US20110117578A1 - Biomarker for selecting patients and related methods - Google Patents

Biomarker for selecting patients and related methods Download PDF

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US20110117578A1
US20110117578A1 US12/811,364 US81136409A US2011117578A1 US 20110117578 A1 US20110117578 A1 US 20110117578A1 US 81136409 A US81136409 A US 81136409A US 2011117578 A1 US2011117578 A1 US 2011117578A1
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cells
patient
activated
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immunogenic composition
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Bruce Acres
Bérangère Marie-Bastien
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Transgene SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/00117—Mucins, e.g. MUC-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5256—Virus expressing foreign proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to the field of immunology and, in particular, to immunotherapy of a patient against diseases caused for example by infection or cancers. More particularly, the invention relates to methods for predicting whether a patient is or is not susceptible to developing a prophylactic or therapeutic immune response after such immunotherapy. The present invention relates to methods and compositions for improving the survival rate of patients to be treated by an immunogenic composition, in particular a vaccine.
  • Live vaccines are typically attenuated non-pathogenic versions of an infectious agent that are capable of priming an immune response directed against a pathogenic version of the infectious agent.
  • recombinant vaccines especially recombinant live vaccines, in which foreign antigens of interest are encoded and expressed from a vector.
  • vectors based on recombinant viruses have shown great promise and play an important role in the development of new vaccines.
  • Many viruses have been investigated for their ability to express proteins from foreign pathogens or tumoral tissue, and to induce specific immunological responses against these antigens in vivo.
  • these gene-based vaccines can stimulate potent humoral and cellular immune responses and viral vectors may be an effective strategy for both the delivery of antigen-encoding genes and the facilitation and enhancement of antigen presentation.
  • the ideal viral vector In order to be utilized as a vaccine carrier, the ideal viral vector should be safe and enable efficient presentation of required pathogen-specific antigens to the immune system. Furthermore, the vector system must meet criteria that enable its production on a large-scale basis.
  • Several viral vaccine vectors have thus emerged to date, all of them having relative advantages and limits depending on the proposed application (for a review on recombinant viral vaccines see for example Harrop and Carroll, 2006, Front Biosci., 11, 804-817; Yokoyama et al., 1997, J Vet Med. Sci., 59, 311-322).
  • a general problem in vaccine field has been the identification of a means of inducing a sufficiently strong immune response in vaccinated individuals to protect and/or treat against infection and disease, and thereby to extend the survival of patient having fatal disease, for example, cancer.
  • IRMs immune response modifiers
  • TLRs Toll-like receptors
  • Such compounds have been shown to stimulate a rapid release of certain dendritic cell, monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to secrete antibodies which play an important role in the antiviral and antitumor activities of IRM compounds.
  • vaccination strategies have been proposed, most of them being based on a prime-boost vaccination regimen.
  • the immune system is first induced by administering to the patient a priming composition and then boosted by administration of a boosting second composition (see for example EP1411974 or US20030191076).
  • NK cell cytotoxicity may play a major role in reproductive outcome (Nitrivalas et al., 2001, Human Reproduction, 16, 855-861). More specifically, Thum et al, 2004, Human Reproduction, 19, 2395-2400, have evaluated the effect of the absolute count of specific marker expression on peripheral blood natural killer (NK) cells on implantation and miscarriage rates after Intra Vitro Fecondation (IVF) treatment. The authors have determined that an increase in the absolute count of activated NK cells in the peripheral blood is associated with a reduced rate of embryo implantation in IVF treatment. Furthermore, women with high peripheral blood NK cell absolute count, who are able to achieve pregnancy, have a significant higher miscarriage rate.
  • the present Invention relates to a method for treating a patient for human disease by administering an immunogenic composition comprising at least one antigen wherein said patient is selected in a patient population composed of patients that have low levels of activated NK cells.
  • the present Invention thus relates to a method for treating a patient for human disease by administering an immunogenic composition comprising at least one antigen, said method comprising the following steps
  • the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition wherein said patient is selected in a patient population composed of patients that have low levels of activated NK cells.
  • the present Invention relates to a method for inducing an immune response to at least one antigen (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition wherein said patient is selected in a patient population composed of patients that have low levels of activated NK cells.
  • the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition wherein said patient is selected in a patient population composed of patients that have low levels of activated NK cells and wherein said raised immune response is innate immune response.
  • the innate immune response is body's initial immune defense against pathogens and is elicited by a variety of cells including antigen-presenting cells or “APCs”. These cells express surface and cytoplasmic receptors that recognize molecules of foreign origin (e.g., bacterial and viral nucleic acids, proteins, carbohydrates).
  • the dendritic cells and macrophage Upon detecting these signals, the dendritic cells and macrophage elicit a defensive response that includes the release of cytokines (including interferons, TNF-.alpha., and IL-12) and chemokines that attract cells such as immature dendritic cells, macrophage, NK cells, and granulocytes, to the site of challenge.
  • cytokines including interferons, TNF-.alpha., and IL-12
  • chemokines that attract cells such as immature dendritic cells, macrophage, NK cells, and granulocytes
  • the present Invention thus relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition, said method comprising the following steps
  • the present Invention relates to a method for inducing an immune response to at least one antigen (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition, said method comprising the following steps:
  • the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition wherein said raised immune response is innate immune response, said method comprising the following steps:
  • the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition, said method comprising the following steps:
  • the present Invention relates to a method for inducing an immune response to at least one antigen (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition, said method comprising the following steps:
  • the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease by administering an immunogenic composition wherein said raised immune response is innate immune response, said method comprising the following steps:
  • the present Invention relates to a method for predicting whether a patient is or is not susceptible to developing prophylactic or therapeutic immune response by administration of an immunogenic composition, said method comprising the steps of:
  • the present Invention relates to a method for selecting a patient susceptible to developing prophylactic or therapeutic immune response by administration of an immunogenic composition, said method comprising the steps of:
  • the present Invention relates to a method for predicting whether a patient is or is not susceptible to respond positively to a treatment comprising administration of an immunogenic composition, said method comprising the steps of:
  • the present Invention relates to a method for selecting a patient susceptible to respond positively to a treatment comprising administration of an immunogenic composition, said method comprising the steps of:
  • the present invention relates to an ex-vivo method for testing whether a patient will respond therapeutically to a method of treatment comprising administration of an immunogenic composition, wherein the testing method comprises the steps of:
  • the present Invention relates to an ex-vivo method for testing whether a patient will respond therapeutically to a method of treating cancer by administration of an immunogenic composition, wherein the testing method comprises the steps of:
  • the terms “a” and “an” are used in the sense that they mean “at least one”, “at least a first”, “one or more” or “a plurality” of the referenced compounds or steps, unless the context dictates otherwise.
  • the term “a cell” includes a plurality of cells including a mixture thereof. More specifically, “at least one” and “one or more” means a number which is one or greater than one, with a special preference for one, two or three.
  • patient refers to a vertebrate, particularly a member of the mammalian species and includes, but is not limited to, domestic animals, sport animals, primates including humans.
  • the term “treatment” or “treating” encompasses prophylaxis and/or therapy. Accordingly the immunogenic compositions or methods of the present invention are not limited to therapeutic applications and can be used in prophylaxis ones. This is covered by the term “to developing a prophylactic or therapeutic immune response” herein. “Prophylaxis” is not limited to preventing immediate diseases (e.g. infectious diseases), it further encompasses prevention of long term consequences of these infections such as cirrhosis or cancer.
  • an “effective amount” or a “sufficient amount” of an active compound is an amount sufficient to effect beneficial or desired results, including clinical results.
  • An effective amount can be administered in one or more administrations.
  • a “therapeutically effective amount” is an amount to effect beneficial clinical results, including, but not limited to, alleviation of one or more symptoms associated with viral infection as well as prevention of disease (e.g. prevention of one or more symptoms of infection).
  • a patient selected in a patient population composed of patients that have low levels of activated NK cells should be understood as meaning a patient for who level of activated NM cells has been measured as disclosed herein, and who has low levels of activated NK cells. When the number of patient tested is above 1, the said patients form a patient population.
  • the terms “activated NK cells” means a lymphocyte cell which expresses CD16, CD56 and CD69 cell surface antigens. According to a preferred embodiment, the said activated NK cells further does not express CD3 surface antigen.
  • the activated NK cells can further be defined based on expression and/or production of IL27 (Villarino et al, 2005, J.
  • the terms “a patient will respond therapeutically” mean that the said patient has an increase of survival rate (see example section).
  • the levels of activated NK cells can be determined for example by flow cytometry (e.g. by flow cytofluorimetry), target cell lysis assay, and more particularly by 3 or more color flow cytometry (e.g. Beckton Dickinson, Beckman Coulter). See for example Ntrivalas et al, 2001, Human Reproduction, 16, 855-861; Borrego et al, 1993, Eur. J. Immunol., 23, 1039-1043.
  • the levels of activated NK cells can be determined on total blood sample or on isolated peripheral blood mononuclear cells (PBMC) [e.g. by Ficoll-Hypaque purification of peripheral blood mononuclear cells (PBMC) (Bennett & Breit 1994, J Leukoc Biol., 56(3), 236-40), or by using Sigma AccuspinTM system (Sigma-Aldrich Ltd.) according to the manufacturer's instructions, an the like].
  • PBMC peripheral blood mononuclear cells
  • the level of activated NK cells is determined by using antibodies.
  • said antibodies are monoclonal antibodies.
  • said antibodies are tagged for example by fluorescence, radiolabel, enzyme, biotin, or any other methods designed to render cells labelled with said antibodies detectable. These techniques are widely used and known in the art.
  • the levels of activated NK cells is determined by using antibodies specific for CD16, CD56 and/or CD69, preferably by antibodies specific for CD16, CD56 and CD69.
  • said levels of activated NK cells are further determined by using antibodies specific for CD3.
  • the levels of activated NK cells is determined by collecting peripheral blood and incubating cells with monoclonal antibodies (e.g. with anti-CD3, anti-CD 4 , anti-CD8, anti-CD19, anti-CD56, anti-CD69 and/or anti-CD 16 ). Then the levels of activated NK cells is determined with the instrument, manufactured by Instrumentation Laboratory-Beckman Coulter, with a He—Ne laser-ray, which recognizes wavelengths of four different fluorochromes (fluorescein isothiocyanate FITC, phycoerythrin PE/RD1, ECD, PC5/PE).
  • monoclonal antibodies e.g. with anti-CD3, anti-CD 4 , anti-CD8, anti-CD19, anti-CD56, anti-CD69 and/or anti-CD 16 .
  • the levels of activated NK cells is determined with the instrument, manufactured by Instrumentation Laboratory-Beckman Coulter, with a He—Ne laser-ray, which recognizes wavelengths of four different flu
  • the levels of activated NK cells can be expressed in either (i) percent (%) of peripheral blood lymphocytes which express CD16, CD56 and CD69 cell surface antigens, or (ii) absolute numbers of activated NK cells per microliter of whole peripheral blood. According to one embodiment said peripheral blood lymphocytes have been isolated from whole blood and stored frozen until analysis.
  • the terms “low levels of activated NK cells” means either (i) levels of activated NK cells of less than about 5%, advantageously less than about 4.5%, preferably less than about 4% and even more preferably less than about 3.5%, and even more particularly less than about 3.45% or (ii) fewer than about 75, preferably fewer than about 60, and more preferably fewer than about 50 activated NK cells, more particularly fewer than about 35 activated NK cells, preferably those present in the mononuclear cells population, per microliter of whole peripheral blood.
  • the terms “immunogenic composition” “vaccine composition”, “vaccine” or similar terms can be used interchangeably and mean an agent suitable for stimulating/inducing/increasing a patient's immune system to ameliorate a current condition or to protect against or to reduce present or future harm or infections (including viral, bacterial, parasitic infections), e.g., reduced tumour cell proliferation or survival, reduced pathogen replication or spread in a patient or a detectably reduced unwanted symptom(s) associated with a condition, extend patient survival.
  • Said immunogenic composition can contain (i) all or part of at least one targeted antigen and/or (ii) at least one recombinant vector expressing in vivo all or part of at least one heterologous nucleotide sequence, especially an heterologous nucleotide sequence encoding all or part of at least one targeted antigen.
  • the immunogenic composition of the Invention comprises (iii) at least one immune response modifier, alone or in combination with (i) and/or (ii). Examples of such immune response modifiers (IRMs), include the CpG oligonucleotides (see U.S. Pat. No.
  • IRMs immune response modifiers
  • small organic molecule such as imidazoquinolinamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines (see for example U.S. Pat. No. 4,689,338; U.S. Pat. No. 5,389,640; U.S. Pat. No. 6,110,929; and U.S. Pat. No. 6,331,539).
  • the term “antigen” refers to any substance, including complex antigen (e.g. tumour cells, virus infected cells, etc. . . . ), that is capable of being the target of an immune response.
  • An antigen may be the target of, for example, a cell-mediated and/or humoral immune response raised by a patient.
  • the term “antigen” encompasses for example all or part of viral antigens, tumour-specific or tumour-related antigens, bacterial antigens, parasitic antigens, allergens and the like:
  • said antigen is encoded by an heterologous nucleotide sequence and is expressed in vivo by a recombinant vector.
  • heterologous nucleotide sequence of the present invention encodes one or more of all or part of the following antigens HBV-PreS1 PreS2 and Surface env proteins, core and polHIV-gp120 gp40, gp160, p24, gag, poi, env, vif, vpr, vpu, tat, rev, nef; HPV-E1, E2, E3, E4, E5, E6, E7, E8, L1, L2 (see for example WO 90/10459, WO 98/04705, WO 99/03885); HCV env protein E1 or E2, core protein, NS2, NS3, NS4a, NS4b, NS5a, NS5b, p7 (see for example WO2004111082, WO2005051420); Muc-1 (see for example U.S. Pat. No. 5,861,381; U.S. Pat. No. 6,054,438;
  • the immunogenic composition contains at least two antigens, or an heterologous nucleotide sequence encoding at least two antigens, or at least two heterologous nucleotide sequences encoding at least two antigens, or any combination thereof.
  • said heterologous nucleotide sequence of the present invention encodes all or part of HPV antigen(s) selected in the group consisting of E6 early coding region of HPV, E7 early coding region of HPV and derivates or combination thereof.
  • the HPV antigen encoded by the recombinant vector according to the invention is selected in the group consisting of an HPV E6 polypeptide, an HPV E7 polypeptide or both an HPV E6 polypeptide and an HPV E7 polypeptide.
  • the present invention encompasses the use of any HPV E6 polypeptide which binding to p53 is altered or at least significantly reduced and/or the use of any HPV E7 polypeptide which binding to Rb is altered or at least significantly reduced (Munger et al., 1989, EMBO J. 8, 4099-4105; Crook et al., 1991, Cell 67, 547-556; Heck et al., 1992, Proc. Natl. Acad. Sci.
  • a non-oncogenic HPV-16 E6 variant which is suitable for the purpose of the present invention is deleted of one or more amino acid residues located from approximately position 118 to approximately position 122 (+1 representing the first methionine residue of the native HPV-16 E6 polypeptide), with a special preference for the complete deletion of residues 118 to 122 (CPEEK).
  • HPV-16 E7 variant which is suitable for the purpose of the present invention is deleted of one or more amino acid residues located from approximately position 21 to approximately position 26 (+1 representing the first amino acid of the native HPV-16 E7 polypeptide, with a special preference for the complete deletion of residues 21 to 26 (DLYCYE).
  • the one or more HPV-16 early polypeptide(s) in use in the invention is/are further modified so as to improve MHC class I and/or MHC class II presentation, and/or to stimulate anti-HPV immunity.
  • HPV E6 and E7 polypeptides are nuclear proteins and it has been previously shown that membrane presentation permits to improve their therapeutic efficacy (see for example WO99/03885).
  • Membrane anchorage can be easily achieved by incorporating in the HPV early polypeptide a membrane-anchoring sequence and if the native polypeptide lacks it a secretory sequence (i.e. a signal peptide).
  • Membrane-anchoring and secretory sequences are known in the art. Briefly, secretory sequences are present at the N-terminus of the membrane presented or secreted polypeptides and initiate their passage into the endoplasmic reticulum (ER).
  • Membrane-anchoring sequences are usually highly hydrophobic in nature and serves to anchor the polypeptides in the cell membrane (see for example Eranden and Tooze, 1991, in Introduction to Protein Structure p. 202-214, NY Garland).
  • membrane-anchoring and secretory sequences which can be used in the context of the present invention is vast. They may be obtained from any membrane-anchored and/or secreted polypeptide comprising it (e.g. cellular or viral polypeptides) such as the rabies glycoprotein, of the HIV virus envelope glycoprotein or of the measles virus F protein or may be synthetic.
  • the membrane anchoring and/or secretory sequences inserted in each of the early HPV-16 polypeptides used according to the invention may have a common or different origin.
  • the preferred site of insertion of the secretory sequence is the N-terminus downstream of the codon for initiation of translation and that of the membrane-anchoring sequence is the C-terminus, for example immediately upstream of the stop codon.
  • HPV E6 polypeptide in use in the present invention is preferably modified by insertion of the secretory and membrane-anchoring signals of the measles F protein.
  • HPV E7 polypeptide in use in the present invention is preferably modified by insertion of the secretory and membrane-anchoring signals of the rabies glycoprotein.
  • the therapeutic efficacy of the recombinant vector can also be improved by using one or more nucleic acid encoding immunopotentiator polypeptide(s).
  • a polypeptide such as calreticulin (Cheng et al., 2001, J. Clin. Invest. 108, 669-678), Mycobacterium tuberculosis heat shock protein 70 (HSP70) (Chen et al., 2000, Cancer Res. 60, 1035-1042), ubiquitin (Rodriguez et al., 1997, J. Virol.
  • the recombinant vector according to the invention comprises a nucleic acid encoding one or more early polypeptide(s) as above defined, and more particularly HPV-16 and/or HPV-18 early E6 and/or E7 polypeptides.
  • said heterologous nucleotide sequence of the present invention encodes all or part of MUC 1 antigen or derivates thereof.
  • said heterologous nucleotide sequence of the present invention encodes one or more of all or part of the followings: HCV env protein E1 or E2, core protein, NS2, NS3, NS4a, NS4b, NS5a, NS5b, p7 or derivates thereof.
  • said heterologous nucleotide sequence of the present invention encodes one or more fusion protein wherein the configuration is not native in the sense that at least one of the NS polypeptides appears in an order which is distinct from that of the native configuration.
  • the fusion protein comprises a NS3 polypeptide, a NS4A polypeptide and a NS5B polypeptide
  • the native configuration would be NS3-NS4A-NS5B with NS3 at the N-terminus and NS5B at the C-terminus.
  • a non-native configuration can be NS5B-NS3-NS4A, NS5B-NS4A-NS3, NS4A-NS3-NS5B, NS4A-NS5B-NS3 or NS3-NS5B-NS4A.
  • the fusion protein according to the invention comprises at least one of the followings:
  • each of the NS polypeptides can be independently native or modified.
  • the NS4A polypeptide included in the NS4A-NS3 portion can be native whereas the NS3 polypeptide comprises at least one of the modifications described below.
  • the nucleic acid molecule in use in the invention may be optimized for providing high level expression of the targeted antigen (e.g. HPV early polypeptide(s)) in a particular host cell or organism, e.g. a human host cell or organism.
  • codon optimisation is performed by replacing one or more “native” (e.g. HPV) codon corresponding to a codon infrequently used in the mammalian host cell by one or more codon encoding the same amino acid which is more frequently used. This can be achieved by conventional mutagenesis or by chemical synthetic techniques (e.g. resulting in a synthetic nucleic acid). It is not necessary to replace all native codons corresponding to infrequently used codons since increased expression can be achieved even with partial replacement. Moreover, some deviations from strict adherence to optimised codon usage may be made to accommodate the introduction of restriction site
  • the term “recombinant vector” refers to viral as well as non viral vectors, including extrachromosomal (e.g. episome), multicopy and integrating vectors (i.e. for being incorporated into the host chromosomes). Particularly important in the context of the invention are vectors for use in gene therapy (i.e. which are capable of delivering the nucleic acid to a host organism) as well as expression vectors for use in various expression systems. Suitable non viral vectors include plasmids such as pREP4, pCEP4.
  • Suitable viral vectors may be derived from a variety of different viruses (e.g. retrovirus, adenovirus, AAV, poxvirus, herpes virus, measle virus, foamy virus and the like).
  • the term “vital vector” encompasses vector DNA/RNA as well as viral particles generated thereof.
  • Viral vectors can be replication-competent, or can be genetically disabled so as to be replication-defective or replication-impaired.
  • replication-competent as used herein encompasses replication-selective and conditionally-replicative viral vectors which are engineered to replicate better or selectively in specific host cells (e.g. tumoral cells).
  • the recombinant vector in use in the invention is a recombinant adenoviral vector (for a review, see “Adenoviral vectors for gene therapy”, 2002, Ed D. Curiel and J. Douglas, Academic Press). It can be derived from a variety of human or animal sources and any serotype can be employed from the adenovirus serotypes 1 through 51. Particularly preferred are human adenoviruses 2 (Ad2), 5 (Ad5), 6 (Ad6), 11 (Ad11), 24 (Ad24) and 35 (Ad35).
  • Such adenovirus are available from the American Type Culture Collection (ATCC, Rockville, Md.), and have been the patient of numerous publications describing their sequence, organization and methods of producing, allowing the artisan to apply them (see for example U.S. Pat. No. 6,133,028; U.S. Pat. No. 6,110,735; WO 02/40665; WO 00/50573; EP 1016711; Vogels et al., 2003, J. Virol. 77, 8263-8271).
  • the adenoviral vector in use in the present invention can be replication-competent.
  • Numerous examples of replication-competent adenoviral vectors are readily available to those skill in the art (see, for example, Hernandez-Alcoceba et al., 2000, Human Gene Ther. 11, 2009-2024; Nemunaitis et al., 2001, Gene Ther. 8, 746-759; Alemany et al., 2000, Nature Biotechnology 18, 723-727).
  • they can be engineered from a wild-type adenovirus genome by deletion in the E1A CR2 domain (see for example WO00/24408) and/or by replacement of the native E1 and/or E4 promoters with tissue, tumor or cell status-specific promoters (see for example U.S. Pat. No. 5,998,205, WO99/25860, U.S. Pat. No. 5,698,443, WO00/46355, WO00/15820 and WO01/36650).
  • the adenoviral vector in use in the invention is replication-defective (see for example WO94/28152; Lusky et al., 1998, J. Virol 72, 2022-2032).
  • Preferred replication-defective adenoviral vectors are E1-defective (see for example U.S. Pat. No. 6,136,594 and U.S. Pat. No. 6,013,638), with an E1 deletion extending from approximately positions 459 to 3328 or from approximately positions 459 to 3510 (by reference to the sequence of the human adenovirus type 5 disclosed in the GeneBank under the accession number M 73260 and in Chroboczek et al., 1992, Virol. 186, 280-285).
  • the cloning capacity can further be improved by deleting additional portion(s) of the adenoviral genome (all or part of the non essential E3 region or of other essential E2, E4 regions). Insertion of a nucleic acid in any location of the adenoviral vector can be performed through homologous recombination as described in Chartier et al. (1996, J. Virol. 70, 4805-4810).
  • the nucleic acid encoding the HPV-16 E6 polypeptide can be inserted in replacement of the E1 region and the nucleic acid encoding the HPV-16 E7 polypeptide in replacement of the E3 region or vice versa.
  • the vector in use in the invention is a poxviral vector (see for example Cox et al. in “Viruses in Human Gene Therapy” Ed J. M. Hos, Carolina Academic Press).
  • poxviral vector see for example Cox et al. in “Viruses in Human Gene Therapy” Ed J. M. Hos, Carolina Academic Press.
  • suitable vaccinia viruses include without limitation the Copenhagen strain (Goebel et al., 1990, Virol. 179, 247-266 and 517-563; Johnson et al., 1993, Virol.
  • the Wyeth strain and the highly attenuated attenuated virus derived thereof including MVA (for review see Mayr, A., et al., 1975, Infection 3, 6-14) and derivates thereof (such as MVA vaccinia strain 575 (ECACC V00120707—U.S. Pat. No. 6,913,752), NYVAC (see WO 92/15672—Tartaglia et al., 1992, Virology, 188, 217-232).
  • the vector may also be obtained from any other member of the poxyiridae, in particular fowlpox (e.g. TROVAC, see Paoletti et al, 1995, Dev Biol Stand., 84, 159-163); canarypox (e.g.
  • the nucleic acid encoding the antigen of the Invention is preferably inserted in a nonessential locus of the poxviral genome, in order that the recombinant poxvirus remains viable and infectious.
  • Nonessential regions are non-coding intergenic regions or any gene for which inactivation or deletion does not significantly impair viral growth, replication or infection.
  • the antigen-encoding nucleic acid is preferably inserted in the thymidine kinase gene (tk) (Hruby et al., 1983, Proc. Natl. Acad. Sci. USA 80, 3411-3415; Weir et al., 1983, J. Virol. 46, 530-537).
  • tk thymidine kinase gene
  • other insertion sites are also appropriate, e.g. in the hemagglutinin gene (Guo et al., 1989, J. Viral. 63, 4189-4198), in the K1L locus, in the u gene (Zhou et al., 1990, J. Gen. Virol.
  • the antigen-encoding nucleic acid can be inserted in any one of the identified deletions I to VII as well as in the D4R locus, but insertion in deletion II or III is preferred (Meyer et al., 1991, J. Gen. Viral. 72, 1031-1038; Sutter et al., 1994, Vaccine 12, 1032-1040).
  • the antigen-encoding nucleic acid is preferably introduced in the intergenic region situated between ORFs 7 and 9 (see for example EP 314 569 and U.S. Pat. No. 5,180,675).
  • said recombinant vector is a recombinant plasmid DNA or a recombinant viral vector.
  • said recombinant viral vector is a recombinant adenoviral vector.
  • said recombinant viral vector is a recombinant vaccinia vector.
  • said recombinant vaccinia vector is a recombinant MVA vector.
  • the antigen-encoding nucleic acid in use in the invention is in a form suitable for its expression in a host cell or organism, which means that the nucleic acid sequence encoding the antigen are placed under the control of one or more regulatory sequences necessary for its expression in the host cell or organism.
  • regulatory sequence refers to any sequence that allows, contributes or modulates the expression of a nucleic acid in a given host cell, including replication, duplication, transcription, splicing, translation, stability and/or transport of the nucleic acid or one of its derivative (i.e. mRNA) into the host cell.
  • the choice of the regulatory sequences can depend on factors such as the host cell, the vector and the level of expression desired.
  • the nucleic acid encoding the antigen is operatively linked to a gene expression sequence which directs the expression of the antigen nucleic acid within a eukaryotic cell.
  • the gene expression sequence is any regulatory nucleotide sequence, such as a promoter sequence or promoter-enhancer combination, which facilitates the efficient transcription and translation of the antigen nucleic acid to which it is operatively linked.
  • the gene expression sequence may, for example, be a mammalian or viral promoter, such as a constitutive or inducible promoter.
  • Constitutive mammalian promoters include, but are riot limited to, the promoters for the following genes: hypoxanthine phosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase, b-actin promoter and other constitutive promoters.
  • HPRT hypoxanthine phosphoribosyl transferase
  • adenosine deaminase pyruvate kinase
  • b-actin promoter a constitutive promoters.
  • Exemplary viral promoters which function constitutively in eukaryotic cells include, for example, promoters from the cytomegalovirus (CMV), simian virus (e.g., 3V40), papilloma virus, adenovirus, human immunodeficiency virus (HIV), Rous sarcoma virus, cytomegalovirus, the long terminal repeats (LTR) of Moloney leukemia virus and other retroviruses, and the thymidine kinase promoter of herpes simplex virus.
  • CMV cytomegalovirus
  • simian virus e.g., 3V40
  • papilloma virus e.g., 3V40
  • HAV human immunodeficiency virus
  • Rous sarcoma virus e.g., Rous sarcoma virus
  • cytomegalovirus e.g., the long terminal repeats (LTR) of Moloney leukemia virus and other retrovirus
  • Inducible promoters are expressed in the presence of an inducing agent.
  • the metallothionein promoter is induced to Promote transcription and translation in the presence of certain metal ions.
  • Other inducible promoters are known to those of ordinary skill in the art.
  • the gene expression sequence shall include, as necessary, 5′ non-transcribing and 5′ non-translating sequences involved with the initiation of transcription and translation, respectively, such as a TATA box, capping sequence, CAAT sequence, and the like.
  • 5′ non-transcribing sequences will include a promoter region which includes a Promoter sequence for transcriptional control of the operably joined antigen nucleic acid.
  • the gene expression sequences optionally include enhancer sequences or upstream activator sequences as desired.
  • Preferred promoters for use in a poxviral vector include without limitation vaccinia promoters 7.5K, H5R, TK, p28, p11 and K1L, chimeric promoters between early and late poxviral promoters as well as synthetic promoters such as those described in Chakrabarti et al. (1997, Biotechniques 23, 1094-1097), Hammond et al. (1997, J. Virological Methods 66, 135-138) and Kumar and Boyle ( 1990 , Virology 179, 151-158).
  • the promoter is of special importance and the present invention encompasses the use of constitutive promoters which direct expression of the nucleic acid in many types of host cells and those which direct expression only in certain host cells or in response to specific events or exogenous factors (e.g. by temperature, nutrient additive, hormone or other ligand).
  • Suitable promoters are widely described in literature and one may cite more specifically viral promoters such as RSV, SV40, CMV and MLP promoters.
  • Preferred promoters for use in a poxviral vector include without limitation vaccinia promoters 7.5K, H5R, TK, p28, p11 and K1L, chimeric promoters between early and late poxviral promoters as well as synthetic promoters such as those described in Chakrabarti et al. (1997, Biotechniques 23, 1094-1097), Hammond et al. (1997, J. Virological Methods 66, 135-138) and Kumar and Boyle ( 1990 , Virology 179, 151-158).
  • the regulatory elements controlling the expression of the nucleic acid molecule of the invention may further comprise additional elements for proper initiation, regulation and/or termination of transcription (e.g. polyA transcription termination sequences), mRNA transport (e.g. nuclear localization signal sequences), processing (e.g. splicing signals), and stability (e.g. introns and non-coding 5′ and 3′ sequences), translation (e.g. peptide signal, propeptide, tripartite leader sequences, ribosome binding sites, Shine-Dalgamo sequences, etc.) into the host cell or organism.
  • transcription e.g. polyA transcription termination sequences
  • mRNA transport e.g. nuclear localization signal sequences
  • processing e.g. splicing signals
  • stability e.g. introns and non-coding 5′ and 3′ sequences
  • translation e.g. peptide signal, propeptide, tripartite leader sequences, ribosome binding sites, Shine-Dalgamo sequences,
  • the recombinant vector in use in the present invention can further comprise at least one nucleic acid encoding at least one cytokine.
  • Suitable cytokines include without limitation interleukins (e.g. IL-2, IL-7, IL-15, IL-18, IL-21) and interferons (e.g. IFN ⁇ , INF ⁇ ), with a special preference for interleukin IL-2.
  • the recombinant vaccine of the invention comprises a cytokine-expressing nucleic acid
  • said nucleic acid may be carried by the recombinant vector encoding the one or more antigen(s) or by an independent recombinant vector which can be of the same or a different origin.
  • the recombinant vector in use in the present invention is encoding all or part of the MUC1 antigen and at least one cytokines above listed, and preferably an interleukin, especially IL2.
  • the recombinant vector in use in the present invention is an MVA encoding all or part of the MUC1 antigen and at least one cytokines above listed, and preferably an interleukin, especially IL2.
  • Infectious viral particles comprising the above-described recombinant viral vector can be produced by routine process.
  • An exemplary process comprises the steps of:
  • Cells appropriate for propagating adenoviral vectors are for example 293 cells, PERC6 cells, HER96 cells, or cells as disclosed in WO 94/28152, WO 97/00326, U.S. Pat. No. 6,127,175.
  • Cells appropriate for propagating poxvirus vectors are avian cells, and most preferably primary chicken embryo fibroblasts (CEF) prepared from chicken embryos obtained from fertilized eggs.
  • CEF primary chicken embryo fibroblasts
  • the infectious viral particles may be recovered from the culture supernatant or from the cells after lysis (e.g. by chemical means, freezing/thawing, osmotic shock, mecanic shock, sonication and the like).
  • the viral particles can be isolated by consecutive rounds of plaque purification and then purified using the techniques of the art (chromatographic methods, ultracentrifugation on caesium chloride or sucrose gradient).
  • the method or use for treating a patient for human disease human disease according to the Invention can be carried out in the selected patients in conjunction with one or more conventional therapeutic modalities (e.g. radiation, chemotherapy and/or surgery).
  • one or more conventional therapeutic modalities e.g. radiation, chemotherapy and/or surgery.
  • the use of multiple therapeutic approaches provides the selected patient with a broader based intervention.
  • the method or use for treating a patient for human disease human disease according to the Invention can be preceded or followed by a surgical intervention. In another embodiment, it can be preceded or followed by radiotherapy (e.g. gamma radiation).
  • the method or use of the invention is associated to chemotherapy with one or more drugs (e.g. drugs which are conventionally used for treating or preventing viral infections, virus-associated pathologic conditions, cancer, and the like).
  • drugs e.g. drugs which are conventionally used for treating or preventing viral infections, virus-associated pathologic conditions, cancer, and the like.
  • the present Invention thus relates to a method for improving the treatment of a cancer patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent, said method comprising the following steps:
  • the present Invention thus relates to a method for improving the treatment of a cancer patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent, said method comprising the following steps
  • the administration of said chemotherapeutic agent is done before administration of said immunogenic composition.
  • the administration of said chemotherapeutic agent is done after administration of said immunogenic composition.
  • the administration of said chemotherapeutic agent is done concomitantly with administration of said immunogenic composition.
  • said chemotherapeutic agent is cisplatin and/or Gemcitabine, or equivalent thereof.
  • the present Invention further concerns a method of improving cytotoxic effectiveness of cytotoxic drugs or radiotherapy which comprises co-treating a patient selected in a patient population composed of patients that have low levels of activated NK cells with an immunogenic composition according to the Invention.
  • the method or use of the invention is carried out according to a prime boost therapeutic modality which comprises sequential administration of one or more primer composition(s) and one or more booster composition(s).
  • the priming and the boosting compositions use different vehicles which comprise or encode at least an antigenic domain in common.
  • the priming composition is initially administered to the host organism and the boosting composition is subsequently administered to the same host organism after a period varying from one day to twelve months.
  • the method of the invention may comprise one to ten sequential administrations of the priming composition followed by one to ten sequential administrations of the boosting composition. Desirably, injection intervals are a matter of one week to six months.
  • the priming and boosting compositions can be administered at the same site or at alternative sites by the same route or by different routes of administration.
  • the Invention relates to a method as above described wherein said human disease is cancer.
  • said cancer is for example breast cancer, colon cancer, kidney cancer, rectal cancer, lung cancer, cancer of the head and neck, renal cancer, malignant melanoma, laryngeal cancer, ovarian cancer, cervical cancer, prostate cancer, non Small cell Lung Cancer, haematological cancers, gastric cancers, myeloma.
  • the invention relates to a method as above described wherein said human disease is infectious disease.
  • said infectious disease is a viral induced disease, such as for example disease induced by HIV, HCV, HBV, HPV, and the like.
  • an immunogenic composition comprising all or part of a targeted antigen for the manufacture of a medicament for treating a patient for human disease in a particular patient population wherein the patients of said population have low levels of activated NK cells.
  • an immunogenic composition for the manufacture of a medicament for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease in a particular patient population wherein the patients of said Population have low levels of activated NK cells.
  • an immunogenic composition for the manufacture of a medicament for inducing an immune response to at least one antigen (i.e. the raised immune response) in a patient for treating human disease in a particular patient population wherein the patients of said population have low levels of activated NK cells.
  • an immunogenic composition for the manufacture of a medicament for inducing an immune response to a targeted antigen (i.e. the raised immune response) in a patient for treating human disease in a particular patient population wherein the patients of said population have low levels of activated NK cells.
  • an immunogenic composition for the manufacture of a medicament for inducing an immune response (i.e. the raised immune response) in a patient for treating human disease in a particular patient population wherein the patients of said population have low levels of activated NK cells and wherein said raised immune response is innate immune response.
  • said “raised immune response” in said patient population is directed towards a tumour-specific or -related antigens and/or viral antigen. According to one embodiment, said “raised immune response” in said patient population is directed towards distinct antigens. According to one special embodiment, said “raised immune response” in said patient population is directed towards all or part of MUC1 antigen. According to another special embodiment, said “raised immune response” in said patient population is T cell immune response, and preferably CD8+ (Cytotoxic T Lymphocytes) immune response. According to another special embodiment, said “raised immune response” in said patient population is a non specific immune response. According to another special embodiment, said “raised immune response” in said patient population is a stimulation of the innate immune response.
  • the ability to induce or stimulate an immune response upon administration in an animal or human organism can be evaluated either in vitro or in vivo using a variety of assays which are standard in the art.
  • assays which are standard in the art.
  • Measurement of cellular immunity can be performed by measurement of cytokine profiles secreted by activated effector cells including those derived from CD4+ and CD8+ T-cells (e.g. quantification of IL-10 or IFN gamma-producing cells by ELIspot), by determination of the activation status of immune effector cells (e.g.
  • T cell proliferation assays by a classical [ 3 H] thymidine uptake), by assaying for antigen-specific T lymphocytes in a sensitized patient (e.g. peptide-specific lysis in a cytotoxicity assay) or by detection of antigen specific T cells by fluorescent MHC and/or peptide multimers (e.g. tetramers).
  • the ability to stimulate a humoral response may be determined by antibody binding and/or competition in binding (see for example Harlow, 1989, Antibodies, Cold Spring Harbor Press).
  • the method of the invention can also be further validated in animal models challenged with an appropriate tumor-inducing agent (e.g. MUC1-expressing TC1 cells) to determine anti-tumor activity, reflecting an induction or an enhancement of an anti-antigen immune response.
  • an appropriate tumor-inducing agent e.g. MUC1-expressing TC1 cells
  • the present invention further concerns a method for extending the survival of a patient treated for human disease, for example cancer, by administering an immunogenic composition, said method comprising the following steps:
  • the present invention further concerns a method for extending the survival rate of a patient treated for human disease, for example cancer, by administering an immunogenic composition, said method comprising the following steps:
  • the present invention further concerns a method for extending the survival rate of a patient treated for human disease, for example cancer, by administering an immunogenic composition and chemotherapeutic agent (see above), said method comprising the following steps:
  • the present Invention relates to the use of activated NK cells as a biomarker for predicting whether a patient is or is not susceptible to developing prophylactic or therapeutic immune response by administration of an immunogenic composition.
  • the present Invention relates to the use of the level of activated NK cells as a biomarker for predicting whether a patient is or is not susceptible to developing prophylactic or therapeutic immune response by administration of an immunogenic composition, wherein low levels of activated NK cells indicates that the patient is predicted to have an increased susceptibility to develop a prophylactic or therapeutic immune response.
  • the present Invention relates to the use of the level of activated NK cells as a biomarker for predicting whether a patient is or is not susceptible to survive longer after administration of an immunogenic composition, wherein low levels of activated NK cells indicates that the patient is predicted to have a longer survival rate compared to treated patients who have higher levels of activated NK cells.
  • the Invention further concerns the use of the level of activated NK cells as a biomarker for predicting whether a patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent is or is not susceptible to developing prophylactic or therapeutic immune response (e.g. to survive longer) after administration of an immunogenic composition.
  • the Invention further concerns the use of the level of activated NK cells as a biomarker for predicting whether a patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent is or is not susceptible to developing prophylactic or therapeutic immune response (e.g. to survive longer) after administration of an immunogenic composition, wherein low levels of activated NK cells indicates that the patient is predicted to have an increased susceptibility to develop a prophylactic or therapeutic immune response.
  • the present Invention thus relates to a method for improving the treatment of a cancer patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent, said method comprising the following steps:
  • the present invention further concerns a method for extending the survival of a patient treated for human disease, for example cancer, by administering an immunogenic composition, said method comprising the following steps:
  • the present invention further concerns a method for extending the survival of a patient treated for human disease, for example cancer, by administering an immunogenic composition and chemotherapeutic agent (see above), said method comprising the following steps:
  • kits i.e. companion test
  • the kit of parts, or kits may include reagents for collecting and or measuring serum levels of activated NK cells. Such reagents may include antibodies.
  • the kits may further include equipment for collecting and/or processing biological samples.
  • the kits are also likely to contain instructions for use, cut-off values and/or instructions for their determination, and instructions for interpreting the data obtained from the use of the kits.
  • the said kit of parts, or kits may further include an immunogenic composition as above disclosed, and/or as disclosed in the Example section below.
  • the invention further provides computer programs and/or algorithms for monitoring clinical trial and activated NK cells levels, determining whether such levels are above or below a threshold level, and/or recommending modifications to a treatment regiment to improve a patient's response to an immunotherapy treatment.
  • the computer programs or algorithms may be provided along with necessary hardware, e.g., in the form of a kit or apparatus, which may also accept biological samples and measure the relative levels of activated NK cells present therein.
  • the above-described computer programs and/or apparatus are likely to be provided to physicians or clinical laboratories with appropriate instructions and reagents, including antibodies.
  • FIG. 1 Survival curves describing vaccine immunotherapy in lung cancer: patients with ⁇ or ⁇ 3.46% Activated NK
  • Vaccine i.e. immunogenic composition
  • chemotherapy in patients with low levels of activated NK cells.
  • Low levels as defined as ⁇ 3.45% CD16+ CD56+ CD69+ lymphocytes in peripheral blood.
  • Vaccine+chemotherapy in patients with high levels of activated NK cells High levels as defined as ⁇ 3.45% CD16+ CD56+ CD69+ lymphocytes in peripheral blood. 21 patients
  • FIG. 2 Survival curves describing vaccine immunotherapy in lung cancer: patients who have ⁇ or ⁇ 35 Activated NK per ⁇ l whole blood.
  • Vaccine+chemotherapy in patients with low levels of activated NK cells Low levels as defined as ⁇ 35 CD16+CD56+ CD69+ lymphocytes per ⁇ l of peripheral blood. 33 patients.
  • Vaccine+chemotherapy in patients with high levels of activated NK cells High levels as defined as ⁇ 35 CD16+ CD56+ CD69+ lymphocytes per ⁇ l peripheral blood. 22 patients.
  • FIG. 3 Survival curves describing chemotherapy in lung cancer: patients with ⁇ or ⁇ 3.45% Activated NK
  • FIG. 4 Survival curves describing chemotherapy in lung cancer: patients who have ⁇ or ⁇ 35 Activated NK per ⁇ l whole blood.
  • the immunogenic composition noted vaccine TG4010, was used to treat non-small cell lung cancer (NSCLC) patients in combination with standard chemotherapy.
  • NSCLC non-small cell lung cancer
  • TG4010 is a recombinant Modified Virus Ankara (MVA) expressing both IL2 and the tumor-associated antigen MUC1.
  • MVA Modified Virus Ankara
  • PFS progression-free survival
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononal antibodies specific for those antigens (IM0814, IM2073 and IM2656, respectively, all from Beckman Coulter).
  • the proportion of cells expressing these antigens can be expressed as % of total lymphocytes evaluated or numbers of CD16+ CD56+ and CD69+ in the PBMC population per ⁇ l of whole blood.
  • FIGS. 3 and 4 demonstrate that the effect of selecting patients based on the expression of CD16, CD56 and CD69 on their lymphocytes is restricted to patients receiving the vaccine.
  • FIG. 3 shows that patients with ⁇ or ⁇ 3.45% CD16+ CD56+ CD69+ lymphocytes at baseline have the same survival expectancy.
  • FIG. 4 shows that the observation using 35 CD16+ CD56+ CD69+ lymphocytes per ⁇ l whole blood at baseline.

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IL209074A0 (en) 2011-01-31
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CN102046196B (zh) 2014-07-30
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