WO2011003905A1 - Biomarker for selecting patients and related methods - Google Patents
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- WO2011003905A1 WO2011003905A1 PCT/EP2010/059635 EP2010059635W WO2011003905A1 WO 2011003905 A1 WO2011003905 A1 WO 2011003905A1 EP 2010059635 W EP2010059635 W EP 2010059635W WO 2011003905 A1 WO2011003905 A1 WO 2011003905A1
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Definitions
- the present invention relates to the field of immunology ana, in particular, to immunotherapy of a patient against diseases caused for example by infection cr cancers. More particularly, the invention relates to methods for predicting whether a patient is or is not susceptible to developing a prophylactic or therapeutic response, preferably 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 therapeutic vaccine.
- Lave 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.
- 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) .
- IRMs xminune response modifiers
- TLRs Toll-like receptors
- Such compounds have been shown to stimulate a rapid release of certain T cell, dendritic ceil, or monocyte/macrophage- derived cytokines and are also capable of stimulating lymphocyte function, such as 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 oy administering to the patient a priming composition and then boosted by administration of a boosting second composition
- one treatment can be effective only in specific group of patients. It is thus desirable to provide to physicians tools and methods that will enable them to tailor optimal personalized patient therapies, i.e. to prescribe the right therapy to the right patient at right time, to provide a higher treatment success rate, to monitor the response to the treatment, to increase drug efficacy and safety, to eliminate the unnecessary treatment of patients for whom therapy is not appropriate, to spare the patient unnecessary toxicity and side effects, to reduce the cost to patients and insurers of unnecessary or dangerous ineffective medication, and tc improve patient quality of life, eventually making cancer a managed disease, with follow up assays as appropriate.
- optimal personalized patient therapies i.e. to prescribe the right therapy to the right patient at right time, to provide a higher treatment success rate, to monitor the response to the treatment, to increase drug efficacy and safety, to eliminate the unnecessary treatment of patients for whom therapy is not appropriate, to spare the patient unnecessary toxicity and side effects, to reduce the cost to patients and insurers of unnecessary or dangerous ineffective medication, and tc improve patient quality of life, eventually making cancer a
- Pharmacogenetics which consist in the study of individual response to drugs as a function of genetic differences. These responses relate to how a drug functions in any given individual, how it is metabolized, its toxicity and dosage requirements. With the human genome project, pharmacogenetics has expanded into pharmacogenomics . Pharmacogenomics goes beyond pharmacogenetics, with the potential to find uses from drug discovery and development, target discovery and validation, and clinical trials;
- Metabolomics can also be applied to the field of predictive medicine. Unlike pharmacogenetics, which is limited to genetic factors, pharr ⁇ aco-metabolomics is able to predict an individual's response to a drug based not only on genetic factors, but also non-genetic factors, such as other drugs in the patient's body, the patient's current state of health, etc.
- biomarker can be an indicator of normal biological processes, disease processes, or pharmacological responses to therapeutic intervention. Their role ranges from, stratifying the patient population in helping to identify responders versus non-responders to determining the efficacy of the therapeutic. Biomarkers can be a valuable tool m making better decisions that will reduce the cost for drug development and enabJ e therapies to reach the most appropriate patient population faster.
- the invention provides rraterials and methods for predicting the efficacy of a treatment involving the administration of an immunogenic composition to a patient ⁇ i.e. immunotherapy treatment) using biological markers (biomarkers) that have been determined to be substantially reliable signature which correlates with the desired clinical outcome, lhe biomarkers are present in biological samples obtained from the patient, prior to the treatment with the said immunogenic composition.
- biological markers biomarkers
- the ability to predict the clinical outcome of a treatment, before its initiation, will enable clinicians and patients to identify ineffective therapy, make informed decisions regarding the course of treatment, including whether to abandon or to allow alternate therapy implementation.
- the present Invention relates to the use of the interleukin-10 /J nterferon-gamma (ILl0/IFN ⁇ ) ratio as a biomarker for predicting whether a patient is or is not susceptible to developing prophylactic or therapeutic response, preferably immune response, by administration of an immunogenic composition.
- the interferon-gamma/ interleukin-10 (IFKy/ ILlO) ratio can be used as a biomarker according to the present invention, but in that case conclusions should be adapted.
- the present Invention relates to a method for treating a patient for human disease by administering an immunogenic composition wherein said patient is selected in a patient population composed of patients that have low IL10/IFN ⁇ ratio.
- the present Invention thus relates to a method for treating a patient for human disease by administering an immunogenic composition, 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 response, preferably immune response, by administration of an immunogenic composition, said method comprising the steps of:
- the present Invention relates to a metfio ⁇ for selecting a patient susceptible to developing prophylactic or therapeutic response, preferaoly 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, saJ d method comprising che steps of:
- IL10/IFN ⁇ ratio calculating IL10/IFN ⁇ ratio, wherein low IL10/IFN ⁇ ratio indicates that the patient is predicted to have an increased susceptibility to develop a prophylactic or Therapeutic response, preferably immune response.
- the present Invention relates to a method for selecting a patient susceptible ic respond positively to a treatment comprising administration of an immunogenic compos.! tion, 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 present Invention further relates to an ex vivo method of treatment comprising administration of an immunogenic composition, wherein the resting method comprises the step of measuring levels of ILlO and INFy in a biological sample, especially blood sample, from the patient, calculating ILlO/IFNf ⁇ ratio, wherein low ILlO/IFN ⁇ ratio indicates that the patient will develop a prophylactic or therapeutic response, in particular immune response, towards the immunogenic composition.
- 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 IL!0/IFN ⁇ ratio,
- the present Invention relates to a method for inducing an immune response io at ieasr 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 thai have low ILlO/IFN ⁇ ratio.
- 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 ILlO/IFN ⁇ ratio and wherein said raised iiurrune response is innate immune response.
- the innate immune response is body's inxtial 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 ceils, 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 ceils, 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 : - selection of one patient in a patient population composed of patients that have low ILlO/IFN ⁇ ratio,
- -he 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 ⁇ .he 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 : measuring in the patient the levels of ILlO and
- the present Invention relates to a method for inducing an immune response (i.e. the raised immune response) in a patient for creating human disease by administering an immunogenic composition wherein said raised immune response is innate immune response, said method comprising the following steps :
- 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.
- 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 cries. This is covered by the term “co 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 we] 1 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 ILlO/IFNy ratio should be understood as meaning a patient for who levels of interleukin-10 and interferon-gamma have beer, measured as disclosed herein, and who has low IL10/IFN ⁇ ratio.
- the terms "a patient will respond therapeutically” or ⁇ a patient will respond positively to a treatment” mean that the said patient has an increase ot survival rate (see example section).
- the method of the invention comprises an mxtial step consisting in measuring the interieukin-10 and interferon-gamma levels in biological samples from the patient before administration of the immunogenic composition.
- the levels of interieukin-10 and interferon-gamma are measured in a biological sample obtained from the patient.
- Biological samples include but are net limited to blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen.
- the biological sample is blood, plasma or serum, in which case obtaining the samples from a patient is relatively simple and non-invasive procedure. Methods of obtaining blood or serum are well-known in the art are not part of the invention.
- detecting and quantifying polypeptides including the instant biomarkers
- methods include but are not limited to anribody-based methods, more specifically monoclonal antibodies-based methods.
- the particular methods of detecting and quantifying the biomarkers are not important to the invention.
- the materials and methods of the present invention may be used with Lurni nex technology (Lur ⁇ inex Corporation, Austin, Tex.) or enzyme-linked immunosorbant assays (ELISA, numerous KLISA kits are commercially available e.g. by CliniScience, Diacione, Biosource) .
- the levels of interleukin-10 and interferon-gamma are determined by using antibodies.
- said antibody (ies) is (are) specific of ILlO or ⁇ NF ⁇ .
- said anc ⁇ bodies are monoclonal antibodies.
- said antibodxe ⁇ 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 method includes determining the levels of interleukin-10 and interferon-gamma in a patient prior administration of an immunogenic composition to the patient; calculating ILlO/IFNy ratio; comparing said IL10/IFM ⁇ ratio to a cut-off value; and predicting the efficacy of immunotherapy treatment based on the levels of ILlO/IFN ⁇ ratio compared to the cut-off value.
- the said cut-off value is about 5, preferably about 4, more preferably about 3 and particularly about 2.
- said cut-off value is about 3.7, and more preferably is 3.7.
- the "Mow ILlO/IFNy ratio" according to r.he present invention is designating ILlO/IFNy ratios below about 5, preferably below about 4 and more preferably below about 3 and particularly blow about ?.
- said the "low ILlO/IFNy ratio" according to the present invention is designating ILlO/IFNy ratios below about 3.7, and more preferably is below 3.7.
- the levels of interleukin-10 and interferon-gamma are measured by Enzyme Linked Immune Sorbant Assay (ELISA) , by Luminex ⁇ analysis, by lab-on-chip systems, by radio-immune assay or other systems based on specific molecular recognition of ILlO and ItNy using antibodies or other specific molecules.
- ELISA Enzyme Linked Immune Sorbant Assay
- the terms "immunogenic conpositicn" "vaccine composition” , “vaccine” or similar terms can be used interchangeably and mean an agent suitable for stiraulating/ind ⁇ ciug/increasing a patient's immune system to ameliorate a current condition, e.g. to improve survival rate, 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 detectabiy reduced unwanted symptom (s) associated with a condition, extend patient survival.
- a current condition e.g. to improve survival rate, 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 detectabiy reduced unwanted symptom (s) associated with a condition, extend patient survival.
- Said immunogenic composition can contain at least (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 ) .
- immune response modifiers include the CpG oligonucleotides (see US
- the immunogenic comDosition comprises cells whicn stimulate a patient immune response to treat a disease, such as cancer.
- Said cells can be antigen presenting cells, such as dendritic cells, combined with an antigenic composition (e.g. Provenge developed. by u i ',. .c- -;>) , tumor cells (e.g. GvAX developed, by Cell Genesis) or lymphocytes,
- an antigenic composition e.g. Provenge developed. by u i ',. .c- -;>
- tumor cells e.g. GvAX developed, by Cell Genesis
- lymphocytes e.g. GvAX developed, by Cell Genesis
- the term "antigen” refers to any substance, including complex antigen (e.g. tamour cells, virus infected cells, dendritic 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:
- Viral antigens include for example antigens from hepatitis viruses A, B, C, D and E, HIV, herpes viruses, cytomegalovirus, varicella zoster, papilloma viruses, Epstein Barr virus, influenza viruses, para-influenza viruses, adenoviruses, coxsdkie viruses, picorna viruses, rotaviruses, respiratory syncytial viruses, pox viruses, rhinoviruses, rubella virus, papovirus, mumps virus, measles virus; some non-limiting examples of known viral antigens include the following : antigens derived from HIV-I such as tat, nef, gpl20 or gpl60, gp40, p24, gag, env, vi£, vpr, vpu, rev or part and/or combinations thereof; antigens derived from human herpes viruses such as gH, gL gM gB gC gK
- tumor-specific or -related antigens include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, renal cancer, malignant melanoma, laryngeal cancer, prostate cancer.
- Cancer antigens are antigens which can potentially stimulate apparently tumor-specific immune responses. Some of these antigens are encoded, although not necessarily expressed, by normal cells. These antigens can be characterized as those which are normally silent (i.e., not expressed) in normal cells, those that are expressed only at low levels or at certain stages of differentiation and those that are temporally expressed such as embryonic and fetal antigens. Other cancer antigens are encoded Dy mutant cellular genes, such as oncogenes (e.g., activated ras oncogene) , suppressor genes (e.g., mutant pb3) , fusion proteins resulting from internal deletions or chromosomal translocations.
- oncogenes e.g., activated ras oncogene
- suppressor genes e.g., mutant pb3
- cancer antigens can be encoded by viral genes such as tnose carried on RNA and DNA tumor viruses.
- t ⁇ mor-specific or -related antigens include MART- 1/Melan-A, gplOO, Dipeptidyl peptidase IV (DPPIV) , adenosine deaminase-binding protein (ADAbp) , cyciophilin b, Colorectal associated antigen (CRC) -C017-1A/GA733, Carcinoembryonic Antigen (CEA) and its immunogenic epitopes CAP-I and CAP-2, etv ⁇ , amll, Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-I, PSATM2, and PSA-3, prostate- specific membrane antigen (PSMA) , T-cell receptor/CD3-zeta chain, MAGE-family of tumor antigens (e.g., MAGE-Al, MAGE-A
- DPPIV
- MUC-I MUC-I
- HER2/neu HER2/neu
- p21ras RCAS
- aipha-fetoprotej n E-cadher in, alpha-catenin, beta- caienin and gamma-catenin, pl20ctn, gplOO . sup .
- Pmelli7 FRAME, NY-E ⁇ O-1, cdc27, adenomatous polyposis coli protein (APC), fodrin, Connexin 37, Ig-idiorype, pl5, gp75, GM2 and GD2 gangliosides , viral products such as human papilloma virus proteins, Smad family of tumor antigens, lmp-1, PlA, ElBV- encoded nuclear antigen (EBNA)-I, brain glycogen phosphorylase, SSX-I, SSX-2 (HOM-MEL-40) , SSX-I, SSX-4, SSX- 5, SCP-I and CT-7, and c-erbB ⁇ 2;
- APC adenomatous polyposis coli protein
- APC adenomatous polyposis coli protein
- APC adenomatous polyposis coli protein
- fodrin Connexin 37
- Ig-idiorype pl5
- gp75 GM
- - bacterial antigens includes for example antigens from Mycobacteria causing TB and leprosy, pneumocci, aerooic grarn negative bacilli, mycoplasma, staphy Ioccocal infections, streptococcal infections, salrr.onellae, chlamydiae, neisseriae;
- antigens includes for exampJ e anzigens from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, schistosomiasis, filariasis;
- allergens refer to a substance that can induce an allergic or asthmatic response in a susceptible patient.
- the list of allergens is enormous and can include pollens, insect venoms, animal dander dust, fungal spores and drugs (e.g. penicillin) .
- natural, animal and plant allergens include but are not limited to proteins specific to the following genuses: Canine (Canis familiaris) ; Dermatophagoides (e.g. Dermatophagoides farinae) ; Felis (Felis domesticus) ; Ambrosia (Ambrosia artemiisfolia; Lolium (e.g. Lolium perenne or Lolium multiflorum) ; Cryptomeria
- Cupress ⁇ s e.g. C ⁇ pressus sempervirens
- Juniperus sabinoides Juniperus virginiana, Juniperus communis and Juniperus ashei
- Thuya e.g. Thuya orientalis
- Chamaecyparis e.g. Chamaecyparis obtusa
- Periplaneta e.g. Periplaneta americana
- Agropyron e.g. Agropyron repens
- Secale e.g. Secale cereale
- Triticum e.g. Triticum aestivum
- Dactylis e.g. Dactylis glomerata
- Festuca ⁇ e.g.
- Festuca elatior ; Poa (e.g. Poa pratensis or Poa compressa) ; Avena (e.g. Avena sativa) ; Holcus (e.g. Holcus lanatus); Anthoxcintbum (e.g. Anthoxanthum odoratum) ; Arrhenatherum (e.g. Arrhenatherum elatius); Agrostis (e.g. Agrostis alba); Phie ⁇ m (e.g. Phle ⁇ m pratense) ; Phalaris (e.g. Phalaris ar ⁇ ndinacea) ; Paspalum (e.g. Paspalum noratum) ; Sorghum (e.g. Sorgnum halepensis) ; and 3romus (e.g. 3romus ir.ermis).
- Avena e.g. Avena sativa
- Holcus e.g
- said anc igen is encoded by an heterologous nucleotide sequence and is expressed in vivo by a recombinant vector.
- the heterologous nucleotide sequence of the present invention encodes one or more of ail or part of the following an t igens HBV-PreSl PreS2 and Surface env proteins, core and polHIV- gpl20 gp40,gpl60, p24, gag, pol, env, vif, vpr, vpu, tat, rev, nef; HPV-El, E2, E3, E4, E5, E6, El, E8, Ll, L2 (see for example WO 90/10459, WO 98/04705, WO 99/03885); HCV env protein El or E2, core protein, NS2, NS3, NS4a f NS4b, NS5a, N35b, p7 (see for example WO2004111082 , WO2005051420 ) ; Muc-1 (see for example US 5,861,381; US6, 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.
- HPV antigen encoded by the recombinant vector according to the invention is selected in the group consisting of an HPV ⁇ 6 polypeptide, an HPV E7 polypeptide or both an HPV E6 polypeptide and an HPV E7 polypeptide.
- the 5 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 lea ⁇ t significantly reduced ⁇ Munger et al., 1989, EMBO J. 8, 4099-
- HPV-16 E6 variant which is suitable for the purpose of the present invention is deleted of one or more amino acid residues
- 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
- HPV-I 6 early polypeptide (s) in use in the invention is/are further modified so as to improve MHC class 1 and/or MHC class ⁇ I presentation, and/or to stimulate anti-HPV immunity.
- HPV E6 and ⁇ 7 polypeptides are nuclear proteins ana
- membrane presentation permits to improve their therapeutic efficacy (see for example WG99/03885) .
- 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).
- Tney usually comprise 15 uo 35 essentially hydrophobic amino acids which are then removed by a specific ER-Iocated en ⁇ opepnidase ⁇ o give the mature polypeptide.
- Membrane- ancncring sequences are usually highly hydrophobic in nature and serves to anchor the polypeptides m the cell membrane
- 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-terrninus downstream of the codon for initiation of translation and thar 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.
- the 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 5 3 miTiunoporentiator polypeptide (s ).
- a polypeptide such as calreticulin (Cheng et ai., 2001, J. Clin, Invest. 108, 669-678), Mycobacterium tuberculosis heat snock procein 70 (HSP70) (Chen et al . , 2000, Cancer Res. 60, 10 1035-1042), ubiquitin ⁇ Rodriguez et al., 1997, J. Virol.
- 15 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.
- 20 sai ⁇ heterologous nucleotide sequence of the present invention encodes all or part of MUC 1 antigen or derlvates thereof.
- said heterologous nucleotide sequence of the present inventdon is said heterologous nucleotide sequence of the present inventdon
- heterologous nucleotide sequence of the present invention encodes one or more fusion protein wherein
- the configuration is not native m the sense that at least one of the NS polypeptides appears in an order which i s distinct from that of the native configuration.
- the native configuration would be H53-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 ai least one of the followings:
- each of the NS polypeptides can be independently native or modified.
- the NS4A polypeptide included in the NS4/- ⁇ -NG3 portion can be native whereas the NS3 polypeptide comprises at i east one of the modifications described below.
- r.ne nucleic acid molecule in use m the invention may be optimized for providing high level expression of the targeted antigen (e.g. HPV early polypeptide ( s )) in a particular host ceil or organism, e.g. a hurran 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
- the term "recombinant vector” refers tc 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) .
- extrachromosomal e.g. episome
- multicopy and integrating vectors i.e. for being incorporated into the host chromosomes
- vectors for use in gene therapy i.e. which are capable of delivering the nucleic acid to a host organism
- expression vectors for use in various expression systems are particularly important in the context of the invention.
- Suitable non viral vectors include plasmids such as pREP4, pCEP4 ( Invitrogene) , pCI (Promega), pCDM8 (Seed, 1987, Nature 329, 840), pVAX and pgWiz (Gene Therapy System Inc; Himoudi et al., 2002, J. Virol. 76, 12735-12746).
- 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 "viral vector” encompasses vector DNA/RNA as well as viral particles generated thereof.
- ViraJ vectors can be i ep] ication-competent , or can be genetically disabled so as to be replication-defective or replication-impaired.
- replication-competent 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. Curlel 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 Ad5
- Ad6 Ad6
- 11 AdIl
- 24 Ad24
- 35 Ad35
- 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,
- they can be engineered from a wild-type adenovirus genome by deletion in the ElA CR2 domain (see for example WO00/24408) and/or by replacement of the native El and/or E4 promoters with tissue, tumor or cell status-specific promoters (see for example " JS 5,998,20s, WO99/25860, US 5,698,443, WO00/46355,
- 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 El- defective (see for example US 6,136,594 and US 6,013,638), with an Ei 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 5 of the non. essential E3 region or of other essential E2, KA regions) .
- Insertion of a nacieic aci ⁇ in any location of the adenoviral vecror can be performed through homologous recombination as described in Charrier et al. (1996, J. Virol. 70, 4805-4810) .
- ⁇ ,he nucleic acid encoding 10 the HPV- 16 E6 polypeptide can be inserted in replacement of the El region and the nucleic aci ⁇ encoding the FPV-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
- suitable vaccinia viruses include without limitation the Copenhagen strain (Goebel et al., 1990, Virol. 179, 247-266
- the vector may also be obtained from any other member of the poxviridae, in particular fowlpox (e.g. TROVAC, see Paoletti et al, 1995, Dev Biol Stand., 84, 159-163); canarypox (e.g. ALVAC, WO 95/27780, Paoletti et al, 1995, Dev Biol Stand., 84, 159-
- fowlpox e.g. TROVAC, see Paoletti et al, 1995, Dev Biol Stand., 84, 159-163
- canarypox e.g. ALVAC, WO 95/27780, Paoletti et al, 1995, Dev Biol Stand., 84, 159-
- said virus can be a replication competent poxvirus, especially replication competent vaccinia virus .
- replication competent poxvirus especially replication competent vaccinia virus .
- examples of these virus are provided m WO9531105 (e.g. products JX594, VV TK- GMCSF or JX963, VV TK- VGF- GMCSF), WO0073479, WO2009/06b547, WO2009/065546.
- the nucleic acid encoding she antigen of the Invention is preferably inserted in a nonessential locus of the poxviral genome, in order that L"he recombinant poxvirus remains viable and infectious.
- Nonessential regions are non- coding intergenic regions or any gene for which inactj vation or deletion does not significantly impair viral growth, replication or infection.
- the antigen- encoding nucleic acid is preferably inserted in the thymidine 5 kinase gene (tic) (Hruby et al., 1983, Proc. Natl. Acad. Sci USA 80, 3411-3415 ; Weir et al., 1983, J. Virol. 46, 530- 537).
- tic thymidine 5 kinase gene
- other insertion sites are also appropriate, e.g. in the hemagglutinin gene (Guo et al., 1989, J. Virol. 63, 4189-4198), in the KlL locus, in the u gene (Zhou et al.,
- the antigen-encoding nucleic acid can be inserted in any one of the identified deletions I TO VII as
- 25 nucleic acid is preferably introduced in the intergenic region situated between ORFs 7 and 9 (see for example EP 314
- said recombinant vector is a recombinant plasmid DNA or a recombinant viral 30 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 m a form suitable for its expression in a host cell or organism, whicn 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, conirio ⁇ tes or modulates the expression of a nucleic acid m 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 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 whicn it is operatively linked.
- the gene expression sequence may, for example, be a mammalian or viiai promoter, such as a constitutive or inducible promoter.
- Constitutive mammalian promoters include, but are not 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 adenosine deaminase
- pyruvate kinase pyruvate kinase
- b-actin promoter b-actin promoter
- Exemplary viral promoters which function constitutively in eukaryotic cells include, for example, promoters from the cytomegalovirus (CMV) , simian virus (e.g., SV40), 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., SV40
- papilloma virus e.g., SV40
- HSV40 human Immunodeficiency virus
- HSV40 human Immunodeficiency virus
- Rous sarcoma virus Rous sarcoma virus
- cytomegalovirus cytomegalovirus
- LTR long terminal
- Inducible promoters are expressed in the presence of an inducing agent.
- the metal lothionein 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, p23, pll and KIT.., chimeric promoters between early and late poxviral promoters as well as synthetic promoters such as those described in Chakrabarti et al. (1997, Biotechnlques 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 a ⁇ RSV, SV40, CMV and MLP promoters.
- Preferred promoters for use in a poxviral vector include without limitation vaccinia promoters 7.5K, H5R, TK, p28, pll and KIL, chimeric promoters between early and late poxviral promoters as well as synthetic promoters such as those described In Chakrabarti et al. (1997, Bi otechn Lques 23, 1094-1097), Hammond et al. (1997, J, Virologies! Methods 66, 135-138) and Kumar and Boyle (1990, Virology 179, 351-158).
- 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 farther 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. 15 "1 Ny, INF ⁇ ) , with a special preference for mterieukin IL-2.
- the recombinant vaccine of the invention comprises a cytokine-expressing nucleic acid
- said nucleic acid may be carried by tne recombinant vector encoding the one or more antigen (s) or by an independent recombinant vector which can De of the same or a different origin.
- the recombinant vector in use in the present invention is encoding all or part of the MUCi antigen and at least one cytokines above listed, and preferably an ⁇ nterleukin, especially IL2,
- the recombinant vector in use in the present invention is an MVA encoding ail or part of the MUCi antigen and at least one cytokines above listed, and preferably an inr.erleuk.in, especially 11,2.
- Infectious viral particles comprising the above- described recombinant viral vector can be produced by routine process.
- Rn 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, US 6,127,175.
- Cells appropriate for propagating poxvirus vectors are avian cells, ana most preferably primary chicken embryo fibroblasts (C ⁇ E" ⁇ prepared from chicken embryos obtained from fertilized eggs.
- the infectious viral particles may be recovered frcm 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 pat Lenr. for human disease human disease according io 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 chemothera sufficientlyic agent is done concomitantly with administ rar 1 on of said immunogenic composition.
- said chemotherapeutic agent is cisplatin and/or Gemcitabine, or similar.
- the present Invention further concerns a method of improving cytotoxic effectiveness of cytotoxic drugs (i.e. chemotherapeutic agent ⁇ or radiotherapy which comprises co- treating a patient selected in a patient population composed of patients that have low ILlO/IFN ⁇ ratio with an immunogenic composition according to the Invention.
- cytotoxic drugs i.e. chemotherapeutic agent ⁇ or radiotherapy
- the method or use of immunogenic composition of the invention is carried out according to a prime boost therapeutic modality which comprises sequential administration of: one or more primer compos It " i on (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 immunogenic composition is initially administered to ⁇ he host organism and the boosting immunogenic composition is subsequently administered to the same host organism after a period varying from one day to tv/elve 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 desired clinical benefit is independent of a demonstrable immune response to the vaccine.
- 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, vicai cancer, prostate cancer, nori Small cell Lung Cancer, haematological cancecs, 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 HTV, HCV, HBV, HPV, and the like.
- an immunogenic composition comprising ail or part of a targeted antigen for the manufacture of a medicament for treat inq a patient for human disease in a particular patient; population wherein the patients of said population have low ILl 0/IF 1 NY ratio.
- 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 ILlO/IFN ⁇ ratio.
- 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 ILlO/IFN ⁇ ratio.
- an immunogenic composition for the manufacture of a medicament for inducing an immune response to a targeted antigen (j . e. the raised immune response) m a patient for treating human disease in a particular patient population wherein the patients of said population have low ILlO/IFN ⁇ ratio.
- 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 J ow ILlO/IFN ⁇ ratio 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 anrigen.
- said "raised immune response” in said patient population is directed towards distinct antigens.
- said "raised immune response” in said patient population is directed towards all or part of MUCl antigen.
- said "raised immune response” in said patient population is T ceil immune response, and preferably CD8+ (Cytotoxic T Lymphocytes) immune response.
- said "raised immune response" in said patient: population is a non specific immune response or an immune response to disease associated antigens not contained in the vaccine formulation or an immune response to disease associated antigens which is not measureable by current techniques.
- said "raised immune response” in said patient population is a stimulation of the innate immune response .
- the ability to induce or stimulate ar. 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 arr..
- assays which are standard in the arr..
- 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.
- IL-IO or IFN gamma-producing cells by ELIspot
- determination of the activation status of immune effector cells e.g. T cell proliferation assays by a classical [ 3 Hl thymidine uptake
- assaying for antigen- specific T lymphocytes in a sensitized patient e.g. pepfi ⁇ e- specific lysis in a cytotoxicity assay
- detection of antigen specific T ceils e.g. tetramers.
- the ability to stimulate a humoral response may be determined by antibody binding and/or competit Lon 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. MUCl-express: ng murine tumor ceils cells) co determine antitumor activity, reflecting an induction or an enhancement of an anti-antigen immune response.
- an appropriate tumor-inducing agent e.g. MUCl-express: ng murine tumor ceils cells
- 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, 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 ILlO/IFN ⁇ ratio as a biomarker for predicting whether a patient is or is not susceptible to developing prophylactic or therapeutic response, preferably immune response, by administration of an immunogenic composition.
- the present Invention relates to the use of ILlO/IFN ⁇ ratio as a biomarker for predicting whether a patient is or is nor su.sceptib] e "co developing prophylactic or therapeutic immune response by administration ot an immunogenic composition, wherein low ILlO/IE " Ny ratio indicates tnar. the patient is predicted to hcve an increased t-usceptibility zo develop a prophylactic or therapeutic response, preferably immune response,
- the present Invention relates to the use of the ILlO/IFN ⁇ ratio as a biomarker for predicting whether a patient is or is not susceptible to survive longer after administration of an immunogenic composition, wherein low ILlO/IFN ⁇ ratio indicates that the patient is predicted to have a longer survival rate compared to treated patients who have higher ILlO/IFN ⁇ ratio.
- the present invention relates to an ex- vivo method for predicting whether a patient is or is not susceptible to survive longer after administration of an immunogenic composition, wherein the testing method comprises the step of measuring levels of TLIO and INFy in a biological sample (e.g. blood or plasma or serum) from che patient, calculating ILlO/IFN ⁇ ratio, wherein low ILlO/TFN ⁇ ratio indicates chat the patient will have a longer survival race.
- a biological sample e.g. blood or plasma or serum
- Trius tne Invention further concerns the use of the ILlO/IFN ⁇ ratio as a biomarker for predicting whether a patient which is undergoing chemotherapeutic treatment with a cheinotherapeutic 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 IL10/IFN ⁇ ratio 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 IT 10/IE 1 N/ ratio indicates that the patient Is predicted to have an increased susceptibility to develop a prophylactic or therapeutic immune response.
- Tne present Invention thus relates to a method for improving the treatment of a cancer patient which is undergoing chemotnerapeutic treatment with a chemotherapeutic agent, 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 levels of ILlO and IFNy. Such reagents may include antibodies.
- the kits may further include equipment for collecting an ⁇ /or processing biological samples.
- the kits are also likely to contain instructions for use, cut-off values (see above) 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, levels of ILlO and IFN ⁇ and ILlO and IFN ⁇ ratio, determining whether such ratio are above or below a threshold level, and/or recommending treatment to improve a patient's response to an immunotherapy treatment.
- the computer programs or algorithms may be provided aJ ong 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 ILlO and IFN ⁇ present therein and calculate ILlO and TFN ⁇ ratio.
- 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. Use of levels of ILlO and INF ⁇ in the generation of an algorithm for recommending modification to a treatment to improve patient' s response io immunotherapy treatment by immunogenic composition.
- Fig-ure 1 Survival curves describing vaccine immunotherapy in lung cancer: patients with a ratio of plasma IL-10/I FNg ⁇ or > 3.7, prior to treatment
- Figure 2 Survival curves describing chemotherapy in lung cancer: patients with a ratio of plasma IL ⁇ 10/IFNg ⁇ or > 3.7 prior to treatment.
- Example 1 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 MUCl (see Rochlitz et al., 2003, J. Gene Med. r 5, 690-699).
- MVA Modified Virus Ankara
- PFS progression-free survival
- Blood samples were taken prior to treatment on day 1 (first day of treatment) and were shipped immediately to a central immunology lab where plasma was isolated and stored frozen until analysis.
- Plasma samples were assessed, at a central laboratory for cytokines, using a Luminex mutli-analyte profiling system.
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BR112012000522A BR112012000522A2 (en) | 2009-07-10 | 2010-07-06 | ex vivo method for testing whether a patient will respond therapeutically to a treatment method, use of the il10 / ifnt ratio as a biomarker, kit for testing whether a patient will therapeutically respond to a treatment method, and ex vivo method for predicting whether whether or not a patient is likely to survive longer after administration of an immunogenic composition |
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TW201105970A (en) | 2011-02-16 |
RU2552292C2 (en) | 2015-06-10 |
CN102483405B (en) | 2015-12-02 |
BR112012000522A2 (en) | 2016-02-16 |
TWI529392B (en) | 2016-04-11 |
AU2010270313B2 (en) | 2014-05-22 |
JP5650212B2 (en) | 2015-01-07 |
CN102483405A (en) | 2012-05-30 |
IL216083A (en) | 2015-04-30 |
EP2452194B1 (en) | 2015-11-11 |
HUE028240T2 (en) | 2016-12-28 |
DK2452194T3 (en) | 2015-11-30 |
ZA201200110B (en) | 2012-10-31 |
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JP2012533052A (en) | 2012-12-20 |
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