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WO2019164870A1 - Expression d'arnm de signature pour l'identification de patients sensibles au traitement par anticorps anti-pd-l1 - Google Patents

Expression d'arnm de signature pour l'identification de patients sensibles au traitement par anticorps anti-pd-l1 Download PDF

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WO2019164870A1
WO2019164870A1 PCT/US2019/018674 US2019018674W WO2019164870A1 WO 2019164870 A1 WO2019164870 A1 WO 2019164870A1 US 2019018674 W US2019018674 W US 2019018674W WO 2019164870 A1 WO2019164870 A1 WO 2019164870A1
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cancer
mrna
patient
patients
durvalumab
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Brandon Higgs
Koustubh Ranade
Philip Brohawn
Christopher MOREHOUSE
Katie Streicher
Rajiv Raja
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MedImmune LLC
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MedImmune LLC
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • Tumors can negatively regulate the immune response by modulating inhibitory cell surface receptors to instill T cell exhaustion. Sustained expression of these receptors imparts a dysfunctional T cell state, which reduces effector and subsequent antitumor function (Wherry 2011). Patients who over-express the immune-checkpoint protein PD-L1 as measured by immunohistochemistry (IHC) at baseline show greater clinical benefit to these therapies.
  • IHC immunohistochemistry
  • Durvalumab is a human monoclonal antibody (IgGl) which inhibits PD-L1 binding to PD-l and CD80, thereby restoring this T cell dysfunctional state and driving antitumor immunity.
  • the disclosure utilizes data from several clinical studies in UBC, NSCLC, SCCN (CP1108, Study 10, ATLANTIC, HAWK and CONDOR), and provides methods that comprise detecting expression levels of mRNAs associated with immune related cell populations including, for example, T cell exhaustion and suppressive cells.
  • the mRNA expression signature(s) is useful for classifying tumors and cancer disease, stratifying cancer patients for likely clinical response and allowing for administration of therapies that are more likely to be effective.
  • the methods also allow for modification of current therapies likely to be ineffective, in favor of alternative therapies that are likely to provide clinical improvement.
  • the disclosure relates to methods for treating cancer (e.g., lung cancer such as non small cell lung cancer, bladder cancer, solid tumors, and the like) with an anti-PD-Ll antibody in a patient identified as having a cancer that expresses one or more mRNAs associated with T cell exhaustion.
  • cancer e.g., lung cancer such as non small cell lung cancer, bladder cancer, solid tumors, and the like
  • the disclosure also provides methods for determining responsiveness of a cancer to therapeutic treatment that comprises an anti-PD-Ll antibody.
  • the disclosure further relates to methods for identifying cancer patients as candidates for a therapy comprising an anti-PD-Ll antibody.
  • the disclosure also relates to methods for identifying cancer patients having a cancer that is unlikely to be responsive to a therapy comprising an anti-PD-Ll antibody.
  • the disclosure generally provides a method of treating cancer in a patient comprising administering an anti-PD-Ll antibody, or an antigen binding fragment thereof, to the patient, wherein the patient is identified for treatment by detecting in a sample obtained from the patient at least one mRNA associated with T cell exhaustion.
  • the disclosure generally provides a method for characterizing the responsiveness of a cancer in a subject to an anti-PD-Ll antibody treatment, the method comprising: detecting expression level of at least one mRNA associated with T cell exhaustion in a sample obtained from the patient; comparing the expression level of the at least one mRNA associated with T cell exhaustion in the patient sample to a mean and/or median expression level of the same mRNA associated with T cell exhaustion in a reference cancer sample; and characterizing the cancer as responsive to anti-PD-Ll antibody treatment when the expression level of the mRNA in the patient sample is higher than the mean and/or median expression level of the same mRNA in the reference sample.
  • the disclosure generally provides a method of identifying a subject having a cancer responsive to an anti-PD-Ll antibody, the method comprising detecting the expression of at least one mRNA associated with T cell exhaustion in a sample obtained from the patient.
  • the disclosure provides methods wherein the at least one mRNA is selected from Programmed cell death protein 1 (PDCD1 ), Cluster
  • CD8A Lymphocyte-activation gene 3
  • LAG3 Lymphocyte-activation gene 3
  • CTLA4 cytotoxic T-lymphocyte- associated protein 4
  • EOMES Eomesodermin/Tbr2
  • CD56 Cluster of Differentiation 8a/ lymphocyte function-associated antigen 3
  • SLAMF8 signaling lymphocyte activation molecule family member 8
  • GNLY Granulysin
  • IL12 Interleukin- 12
  • MMP8 metalloproteinase-8
  • T-box transcription factor TBX21
  • the disclosure provides methods wherein the methods comprise detecting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from PDCD1, CD8A, LAG3, CTLA4, EOMES , CD56, SLAMF8, GNLY, IE12, and TBX21.
  • the methods comprise detecting PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IE12, MMP8 and TBX21.
  • the disclosure provides methods of treatment comprising administering an anti-PD-Ll antibody, or an antigen-binding fragment thereof, to a patient identified as having a solid tumor cancer (e.g., sarcoma, carcinoma, lymphoma) that expresses one or more mRNA markers disclosed herein.
  • the anti-PD-Ll antibody is durvalumab.
  • the disclosure provides a method of treatment comprising administering durvalumab or an antigen binding fragment thereof to a patient identified as having a lung cancer (e.g., non-small cell lung cancer (NSCLC)) or bladder cancer (e.g., urothelial bladder cancer (UBC)).
  • the NSCLC is squamous cell carcinoma, non-squamous cell carcinoma, adenocarcinoma, large cell carcinoma,
  • adenosquamous carcinoma or sarcomatoid carcinoma adenosquamous carcinoma or sarcomatoid carcinoma.
  • the disclosure provides methods that further comprise detecting expression of PD-L1 in a tumor sample obtained from the subject.
  • the disclosure provides methods that identify a subject having a lung cancer responsive to an anti-PD-Ll therapy, comprising detecting the expression of mRNAs comprising PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21 in a sample obtained from the subject.
  • the disclosure provides methods that identify a subject having a bladder cancer responsive to an anti-PD-Ll therapy, comprising detecting the expression of mRNAs comprising PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21 in a sample obtained from the subject.
  • the patient is identified as having a cancer responsive to durvalumab.
  • the patient is further identified as having a tumor expressing PD-L1.
  • treatment may comprise administration of at least about 0.1, about 0.3, about 1, about 3, about 10, or about 15 mg/kg durvalumab, or an antigen-binding fragment thereof. In other embodiments, at least about 1 mg/kg, 3 mg/kg, 10 mg/kg, or 15 mg/kg durvalumab, or an antigen-binding fragment thereof, is administered. In other embodiments, the administration is repeated about every 14 or 21 days. In other embodiments, at least two, three, four, or five doses is administered.
  • the disclosure provides a method for characterizing the
  • responsiveness of a cancer in a subject to an anti-PD-Ll antibody treatment comprising: detecting expression level of at least one mRNA associated with suppressive cells in a sample obtained from the patient; comparing the expression level of the at least one mRNA associated with suppressive cells in the patient sample to a mean and/or median expression level of the same mRNA associated with T suppressive cells in a reference cancer sample; and characterizing the cancer as non-responsive to anti-PD-Ll antibody treatment when the expression level of the mRNA in the patient sample is higher than the mean and/or median expression level of the same mRNA in the reference sample.
  • the disclosure generally provides a method of identifying a subject having a cancer that is non-responsive to an anti-PD-Ll antibody, the method comprising detecting the expression of at least one mRNA associated with suppressive cells in a sample obtained from the patient.
  • the disclosure provides methods wherein the at least one mRNA is selected from arginase 1 ( ARG1 ), interleukin- 10 (IL10 ), matrix
  • MMP8 metalloproteinase-8
  • TGFB1 transforming growth factor beta 1
  • the disclosure provides methods wherein the methods comprise detecting at least two or at least three mRNAs selected from AKGI, IL10, and TGFB1. In yet further embodiments, the methods comprise detecting AKGI, IL10, and TGFB1. In further embodiments, the methods comprise detecting AKGI, IL10, MMP8 and TGFB1
  • the disclosure provides methods that further comprise detecting expression of PD-L1 in a tumor sample obtained from the subject.
  • the disclosure provides a method of identifying a subject having a cancer that is responsive to an anti-PD-Ll antibody, the method comprising detecting in a sample obtained from the patient (i) the expression of at least one mRNA associated with T cell exhaustion; and (ii) detecting a decrease or no expression of at least one mRNA associated with suppressive cells.
  • the disclosure provides a method that comprises (i) detecting the expression of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, Sand TBX21 ; and (ii) detecting decreased or no expression of one, two, or three mRNAs selected from ARG1, IL10, MMP8 and TGFB1.
  • the methods identify a patient having a solid tumor cancer (e.g., sarcoma, carcinoma, lymphoma) that expresses one or more suppressive cell mRNA markers disclosed herein.
  • the method identifies patient having a non-responsive lung cancer (e.g., non-small cell lung cancer (NSCLC)), non-responsive head and neck cancer (e.g., squamous cell carcinoma of the head and neck, (SCCHN)), or non-responsive bladder cancer (e.g., urothelial bladder cancer (UBC)).
  • the non- responsive NSCLC is squamous cell carcinoma, non-squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma or sarcomatoid carcinoma.
  • “ATLANTIC” means A Global Study to Assess the Effects of MEDI4736 (Durvalumab) in Patients With Locally Advanced or Metastatic Non Small Cell Lung
  • “Study 10” means A Phase II Study of Durvalumab (MEDI4736) (Anti-PD-Ll Antibody) in Combination with Tremelimumab (Anti-CTEA-4 Antibody) in Subjects with Advanced Rare Solid Tumors (ClinicalTrials.gov Identifier: NCT02938793).
  • Anti-PD-Ll antibody means an antibody or antigen binding fragment thereof that selectively binds a PD-L1 polypeptide. Exemplary anti-PD-Ll antibodies are described for example at U.S. Patent Nos. 8,779,108 and 9,493,565, which are herein incorporated by reference.
  • Durvalumab is an exemplary PD-L1 antibody. Following successful treatment with durvalumab, a patient achieves disease control (DC). Disease control can be a complete response (CR), partial response (PR), or stable disease (SD).
  • a "complete response" refers to the disappearance of all lesions, whether measurable or not, and no new lesions. Confirmation can be obtained using a repeat, consecutive assessment no less than four weeks from the date of first documentation. New, non-measurable lesions preclude CR.
  • a "partial response" refers to a decrease in tumor burden > 50% relative to baseline. Confirmation can be obtained using a consecutive repeat assessment at least 4 weeks from the date of first documentation.
  • PD Progressive disease
  • Stable disease refers to not meeting the criteria for CR, PR, or PD. SD indicates a decrease in tumor burden of 50% relative to baseline cannot be established and a 25% increase compared to nadir cannot be established.
  • T cell exhaustion can include any mRNA that is expressed during a state of T (or NK) cell dysfunction that arises during chronic infections and/or cancer.
  • T cell exhaustion is often defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells.
  • Non-limiting examples of mRNAs associated with T cell exhaustion include mammalian mRNA encoded by the genes programmed cell death protein 1 (PDCD1 ; or PD-1 ); Cluster of Differentiation 8a ( CD8A ); Lymphocyte-activation gene 3 ( LAG3 ); cytotoxic T-lymphocyte-associated protein 4 ( CTLA4) Eomesodermin/Tbr2 ( EOMES ); Cluster of Differentiation 8a, or lymphocyte function-associated antigen 3, ( CD56 ), signaling lymphocyte activation molecule family member 8 ( SLAMF8 ), Granulysin ( GNLY ), Interleukin- 12 ( IL12 ), matrix metalloproteinase- 8 ( MMP8 ) and T-box transcription factor ( TBX21 ).
  • PDCD1 programmed cell death protein 1
  • PD-1 programmed cell death protein 1
  • CD8A Cluster of Differentiation 8a
  • LAG3 Lymphocyte-activation gene 3
  • CTLA4 cytotoxic
  • PDCD1 Programmed cell death protein 1
  • PD-1 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_0050l8.
  • Cluster of Differentiation 8a refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_0050l8.
  • Lymphocyte-activation gene 3 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_002286.
  • Cytotoxic T-lymphocyte-associated protein 4 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_00l03763l or NM_0052l4.
  • Eomesodermin/Tbr2 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_005442. NM_001278183, or NM_001278182.
  • Neural cell adhesion molecule or (NCAM) refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_0006l5, NM_181351, NM_001076682, NMJ301242607, or NMJ301242608.
  • SLAMF8 Signaling lymphocyte activation molecule family member 8 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NMJ320125 or NM 001330741.
  • Granulysin refers to an mRNA, or fragment thereof, that has at least about
  • Interleukin- 12 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_000882 or NM_002l87.
  • T-box transcription factor refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_0l335l.
  • the methods discussed herein refer to“mRNA associated suppressive cell(s)” and can include any mRNA that is expressed and associated with an immune cell that can function as a suppressor cell, which may be associated with chronic infections and/or cancer.
  • suppressor cells include regulatory T cells (e.g., those that express CD4, CD25, and FQXP3), CD4+CD25+ regulatory T cells, and myeloid-derived suppressor cells (MDSC).
  • mRNAs associated with suppressive cells include mammalian mRNA encoded by the genes arginase 1 ( ARG1 ), interleukin- 10 ( IL10 ), and transforming growth factor beta 1 ( TGFB1 ).
  • Arginase 1 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NMJ300045, or NMJ301244438.
  • Interleukin- 10 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_000572.
  • Transforming growth factor beta 1 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NM_000660.
  • Matrix metalloproteinase-8 refers to an mRNA, or fragment thereof, that has at least about 85%, 95%, or 100% identity to NCBI Accession No. NC_0000l l.
  • PD-L1 polypeptide is meant a polypeptide or fragment thereof having at least about 85%, 95% or 100% amino acid identity to NCBI Accession No. NP_00l254635 and having PD-l and CD80 binding activity.
  • antibody refers to an immunoglobulin or a fragment or a derivative thereof, and encompasses any polypeptide comprising an antigen binding site, regardless whether it is produced in vitro or in vivo.
  • the term includes, but is not limited to, polyclonal, monoclonal, monospecific, polyspecific, non-specific, humanized, single chain, chimeric, synthetic, recombinant, hybrid, mutated, and grafted antibodies.
  • the term“antibody” also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen -binding function, i.e., the ability to bind PD-L1 specifically. Typically, such fragments would comprise an antigen-binding domain.
  • the terms“antigen-binding domain,”“antigen-binding fragment,” and“binding fragment” refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen. In instances, where an antigen is large, the antigen-binding domain may only bind to a part of the antigen. A portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as“epitope” or“antigenic determinant.”
  • An antigen-binding domain typically comprises an antibody light chain variable region (V L ) and an antibody heavy chain variable region (V H ), however, it does not necessarily have to comprise both. For example, a so-called Fd antibody fragment consists only of a V H domain, but still retains some antigen-binding function of the intact antibody.
  • Antibodies of the invention comprise without limitation whole native antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and unconventional antibodies.
  • sample is meant a biological sample derived from any tissue, cell, fluid, or other material derived from an organism.
  • a biological sample is a blood or plasma sample.
  • A“biomarker” or“marker” as used herein typically refers to mRNA associated T/NK cell exhaustion, or to mRNA associated with suppressive cells, and may be detected in a subject having a cancer.
  • an mRNA marker comprises expression of a gene in a patient having a cancer.
  • an mRNA marker is differentially present in a biological sample obtained from a subject having a disease (e.g., lung cancer) relative to the level present in a control sample or reference.
  • an mRNA marker is differentially present in a biological sample obtained from a subject prior to treatment of a disease (e.g., lung cancer) relative to the level present in a sample obtained from the same subject during or after treatment of a disease.
  • the methods disclosed herein comprise detection of mRNA markers and may include detection of the total number of mRNA counts for a particular marker or set of markers, detection of the mean mRNA marker, detection of a change in the mean mRNA marker, and/or detection of the median mRNA for a particular marker or set of markers, or detection of the presence of a particular mRNA marker or set of mRNA markers. Accordingly, in any of the aspects and embodiments disclosed herein, methods include detection of the presence, number, mean, median, or change in frequency of one or more of the mRNA markers.
  • Detect refers to identifying the presence, absence or amount of the analyte to be detected, which in the various aspects and embodiments disclosed herein, comprises mRNA.
  • mRNA markers i.e., mRNAs associated with T cell exhaustion or suppressive cells
  • the detection of mRNA markers can be used to assess the mean expression level, total expression level, and/or median expression level, in a patient who may be selected for cancer treatment.
  • the detection of mRNA may be performed on samples that are derived from a patient once, or at plurality of time points.
  • patient samples may be obtained prior to treatment (e.g., during screening and diagnosis), during treatment (e.g., prior to or following administration of a therapeutic dose), and/or following the course of treatment.
  • the disease is typically a cancer such as, for example, a solid tumor cancer.
  • the cancer may include lung cancer, bladder cancer, and/or head and neck cancer.
  • Lung cancer includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • Head and neck cancer includes squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, oral and oropharyngeal cancer, and salivary gland cancer.
  • Bladder cancer includes urothelial carcinoma (also called transitional cell carcinoma), squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell anaplastic cancer.
  • isolated refers to material that is free to varying degrees from components which normally accompany it as found in its native state.
  • subject is meant a mammal, including, but not limited to, a human or non human mammal, such as a bovine, equine, canine, ovine, or feline.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
  • the terms“treat,” treating,”“treatment,” and the like refer to reducing, ameliorating, or slowing the progression of a disorder or disease and/or symptoms associated with a disorder or disease. It will be appreciated that, although not precluded, treating a disorder, disease, or condition does not require that the disorder, disease, or condition or associated symptoms be completely eliminated.
  • the term“about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • FIGURE 1 provides analysis showing improvement in overall survival (OS) upon anti-PD-Ll antibody (durvalumab) treatment in TNK mRNA signature positive (22.7 months) and PDL1 positive (19.2 months) NSCLC patients relative to TNK negative (5.7 months) and PD-L1- (7.5 months) patients.
  • OS overall survival
  • durvalumab anti-PD-Ll antibody
  • FIGURE 2A-2B statistical analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in progression free survival (PFS) in TNK mRNA signature positive NSCLC patients relative to negative patients (2A), and in PD-L1+ patients relative to PD-L1- patients (2B).
  • FIGURE 3 multivariate Cox PH regression model HRs and 95% CIs for overall survival among baseline clinical covariates in NSCLC patients.
  • FIGURE 4 provides analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive (18.4 months) and PDL1+ (20.3 months) UBC patients relative to TNK negative (8.2 months) and PDL1- (5 months) patients.
  • FIGURE 5A-5B statistical analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in progression free survival (PFS) in TNK mRNA signature positive UBC patients relative to negative patients (5A), and showing no statistical difference in PD-L1+ patients relative to PD-L1- patients (5B).
  • FIGURE 6 multivariate Cox PH regression model HRs and 95% CIs for overall survival among baseline clinical covariates in UBC patients.
  • FIGURE 7 provides analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive (14.1 months) in NSCLC (Stage IIIB-IV) patients relative to TNK negative (6 months). PD-L1 as measured by IHC is also provided for comparison.
  • FIGURE 8A-8B statistical analysis and validation of TNK signature in Phase 2 clinical trial showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in progression free survival (PFS) in TNK mRNA signature positive UBC patients relative to negative patients (8A), and showing no statistical difference in PD-L1+ patients relative to PD- Ll- patients (8B).
  • FIGURE 9 multivariate Cox PH regression model HRs and 95% CIs for overall survival among baseline clinical covariates in Phase 2 NSCLC patients.
  • FIGURE 10 statistical analysis of TNK mRNA signature applied to previously published study involving 108 NSCLC patients with tumor stages I-IIIA who underwent surgical resection.
  • FIGURE 11 multivariate Cox PH regression model HRs and 95% CIs for overall survival among baseline clinical covariates from previously published study referenced in Figure 10.
  • FIGURE 12 provides training/discovery cohort analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive (10.1 months) SCCHN patients relative to TNK negative (5.1 months). PD-L1 as measured by IHC is also provided for comparison.
  • FIGURE 13 provides test/validation cohort analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive (10.4 months) SCCHN patients relative to TNK negative (6.8 months). PD-L1 as measured by IHC is also provided for comparison.
  • FIGURE 14 provides analysis showing improvement upon combination treatment with anti-PD-Ll antibody (durvalumab) and anti-CTLA4 antibody (tremelimumab) in overall survival (OS) in TNK mRNA signature positive (9.4 months) SCCHN patients relative to TNK negative (4.2 months) (all patients exhibiting PDL1- tumors).
  • FIGURE 15A-C show that high expression levels of the TNK mRNA signature correlates with overall response rate on durvalumab in clinical trials for three different cancers (NSCLC - 15A; and SCCHN -15B; and UBC -15C).
  • ORR overall response rate
  • FIGURE 16 provides analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive patients (24 months; 9.5 months) for NSCLC patients having the same neutrophil to lymphocyte ratio (NLR) positive/negative status (18.7 months; 4.2 months).
  • OS overall survival
  • NLR neutrophil to lymphocyte ratio
  • FIGURE 17 provides analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive patients (17.4 months; 8.3 months) for SCCHN patients having the same neutrophil to lymphocyte ratio (NLR) positive/negative status (6.4 months; 6 months).
  • OS overall survival
  • NLR neutrophil to lymphocyte ratio
  • FIGURE 18 provides analysis showing improvement upon anti-PD-Ll antibody (durvalumab) treatment in overall survival (OS) in TNK mRNA signature positive patients (18.4 months; 4.7 months) for UBC patients having the same neutrophil to lymphocyte ratio (NLR) positive/negative status (NR; 3.6 months).
  • OS overall survival
  • NLR neutrophil to lymphocyte ratio
  • FIGURE 19A-B provide analysis showing mono- (19A) and combination (19B) anti- PD-Ll antibody (durvalumab) treatments in overall survival (OS) in TNK mRNA signature positive SCCHN patients.
  • OS overall survival
  • durvalumab anti- PD-Ll antibody
  • TNK signature positive or negative patients there is no significant difference between TNK signature positive or negative patients among low NLR patients (B)
  • TNK signature positive patients had OS of (NR) and 9.6 months relative to (NR) and 4.7 months for signature negative patients with the same neutrophil to lymphocyte ratio (NLR)
  • FIGURE 20A-B provide analysis showing anti-PD-Ll antibody (durvalumab) treatment on overall survival (OS) in (A) PDL1 and NLR positive and negative status NSCLC patients and (B) combined PDL1 and NLR status.
  • PDL1+ and NLR- patients had OS of 19.2 months and 23.4 months relative to 7.5 months and 5.4 months for PDL1- and NLR+ patients, respectively.
  • NLR- patients had OS of 24.5 months and 14.2 months relative to 5.6 months and 4.3 months for NLR+ patients with the same PDL1 positive/negative status.
  • FIGURE 21A-C show that high expression levels of suppressive cell mRNA signature associates with overall response rate on durvalumab in clinical trials for three different cancers (NSCLC - 21A; UBC -21B; and SCCHN -21C).
  • Suppressive cell signature positive NSCLC patients have OS of 5.6 months relative to 21.1 months for signature negative patients, with PDL1+/- patients exhibiting OS of 19.2 months and 7.5 months, respectively.
  • B Suppressive cell signature positive NSCLC patients have OS of 5.6 months relative to 21.1 months for signature negative patients, with PDL1+/- patients exhibiting OS of 19.2 months and 7.5 months, respectively.
  • Suppressive cell signature positive UBC patients have OS of 3.7 months relative to 20.3 months for signature negative patients, with PDL1+/- patients exhibiting OS of 20.3 months and 5 months, respectively.
  • Suppressive cell signature positive SCCHN patients have OS of 8.7 months relative to 11.1 months for signature negative patients, with PDL1+/- patients exhibiting OS of 9.7 months and 9.6 months, respectively.
  • FIGURE 22A-C show that high expression levels of suppressive cell mRNA signature associates with overall response rate on durvalumab in three clinical trials for SCCHN.
  • Suppressive cell signature positive SCCHN patients have OS of 4 months relative to 10.5 months for signature negative patients, with PDL1+/- patients exhibiting OS of 5.7 months and 7.1 months, respectively.
  • suppressive cell signature positive SCCHN patients have OS of 6.3 months relative to 12.2 months for signature negative patients, with PDL1+/- patients exhibiting OS of 8.6 months and 8.8 months, respectively.
  • C In a third clinical evaluation (durvalumab + trememlimumab) suppressive cell signature positive SCCHN patients have OS of 4 months relative to 11.5 months for signature negative patients.
  • FIGURE 23A-C show that high expression levels of suppressive cell mRNA signature and NLR status associates with overall response rate on durvalumab in three types of cancer.
  • Suppressive cell signature positive NSCLC patients have OS of 4.3 months and 14.2 months relative to 6.5 months and 24 months for signature negative patients with the same NLR+/- status.
  • Suppressive cell signature positive UBC patients have OS of 3.4 months and 14.3 months relative to (NR) and 20.3 months for signature negative patients with the same NLR+/- status.
  • Suppressive cell signature positive SCCHN patients have OS of 5.9 months and 14.1 months relative to 7.3 months and 13.2 months for signature negative patients with the same NLR+/- status.
  • FIGURE 24A-B show that high expression levels of suppressive cell mRNA signature and NLR status associates with overall response rate on durvalumab and durvalumab + tremelimumab in SCCHN cancer.
  • Suppressive cell signature positive patients treated with monotherapy have OS of 5.1 months and 6.4 months relative to 5.7 months and 14.3 months for signature negative patients with the same NLR+/- status.
  • Suppressive cell signature positive patients treated with combination therapy have OS of 3.7 months and 6.9 months relative to 11.5 months and (NR) for signature negative patients with the same NLR+/- status.
  • FIGURE 25A-B depicts gene expression as a heatmap and identifies the TNK and suppressive cell genes as anti-correlated to patient outcomes for durvalumab treatment.
  • FIGURE 26A-C show that the ratio of TNK signature: suppressive cell signature and NLR status associates with overall response rate on durvalumab monotherapy for (A) NSCLC, (B) UBC and (C) 3 rd line NSCLC.
  • FIGURE 27A-B show that the ratio of TNK signature: suppressive cell signature and NLR status associates with overall response rate on monotherapy (durvalumab) (A) and on combination therapy (durvalumab + tremelimumab) in SCCHN patients.
  • A Positive ratio of TNK:SCS in SCCHN patients on monotherapy have OS of 5.4 months and 14.3 months relative to 5.7 months and 6.4 months for negative ratio patients with the same NLR+/- status.
  • B Positive ratio of TNK:SCS in SCCHN patients on combination therapy have OS of (NA) and (NA) relative to 4.7 months and 5.1 months for negative ratio patients with the same NLR+/- status.
  • FIGURE 28 shows that a low suppressive signature ( ARGJ TGFB1, IL-10 and MMP8 ) prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients discovery.
  • OS overall survival
  • FIGURE 29 shows that a low suppressive signature ( ARGJ TGFB1, IL-10 and MMP8) prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients discovery.
  • OS overall survival
  • FIGURE 30 shows that a low suppressive signature ( ARG1 , TGFB1, IL-10 and MMP8 ) prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients discovery.
  • OS overall survival
  • FIGURE 31 shows that a low suppressive signature ( ARG1 , TGFB1, IL-10 and MMP8) prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients discovery.
  • OS overall survival
  • FIGURE 32 shows that a low suppressive signature ( ARG1 , TGFB1, IL-10 and MMP8) prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients’ discovery.
  • ARG1 , TGFB1, IL-10 and MMP8 prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients’ discovery.
  • OS overall survival
  • FIGURE 33 shows that a low suppressive signature (ARG1, TGFB1, IL-10 and MMP8) prior to treatment was associated with longer overall survival (OS) compared to high suppressive signature patients.
  • OS overall survival
  • CDR3 SEQ ID NOs: 3-5.
  • Tremelimumab light chain variable region amino acid sequence SEQ ID NO: 9
  • Tremelimumab heavy chain variable region amino acid sequence SEQ ID NO: 10.
  • CDR3 SEQ ID NOs: 11-13.
  • Tremelimumab light chain variable region amino acid sequence of CDR1, CDR2, and CDR3 SEQ ID NOs: 14-16.
  • the disclosure relates to the determination of expression of a signature panel of mRNAs that are detectable in blood samples obtained from a subject suffering from a cancer (e.g., solid tumor cancers, such as lung cancer or bladder cancer), which can be used to identify patients who are likely to respond to treatment with an anti-PD-Ll antibody.
  • a signature panel of mRNAs can be used to identify patients who are likely to be non-responsive to treatment with an anti-PD-Ll antibody.
  • the methods disclosed herein comprise detecting at least one mRNA from a gene associated with T/NK cell exhaustion and can be used to determine the responsiveness of a cancer to anti-PD-Ll antibody therapy.
  • the methods disclosed herein can also comprise detecting the presence or absence of at least one mRNA from a gene associated with suppressive cells and can be used to determine the (non)-responsiveness of a cancer to anti-PD-Ll antibody therapy.
  • the mRNAs can be used to provide mean and median mRNA expression thresholds in order to assess the likelihood of positive clinical response to therapy, or likelihood of a non-response to treatment, in patients to be evaluated and screened. Methods and assays utilizing mRNAs are convenient as they can be detected in blood samples and do not rely on biopsies or immunohistochemistry techniques applied to individual tissue and/or tumor samples.
  • B7-H1 also known as PD-L1
  • PD-L1 is a type I transmembrane protein of approximately
  • B7-H1 is expressed on a number of immune cell types including activated and anergic/exhausted T cells, on naive and activated B cells, as well as on myeloid dendritic cells (DC), monocytes and mast cells. It is also expressed on non-immune cells including islets of the pancreas, Kupffer cells of the liver, vascular endothelium and selected epithelia, for example airway epithelia and renal tubule epithelia, where its expression is enhanced during inflammatory episodes.
  • immune cell types including activated and anergic/exhausted T cells, on naive and activated B cells, as well as on myeloid dendritic cells (DC), monocytes and mast cells. It is also expressed on non-immune cells including islets of the pancreas, Kupffer cells of the liver, vascular endothelium and selected epithelia, for example airway epithelia and renal tubule epithelia, where its expression is enhanced during inflammatory episodes.
  • B7-H1 expression is also found at increased levels on a number of tumors including, but not limited to breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), and pancreatic cancer, as well as melanoma.
  • tumors including, but not limited to breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), and pancreatic cancer, as well as melanoma.
  • NSCLC non-small cell lung cancer
  • HCC hepatocellular cancer
  • pancreatic cancer pancreatic cancer
  • B7-H1 is known to bind two alternative ligands, the first of these, PD-l, is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-l is expressed on activated T cells, B cells, and monocytes, as well as other cells of the immune system and binds both B7-H1 (PD-L1) and the related B7-DC (PD-L2). The second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
  • B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumor infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumor micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumor cells from lysis by tumor cell specific cytotoxic T cells.
  • Antibodies that specifically bind and inhibit PD-L1 activity are useful for the treatment of lung cancer (e.g., non-small cell lung cancer
  • Durvalumab is an exemplary anti-PD-Ll antibody that is selective for B7-H1 and blocks the binding of B7-H1 to the PD-l and CD80 receptors.
  • MEDI4736 can relieve B7-H1- mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
  • Other agents that could be used include agents that inhibit PD-L1 and/or PD-l (AB or other).
  • Durvalumab (or fragments thereof) for use in the methods provided herein can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, the disclosures of which are incorporated herein by reference in its entirety.
  • the fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgGl heavy chain that reduces binding to the complement component Clq and the Fey receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).
  • Durvalumab and antigen-binding fragments thereof for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
  • durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
  • durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
  • the heavy chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5
  • the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
  • durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in U.S. Patent Nos. 8,779,108 and 9,493,565, which are herein incorporated by reference in their entirety.
  • Patients identified as likely responders to anti-PD-Ll antibody therapy are administered an anti-PD-Ll antibody, such as durvalumab, or an antigen-binding fragment thereof.
  • Durvalumab or an antigen-binding fragment thereof can be administered only once or infrequently while still providing benefit to the patient.
  • the patient is administered additional follow-on doses.
  • Follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and/or other factors, including the judgment of the attending physician.
  • At least two doses of durvalumab or an antigen-binding fragment thereof are administered to the patient.
  • at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, or at least fifteen doses or more can be administered to the patient.
  • durvalumab or an antigen-binding fragment thereof is administered over a two-week treatment period, over a four- week treatment period, over a six- week treatment period, over an eight- week treatment period, over a twelve-week treatment period, over a twenty-four- week treatment period, or over a one-year or more treatment period.
  • durvalumab or an antigen-binding fragment thereof is administered over a three- week treatment period, a six-week treatment period, over a nine-week treatment period, over a twelve-week treatment period, over a twenty-four-week treatment period, or over a one- year or more treatment period. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered over a two-month treatment period, over a four-month treatment period, or over a six-month or more treatment period (e.g., during a maintenance phase).
  • the amount of durvalumab or an antigen-binding fragment thereof to be administered to the patient will depend on various parameters, such as the patient's age, weight, clinical assessment, tumor burden and/or other factors, including the judgment of the attending physician.
  • the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 0.1 mg/kg. In certain aspects the patient is administered one or more doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 0.3 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 1 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab or an antigen binding fragment thereof wherein the dose is about 3 mg/kg.
  • the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 10 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 15 mg/kg.
  • the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 0.1 mg/kg. In certain aspects the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 0.3 mg/kg. In certain aspects the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 1 mg/kg. In certain aspects the patient is administered at least two doses of durvalumab or an antigen binding fragment thereof wherein the dose is about 3 mg/kg.
  • the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 10 mg/kg. In certain aspects the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 15 mg/kg. In some embodiments, the at least two doses are administered about two weeks apart. In some embodiments, the at least two doses are administered about three weeks apart.
  • the patient is administered at least three doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 0.1 mg/kg. In certain aspects the patient is administered at least three doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 0.3 mg/kg. In certain aspects the patient is administered at least three doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 1 mg/kg. In certain aspects the patient is administered at least three doses of durvalumab or an antigen binding fragment thereof wherein the dose is about 3 mg/kg.
  • the patient is administered at least three doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 10 mg/kg. In certain aspects the patient is administered at least three doses of durvalumab or an antigen-binding fragment thereof wherein the dose is about 15 mg/kg. In some embodiments, the at least three doses are administered about two weeks apart. In some embodiment, the at least three doses are administered about three weeks apart.
  • administration of durvalumab or an antigen-binding fragment thereof according to the methods provided herein is through parenteral administration.
  • durvalumab or an antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection. In some embodiments, the administration is by intravenous infusion.
  • durvalumab or an antigen-binding fragment thereof is administered according to the methods provided herein in combination or in conjunction with additional cancer therapies.
  • Such therapies include, without limitation, chemotherapeutic agents such as Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib, or
  • the methods provided herein can decrease tumor size, retard tumor growth or maintain a steady state.
  • the reduction in tumor size can be significant based on appropriate statistical analyses.
  • a reduction in tumor size can be measured by comparison to the size of patient's tumor at baseline, against an expected tumor size, against an expected tumor size based on a large patient population, or against the tumor size of a control population.
  • the administration of durvalumab can reduce a tumor size by at least 25%.
  • the administration of durvalumab can reduce a tumor size by at least 25% within about 6 weeks of the first treatment.
  • the administration of durvalumab can reduce a tumor size by at least 50%. In certain aspects provided herein, the administration of durvalumab can reduce a tumor size by at least 50% within about 10 weeks of the first treatment. In certain aspects provided herein, the administration of durvalumab can reduce a tumor size by at least 75%. In certain aspects provided herein, the administration of durvalumab can reduce a tumor size by at least 75% within about 10 weeks of the first treatment.
  • use of the methods provided herein i.e., administration of durvalumab or an antigen-binding fragment thereof can decrease tumor size within 6 weeks, within 7 weeks, within 8 weeks, within 9 weeks, within 10 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, or within 52 weeks of the first treatment.
  • administering can be sufficient to reduce tumor size.
  • doses can also be administered, for example, to optimize efficacy, number of doses necessary, or certain pharmacokinetic parameters.
  • the methods provided herein can decrease or retard tumor growth. In some aspects the reduction or retardation can be statistically significant. A reduction in tumor growth can be measured by comparison to the growth of patient's tumor at baseline, against an expected tumor growth, against an expected tumor growth based on a large patient population, or against the tumor growth of a control population. [0132] In certain aspects, administration of durvalumab or an antigen-binding fragment thereof can increase overall survival (OS).
  • OS overall survival
  • administration of v or an antigen-binding fragment thereof can result in desirable pharmacokinetic parameters.
  • Total drug exposure can be estimated using the "area under the curve" (AUC).
  • AUC (tau) refers to AUC until the end of the dosing period, whereas “AUC (inf) "refers to the AUC until infinite time.
  • the administration can produce AUC (tau) of about 100 to about 2,500 d-pg/mL.
  • the administration can produce a maximum observed concentration (Cmax) of about 15 to about 350 pg/mL.
  • the half-life of the durvalumab or the antigen-binding fragment thereof can be about 5 to about 25 days.
  • the clearance of the MED 14736 or the antigen-binding fragment thereof can be about 1- 10 ml/day/kg.
  • durvalumab or an antigen-binding fragment thereof can also decrease free B7-H1 levels.
  • Free B7-H1 refers to B7-H1 that is not bound (e.g., by durvalumab).
  • B7-H1 levels are reduced by at least 80%.
  • B7-H1 levels are reduced by at least 90%.
  • B7-H1 levels are reduced by at least 95%.
  • B7-H1 levels are reduced by at least 99%.
  • B7-H1 levels are eliminated following administration of durvalumab or an antigen-binding fragment thereof.
  • administration of durvalumab or an antigen-binding fragment thereof reduces the rate of increase of B7-H1 levels as compared, e.g., to the rate of increase of B7-H1 levels prior to the administration of durvalumab or an antigen-binding fragment thereof.
  • Tumelimumab an antibody or antigen binding fragment thereof that selectively binds a CTLA4 polypeptide and comprises at least a portion of a light chain variable region comprising the amino acid sequence of SEQ ID NO:9 and/or at least a portion of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10.
  • Exemplary anti- CTLA4 antibodies are described for example at US Patent Nos. 6,682,736; 7,109,003;
  • Tremelimumab is 11.2.1, therein), which are herein incorporated by reference.
  • Tremelimumab is an exemplary anti- CTLA4 antibody.
  • Tremelimumab sequences are provided in the sequence listing below. [0035] Information regarding tremelimumab (or antigen-binding fragments thereof) for use in the methods provided herein can be found in US 6,682,736 (where it is referred to as 11.2.1, the disclosure of which is incorporated herein by reference in its entirety.
  • Tremelimumab also known as CP-675,206, CP-675, CP-675206, and ticilimumab
  • CP-675,206, CP-675, CP-675206, and ticilimumab is a human IgG2 monoclonal antibody that is highly selective for CTLA4 and blocks binding of CTLA4 to CD80 (B7.1) and CD86 (B7.2). It has been shown to result in immune activation in vitro and some patients treated with tremelimumab have shown tumor regression.
  • Tremelimumab and antigen-binding fragments thereof for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
  • tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region
  • tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 11-13, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16.
  • the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 11-13
  • the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16.
  • tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises or the variable heavy chain and variable light chain CDR sequences of the 11.2.1 antibody as disclosed in US 6,682,736, which is herein incorporated by reference in its entirety.
  • the disclosed methods comprising detection of at least one mRNA marker provide for the identification of cancers having a likelihood of positive clinical response prior to or during therapy, and also allow for modification of therapy when no signs of responsiveness, or a low likelihood of responsiveness, to a current therapy may be observable, or that may be expected based on the methods.
  • the disclosure provides a method of treating cancer in a patient comprising administering an anti-PD-Ll antibody, or an antigen binding fragment thereof, to the patient, wherein the patient is identified for treatment by detecting in a sample obtained from the patient at least one mRNA associated with T cell exhaustion.
  • the disclosure provides methods for treating a solid tumor cancer with an anti-PD-Ll antibody in a patient identified by detecting at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12 , and TBX21.
  • the methods comprise detecting PDCD1, CD8A, LAG3, CTLA4, EOMES , CD56, SLAMF8, GNLY, IE12, and TBX21
  • the disclosure provides methods for treating lung cancer (e.g., NSCLC) with an anti-PD-Ll antibody in a patient identified by detecting at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21.
  • the methods comprise detecting PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SEAMF8, GNLY, IE12, and TBX21.
  • the disclosure provides methods for treating bladder cancer with an anti-PD-Ll antibody in a patient identified by detecting at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from PDCD1, CD8A, LAG3, CTEA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21.
  • the methods comprise detecting PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SEAMF8, GNLY, IE12, and TBX21.
  • the methods disclosed above comprise identifying patients having a cancer that is responsive to treatment with an anti-PD-Ll antibody.
  • the disclosure provides for aspects and embodiments that include methods of identifying a subject having a cancer that is responsive to an anti-PD-Ll antibody, where the methods comprise detecting the expression of at least one mRNA associated with T cell exhaustion as described herein and in the above aspects and embodiments.
  • the disclosure provides methods that identify patients having a solid tumor cancer for an anti-PD-Ll antibody therapy comprising detecting and determining a decrease in expression level at least one, at least two, or at least three mRNAs selected from ARG1, IL-10, and TGFB1 in a sample obtained from the patient.
  • the methods comprise detecting and determining a decrease in expression level of ARG1, IL-10 , and TGFB1.
  • the expression level may be determined by analyzing the expression data relative to a reference expression level determined in a healthy subject or in a patient having a cancer that is responsive to anti-PD-Ll antibody therapy, or in a pool of such subjects and/or patients.
  • the disclosure provides a method of identifying a patient having a cancer that is likely to be non-responsive to treatment comprising an anti-PD-Ll antibody, wherein the patient is identified by detecting in a sample obtained from the patient at least one mRNA associated with suppressive cells.
  • the disclosure provides methods that identify patients having a solid tumor cancer for a therapy comprising a therapeutic that does not include an anti-PD-Ll antibody, identifying the patient by detecting at least one, at least two, or at least three mRNAs selected from ARG1, IL-10 , and TGFB1.
  • the methods comprise detecting ARG1, IL-10, and TGFB1.
  • the disclosure provides methods that identify patients having lung cancer (e.g., NSCLC) as likely to be non-responsive to therapy comprising an anti-PD-Ll antibody.
  • lung cancer e.g., NSCLC
  • the disclosure provides methods that identify patients having bladder cancer (e.g., UBC) as likely to be non-responsive to therapy comprising an anti-PD-Ll antibody.
  • bladder cancer e.g., UBC
  • the disclosure provides methods that identify patients having head and neck cancer (e.g., SCCHN) as likely to be non-responsive to therapy comprising an anti-PD-Ll antibody.
  • SCCHN head and neck cancer
  • the methods disclosed above comprise identifying patients having a cancer that is responsive to treatment with an anti-PD-Ll antibody.
  • the disclosure provides for aspects and embodiments that include methods of identifying a subject having a cancer that is responsive to an anti-PD-Ll antibody, where the methods comprise detecting the expression of at least one mRNA associated with T cell exhaustion and at least one mRNA associated with suppressive cells as described herein and in the above aspects and embodiments.
  • the disclosure provides a method for characterizing the responsiveness of a cancer in a subject, such as a lung cancer or bladder cancer, to anti-PD-Ll antibody treatment, wherein the method comprises detecting expression level of at least one mRNA associated with T cell exhaustion in a sample obtained from the patient; comparing the expression level of the at least one mRNA associated with T cell exhaustion in the patient sample to a mean and/or median expression level of the same mRNA associated with T cell exhaustion in a reference cancer sample; and characterizing the cancer as responsive to anti-PD-Ll antibody treatment when the expression level of the mRNA in the patient sample is higher than the mean and/or median expression level of the same mRNA in the reference sample.
  • the methods for characterizing responsiveness are based on the mean expression level of the same mRNA associated with T cell exhaustion in a reference cancer. In some embodiments, the methods for characterizing responsiveness are based on the median expression level of the same mRNA associated with T cell exhaustion in a reference cancer sample.
  • the one or more mRNA markers are selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21.
  • the method may comprise detection of marker mRNAs associated with T cell exhaustion optionally in combination with detection of PD-L1, measured in one or more types of biological samples (e.g., tumor sample).
  • the method identifies a subject who is responsive to anti-PD-Ll antibody treatment by determining an increase in the mean expression level and an increase in the median expression level relative to threshold levels.
  • the method can further comprise characterizing responsiveness based on the median expression level of mRNA associated with suppressive cells in a reference cancer sample.
  • the one or more suppressive cells mRNA markers are selected from ARG1, IL-10, and TGFB1, and a decrease in the level of expression further identifies the cancer as likely to be responsive to anti-PD-Ll antibody therapy.
  • the method may comprise detection of marker mRNAs associated with T cell exhaustion and suppressive cells, in combination with detection of PD-L1, as measured in one or more types of biological samples (e.g., tumor sample).
  • Subjects suffering from a cancer such as, for example, lung cancer (e.g., NSCLC), head and neck cancer (SCCHN), or bladder cancer (UBC) may be screened for at least one mRNA selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21, in the course of selecting a treatment method.
  • a cancer such as, for example, lung cancer (e.g., NSCLC), head and neck cancer (SCCHN), or bladder cancer (UBC)
  • NSCLC lung cancer
  • SCCHN head and neck cancer
  • UBC bladder cancer
  • subjects suffering from NSCLC who express all mRNA selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21 may be identified as likely responders to anti-PD-Ll treatment.
  • subjects suffering from head and neck cancer who express all mRNA selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21 may be identified as likely responders to anti-PD-Ll treatment.
  • subjects suffering from bladder cancer who express all mRNA selected from PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SEAMF8, GNLY, IE12, and TBX21 may be identified as likely responders to anti-PD-Ll treatment.
  • the expression level of at least one mRNA selected from ARG1, IL-10, and TGFB1 may be determined, and may indicate that the subject may have a cancer that is likely responsive to anti-PD-Ll treatment.
  • the expression level of one or more of ARG1, IL-10, and TGFB1 is determined to be decreased relative to a reference sample, and the cancer expresses one or more of PDCD1, CD8A, LAG3, CTLA4, EOMES,
  • the cancer may be identified as responsive to anti-PD- Ll therapy.
  • subjects suffering from a cancer such as, for example, lung cancer (e.g., NSCLC), head and neck cancer (SCCHN), or bladder cancer (UBC) may be screened for at least one mRNA selected from ARG1, IL-10, and TGFB1, in the course of selecting a treatment method.
  • a cancer such as, for example, lung cancer (e.g., NSCLC), head and neck cancer (SCCHN), or bladder cancer (UBC) may be screened for at least one mRNA selected from ARG1, IL-10, and TGFB1, in the course of selecting a treatment method.
  • subjects suffering from NSCLC who express all mRNA selected from ARG1, IL-10, and TGFB1 may be identified as likely non responders to anti-PD-Ll treatment, and candidates for a different therapy.
  • subjects suffering from head and neck cancer who express all mRNA selected from ARG1, IL-10, and TGFB1 may be identified as likely non-responders to anti-PD-Ll treatment, and candidates for a different therapy.
  • subjects suffering from bladder cancer who express all mRNA selected from ARG1, IL-10, and TGFB1 may be identified as likely non-responders to anti-PD-Ll treatment, and candidates for a different therapy.
  • RNA profiling methods have been described (Yao et al, 2009, incorporated herein by reference), however in brief summary, for a gene, replicate raw cycle threshold (Ct) values within a patient were averaged and delta Ct values were calculated using the mean of the following housekeeping genes B2M, GAPDH, GUSB, TFRC, and UBC.
  • the expression profiling of samples obtained from the NSCLC nonrandomized trial identified mRNAs that provide an indicator of overall survival (OS) and progression-free survival (PFS) for patients receiving a PD-L1 therapy (durvalumab).
  • OS overall survival
  • PFS progression-free survival
  • a panel of ten mRNAs associated with T or NK cell exhaustion was identified as providing the best indication of overall survival (OS) and progression-free survival (PFS).
  • the Kaplan-Meier method was used to estimate median OS and PFS, and differences between patient subsets were evaluated using a log-rank test in all biomarker evaluable patients.
  • HRs hazard ratios
  • R was used for all analyses (R Core Team (2016).
  • Example 1 mRNA signature identifying clinical outcomes in NSCLC patients
  • each of the 100 genes were independently correlated with clinical outcomes and the top ranked genes identified as the strongest indicators of OS and PFS included: PDCD1, CD8A, LAG3, CTLA4, EOMES, CD56, SLAMF8, GNLY, IL12, and TBX21.
  • the mean expression level of these genes was calculated to form an exhaustive TNK cell mRNA signature. Different gene weighting methods were evaluated in comparison to the mean, but did not improve the correlation of this signature with clinical outcomes.
  • 238 had matching tumoral PD-L1 measured by immunohistochemistry (SP263 assay; positive group: >25%; negative group: ⁇ 25%).
  • the median gene signature value across the 238 patient blood samples was calculated as -5.518 and used to divide patients into signature high or low groups.
  • Example 2 TNK cell mRNA signature and tumor PD-L1 IHC identifying OS and PFS in NSCLC patients
  • the median OS and PFS was 21.4 and 3 months, respectively for gene signature positive patients compared to 18.1 and 3.6 months, respectively, for PD-L1+ patients.
  • OS in gene signature positive patients was 81.1% and 62.9%, respectively, and 70.4% and 59.1% in PDL1+ patients ( Figures 1 and 2A-2B).
  • Figure 3 provides a multivariate Cox PH regression model HRs and 95% CIs for overall survival among baseline clinical covariates.
  • Example 7 TNK cell mRNA signature associates with ORR in cancer patients
  • Example 8 Neutrophil-to-lymphocyte ratio (NLR) and mRNA signature associates with OS
  • NLR neutrophil to lymphocyte ratio
  • Example 9 Suppressive cell mRNA signature associated with OS in cancer patients
  • mRNAs known as biomarkers associated with suppressive cells were also shown to be associated with OS in cancer patients.
  • the three-mRNA signature is arginase 1 ( ARG1 ), interleukin- 10 (IL10 ), and transforming growth factor beta 1 ( TGFB1 ).
  • ARG1 arginase 1
  • IL10 interleukin- 10
  • TGFB1 transforming growth factor beta 1
  • NSCLC, SCCHN, and UBC patients having cancers that exhibit a signature decrease (negative) expression of mRNAs indicative of suppressive cells were associated with an improvement in OS when treated with anti-PD-Ll antibody (durvalumab).
  • the suppressive cell mRNA signature appeared to be anti-correlative to the PDL1 status of each of the cancer types.
  • Example 10 Four-gene suppressive cell mRNA signature
  • mRNA profiling of 154 immune genes was done on blood from patients treated with anti-PD-Ll antibody (durvalumab) in the 1108, HAWK, ATLANTIC, Study 10 and CONDOR clinical trials.
  • a suppressive signature was developed from mean levels of four mRNAs ( ARG1 , TGFB1, IL10, MMP8 ), expressed by T/B-reg. cells, neutrophils, CD56 NK cells, and/or MDSCs.
  • Low suppressive signature prior to treatment was associated with better ORR and longer overall survival (OS) compared to high suppressive signature patients discovery and replication cohorts (Table 1 and Figures 28-33).
  • Hazard ratios for SC were comparable to those for PD-L1 in tumor biopsies.
  • One or more mRNA markers can be conveniently identified in whole blood samples - and without the requirement for immunohistochemical identification of PD-L1 in tumor biopsies - from subjects suffering from solid tumor cancers (e.g., lung cancer or bladder cancer) and identify them as likely responders to treatment with an anti-PD-Ll antibody.
  • solid tumor cancers e.g., lung cancer or bladder cancer
  • detection of one or more mRNAs associated with suppressive cells can provide for the diagnosis, prognosis, and treatment of cancers that may are unlikely to be responsive to an anti- PD-Ll antibody therapy.
  • inventions provide for identification and stratification cancer patients who are unlikely to benefit from anti-PD-Ll antibody therapy allowing for tailored, personalized therapeutic intervention when one or more mRNA markers, including ARG1, IL-10, MMP8 and TGFB1, are detected in whole blood samples.
  • the methods provided herein further advance the field of personalized medicine by providing for the treatment and identification of cancer patients having a higher likelihood of positive outcomes (increased OS and PFS) when administered an anti-PD-Ll antibody therapy such as durvalumab.

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Abstract

La présente invention concerne des procédés de traitement du cancer (par exemple, le cancer du poumon et le cancer de la vessie) avec un anticorps anti-PD-L1 chez un sujet identifié comme étant sensible à une thérapie par anticorps anti-PD-L1 par détection d'au Moins un ARNm associé à l'épuisement des cellules T / NK dans un échantillon obtenu à partir du sujet. L'invention concerne en outre des procédés de détermination de l'efficacité d'un traitement par anticorps thérapeutique anti-PD-L1 chez un sujet atteint d'un cancer du poumon ou d'un cancer de la vessie, comprenant la détection d'au moins un ARNm associé à l'épuisement des cellules T / NK dans un échantillon de sang provenant du sujet et la comparaison du taux d'expression dudit ARNm à un niveau d'expression moyen et/ou médian du même ARNm d'un échantillon de référence. L'invention concerne en outre des procédés d'identification d'un sujet ayant un cancer sensible à une thérapie comprenant un anticorps anti-PD-L1 par détection de l'expression d'au moins un ARNm associé à l'épuisement de cellules T dans un échantillon obtenu à partir d'un sujet. L'invention concerne en outre ces procédés qui comprennent la détection du taux d'expression d'au moins un ARNm associé à des cellules suppressives.
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