharmaceuticals). Zymogenetics, Inc.
  • Colony-stimulating factors contemplated by the present invention include granulocyte colony stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony stimulating factor (GM-CSF or sargramostim) and erythropoietin (epoetin alfa, darbepoietin). Treatment with one or more growth factors can help to stimulate the generation of new blood cells in subjects undergoing traditional chemotherapy.
  • CSFs can be helpful in decreasing the side effects associated with chemotherapy and can allow for higher doses of chemo therapeutic agents to be used.
  • Various-recombinant colony stimulating factors are available commercially, for example, Neupogen® (G-CSF; Amgen), Neulasta (pelfilgrastim; Amgen), Leukine (GM-CSF; Berlex), Procrit (erythropoietin; Ortho Biotech), Epogen (erythropoietin; Amgen), Arnesp (erytropoietin).
  • immunotherapeutic agents can be active, i.e. stimulate the body's own immune response, or they can be passive, i.e.
  • Passive specific immunotherapy typically involves the use of one or more monoclonal antibodies that are specific for a particular antigen found on the surface of a cancer cell or that are specific for a particular cell growth factor.
  • Monoclonal antibodies may be used in the treatment of cancer in a number of ways, for example, to enhance a subject's immune response to a specific type of cancer, to interfere with the growth of cancer cells by targeting specific cell growth factors, such as those involved in angiogenesis, or by enhancing the delivery of other anticancer agents to cancer cells when linked or conjugated to agents such as chemotherapeutic agents, radioactive particles or toxins.
  • Monoclonal antibodies currently used as cancer immunotherapeutic agents that are suitable for inclusion in the combinations of the present invention include, but are not limited to, rituximab (Rituxan®), trastuzumab (Herceptin®), ibritumomab tiuxetan (Zevalin®), tositumomab (Bexxar®), cetuximab (C-225, Erbitux®), bevacizumab (Avastin®), gemtuzumab ozogamicin (Mylotarg®), alemtuzumab (Campath®), and BL22.
  • Other examples include anti-CTLA4 antibodies (e.g.
  • antibodies include B cell depleting antibodies.
  • Typical B cell depleting antibodies include but are not limited to anti-CD20 monoclonal antibodies [e.g.
  • the immunotherapeutic treatment may consist of allografting, in particular, allograft with hematopoietic stem cell HSC.
  • the immunotherapeutic treatment may also consist in an adoptive immunotherapy as described by Nicholas P. Restifo, Mark E.
  • NK cells circulating lymphocytes
  • the activated lymphocytes or NK cells are most preferably be the subject's own cells that were earlier isolated from a blood or tumor sample and activated (or "expanded") in vitro.
  • FIGURES
  • Clq is associated with bad prognosis in human ccRCC.
  • the first primary cohort includes 135 patients undergoing nephrectomy in the hospital Necker-Enfants Malades (Paris, France) between 1999 and 2003.
  • the second retrospective cohort is composed by 51 primary ccRCC specimens with metastases operated in 3 French and 1 Belgian hospitals from 1994 to 2011.
  • a third retrospective primary cohort includes 66 patients operated at the Institut Mutualiste Montsouris (IMM) (Paris, France) between 2002 and 2010.
  • Histopathologic features such as the histologic subtype, tumor size, regional lymph node invasion, distant metastases, Furhman nuclear grade, TNM stage were available for almost all patients and the duration of follow-up was calculated from the date of the surgery to the date of cancer progression, last follow-up or death.
  • the TCGA-KIRC cohort composed by 537 primary ccRCC samples with clinical and expression data is also used in this study.
  • Immunohistochemistry (IHC) and immunofluorescence (IF) on human tumor specimens The formalin- fixed-paraffin-embedded (FFPE) tumors specimens were cut at 3 ⁇ tick sections.
  • the antigen retrieval were carried out on a PT-link (Dako) using the En Vision FLEX Target Retrieval Solutions (Dako) with low or high pH for the detection of Clq, CD 163, LAG3 and PD-1 or with Proteinase K (Dako, S3020) for IgG staining. Endogenous peroxidase and non-specific staining were blocked with H202 3% (Gifrer, 10603051) and protein block (Dako, X0909) respectively.
  • Ct threshold cycle
  • Caki-1 and HCT116 were cultured in McCoy's medium (Gibco) + 10% FCS + lx penicilin/streptomycin (Gibco)
  • SW620 were cultured in Leibovitz medium (Gibco) + 10% FCS lx penicilin/streptomycin (Gibco)
  • Superfrost plus slides were divided by Dakopen into 4 equivalent parts, coated either by bovine serum albumin, human Clq, fibronectin or polylysine 20 ⁇ g/mL. 200 000 cells/quadrant, suspended in Opti MEM (Gibco, 31985-062) medium were placed in each part. After 10 minutes or an overnight incubation at 37°C, the cells on the slides were washed and fixed with PFA 4% for 30 minutes. After an antigen retrieval at low pH and a blocking with protein block (Dako, X0909), a goat anti mouse antibody Na/K ATP-ase followed by anti- mouse IgG-Cy3 was used.
  • Opti MEM Gibco, 31985-062
  • Complement genes expression The expression of complement genes by the human and mouse cell lines was determined by real time PCR or custom low density array. After 48h of culture in a synthetic medium without serum Opti-MEM (ref), the cells were recovered in RLT- ⁇ -mercaptoethanol. The R A was extracted with R easy mini kit (Qiagen, 74106). The quality and quantity of RNA were determined with 2100 Bioanalyzer (Agilent) using Agilent RNA 6000 Nano assay kit (5067- 1511). The reverse transcription was made from 250ng RNA with the Applied Biosystem High capacity cDNA Reverse Transcription kit (Applied Biosystem, 4368814).
  • the quantitative gene expression was assessed by a Taqman 96 wells plate read by an Applied Biosystem 7900HT Fast Real-Time PCR System. Expression levels were determined using threshold cycle (Ct) values normalized to GAPDH (ACt) and expressed with 2 A (-ACt).
  • Ct threshold cycle
  • the supernatants of the human and mouse cell lines were recovered and concentrated using amicon ultra, ultracel 3K (UFC 900324).
  • the samples were prepared into NuPAGE® LDS sample buffer (4X) (Thermo fisher) with or without reducing agent (DTT) and then denatured at 80°C for 10 minutes. Proteins were separated in NuPage 10% Bis-Tris gel (Thermo fisher). The proteins were transferred on a nitrocellulose membrane using iBlot (Invitrogen). Further, the membranes were stained with the SNAP i.d.
  • Protein Detection System using a primary goat anti-human Cls antiserum (Quidel, A302) 1/5000, a polyclonal rabbit anti-human Clr (Abeam, ab 155060) 1/500, rabbit polyclonal anti-mouse Clr (Abeam ab205546, 1/500). Secondary antibodies were: rabbit anti-goat-HRP (Santa Cruz, H0712) or a goat anti-rabbit-HRP (Santa Cruz, J512) as a secondary antibody. After washes, the membranes were developed with an ECL reagent (Pierce #32106) and the chemiluminescence was detected with MyECL Imager (Thermo Scientific). The purified human proteins Cls (Comptech, A104) or Clr (Comptech, A102) were used as positive controls.
  • a first ELISA assay was used, as described previously.
  • a polyclonal anti Clq (Dako, A0136), diluted 1/1000 in PBS, was coated overnight on 96 wells Nunc plates (Nunc maxisorb). A BSA 1% solution was then used for blocking for 1 hour at room temperature. The washing steps were performed with TBS Tween 0,05% CaC12 ImM.
  • a second ELISA was set up as in (31).
  • the 96 wells plates were coated with human IgGl, 50 ⁇ g/ml, for lh at 37°C.
  • BSA 1% solution was then used to block the plate during 1 hour at room temperature.
  • the washing steps were performed with lOmM Hepes, 75mM NaCl, CaC12 lmM, MgCl ImM and 0.05% Tween 20.
  • the supernatants of cultured cells lines and increasing doses of human Clq from 0,125 ⁇ g/mL to 4 ⁇ g/mL, diluted in this washing were added to the plates and incubated for 1 hour at 37°C.
  • the survival analyses were realized with R software and the package survival. Impact on survial was assessed using Kaplan-Meier estimates and log-rank test, as well univariate and multivariate Cox regression analyses. The association between the distributions of different variable was assessed by a Fisher's exact test or a Mann- Whitney test. For quantitative variables, the cut-off was chosen according to the distribution density curves.
  • mice tumor growth were analyzed using a two-way ANOVA test for the curve and independently to each days with a non-parametric Mann- Whitney test. Data from mice immunofluorescence quantifications, flow cytometry and RTqPCR were analysed using Mann- Whitney tests. These statistical analysis were performed using GraphPad Prism 6. Results
  • Clq density is associated with poor prognosis in advanced ccRCC.
  • Clq is mainly produced by macrophages
  • Clq positivity was detected in scarce neutrophils (double staining with CD66b, data not shown) and some endothelial cells (identified by double staining with CD31, data not shown).
  • ClqA gene expression was coordinated with the one of ClqC gene and other genes of macrophages activation, including PDL-2 (CD273, PDCD1LG2), HLA-DR, CD86, ADAP2, C3aR, and PDL-1 (CD274, PDCDILGI) (data not shown).
  • ClqA and C genes correlated to a less extend with classical M2 macrophages genes such as CD 163, VSIG4 or LAIR-1.
  • ClqA and C genes were not correlated with genes encoding IL-10, CD206 (MRC1), C5aRl (CD88), SIGLECl and VEGFA.
  • Gene to gene correlation showed a strong coordination of ClqA with PDL-2, CD86, LAIR1 and HLA-DR but not with CD 163 (data not shown), confirming that Clq may be produced by a population of activated macrophages that does not reflect only the presence of M2 macrophages.
  • High density of Clq producing cells is associated with an exhausted immune phenotype in ccRCC tumors
  • Tumors from Clq-/- mice are infiltrated by activated macrophages and have higher levels of CD8+ T-cells.
  • N cells and cDCs are infiltrated by activated macrophages and have higher levels of CD8+ T-cells.
  • TME content by flow cytometry revealed that TC-1 tumors from WT mice had a significantly lower infiltration of hematopoietic cells (CD45+) than Clq-/- mice even at day 10, when there was not yet a detectable difference in tumor volume between the two strains of mice (data not shown). This difference persisted until day 20, when the WT mice had a significantly larger tumor mass than Clq-/- mice.
  • the composition of the TME was strikingly different between tumors growing in WT and Clq-/- mice, with significantly more macrophages in the WT mice (data not shown) and a lower proportion of IA/IE+ cells, IA/IE being an Ml phenotype marker (data not shown).
  • Tumors from WT mice also exhibited lower percentages of antigen-presenting cDCs at both day 10 and day 20 (data not shown). In contrast, the tumors contained more potentially suppressive PMN-MDSCs at day 20 (data not shown), whereas no significant differences in M-MDSCs were found (data not shown).
  • the WT mice showed fewer lymphocytes, particularly those with a cytotoxic potential, such as NK and CD8+ T-cells (data not shown), without reaching significance for CD4+ T-cells (data not shown).
  • Roumenina LT Roumenina LT, Rayes J, Frimat M, and Fremeaux-Bacchi V. Endothelial cells: source, barrier, and target of defensive mediators. Immunological reviews. 2016;274(1):307-
  • Bossi F, et al. Clq as a unique player in angiogenesis with therapeutic implication in wound healing. Proceedings of the National Academy of Sciences of the United
  • Petry F, et al. The mouse Clq genes are clustered on chromosome 4 and show conservation of gene organization. Immunogenetics. 1996;43(6):370-6.
  • Roumenina LT Sene D, Radanova M, Blouin J, Halbwachs-Mecarelli L, Dragon-Durey MA, Fridman WH, and Fremeaux-Bacchi V. Functional complement Clq abnormality leads to impaired immune complexes and apoptotic cell clearance. Journal of immunology. 2011 ; 187(8) :4369-73.
  • the Clq inhibitor in serum is a chondroitin 4-sulfate proteoglycan. J Biol Chem. 1981 Jul 25;256(14):7383-7.

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Abstract

La présente invention concerne le pronostic du cancer et en particulier du cancer du rein. Ici, les inventeurs ont étudié la présence et l'impact de C1q, produit par les macrophages, dans le microenvironnement tumoral du carcinome rénal à cellules claires (clear cell Renal Cell Carcinoma - ccRCC) et ont montré qu'il est associé à un pronostic médiocre, en particulier chez des patients atteints de tumeurs avancées et métastatiques. Ils suggèrent que ceci soit dû à l'activation d'au moins les étapes précoces du complément. Leurs données fournissent un nouveau mécanisme de modulation immunitaire du microenvironnement tumoral dans le ccRCC qui peut expliquer l'impact clinique particulièrement médiocre du microenvironnement tumoral dans ces tumeurs. Par conséquent, l'invention concerne un procédé de prédiction du temps de survie d'un patient souffrant d'un cancer par la détermination du niveau d'expression de C1q.
PCT/EP2018/073429 2017-09-01 2018-08-31 Procédé de prédiction de l'issue d'un cancer Ceased WO2019043138A1 (fr)

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WO2021186014A1 (fr) * 2020-03-20 2021-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode de prédiction de la durée de survie d'un patient atteint d'un cancer

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