WO2018057506A1 - Compositions et procédés pour caractériser la réactivité de tumeurs solides à une monothérapie d'anticorps anti-pd-l1 - Google Patents

Compositions et procédés pour caractériser la réactivité de tumeurs solides à une monothérapie d'anticorps anti-pd-l1 Download PDF

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WO2018057506A1
WO2018057506A1 PCT/US2017/052246 US2017052246W WO2018057506A1 WO 2018057506 A1 WO2018057506 A1 WO 2018057506A1 US 2017052246 W US2017052246 W US 2017052246W WO 2018057506 A1 WO2018057506 A1 WO 2018057506A1
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Prior art keywords
ifng
cxcl9
lag3
cancer
antibody
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PCT/US2017/052246
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English (en)
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Brandon W. Higgs
Chris Morehouse
Philip Brohawn
Katie Streicher
Koustubh Ranade
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Medimmune, Llc
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Priority to CN201780070587.5A priority Critical patent/CN109963572A/zh
Priority to JP2019515363A priority patent/JP2019529437A/ja
Priority to EP17853747.8A priority patent/EP3515456A4/fr
Publication of WO2018057506A1 publication Critical patent/WO2018057506A1/fr

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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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Cancer continues to be a major global health burden. Despite progress in the treatment of cancer, there continues to be an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancers that are resistant to existing therapeutics.
  • Lung cancer is among the most common forms of cancer and is the leading cause of cancer deaths among men and women. More people die of lung cancer annually than of colon, breast, and prostate cancers combined. Non-small cell lung cancer is the most common form of lung cancer. While the risk of acquiring lung cancer is higher among patients with a history of smoking, lung cancer also affects non-smokers. Improving survival of lung cancer patients remains difficult despite improved medical therapies. Most lung cancer is detected only in advanced stages when therapy options are limited. There is a growing recognition that lung cancer and other malignancies arise from a variety of pathogenic mechanisms. Methods of characterizing these malignancies at a molecular level are useful for stratifying patients, thereby quickly directing them to effective therapies. Improved methods for predicting the
  • Bladder cancer is among the five most common malignancies in North America and Europe. The overall incidence of bladder cancer appears to be rising, particularly among patients more than 55 years of age. More than 70% of the bladder cancers are non-muscle-invasive while about 20-30% are muscle-invasive which have a much less favorable prognosis.
  • T cell-mediated cytotoxicity The role of the immune system, in particular T cell-mediated cytotoxicity, in tumor control is well recognized. There is mounting evidence that T cells control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients.
  • PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell activation.
  • PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, as well as various non-hematopoietic cells. Its normal function is to regulate the balance between T-cell activation and tolerance through interaction with its two receptors: programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1 or B7.1).
  • PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system.
  • PD-L1 is expressed in a broad range of cancers with a high frequency. In some cancers, expression of PD-L1 has been associated with reduced survival and unfavorable prognosis.
  • Antibodies that block the interaction between B7-H1 and its receptors are able to relieve PD-L1 - dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T cells in vitro.
  • Durvalumab is a human monoclonal antibody directed against human PD-L1 that is capable of blocking the binding of PD-L1 to both the PD-1 and CD80 receptors.
  • the present invention provides methods for selecting patients as having a solid tumor (e.g., bladder cancer, ovarian cancer, colorectal cancer, head and neck cancer, cervical cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC)) that is responsive to treatment with an anti-PD-Ll antibody, and methods of treating such patients.
  • a solid tumor e.g., bladder cancer, ovarian cancer, colorectal cancer, head and neck cancer, cervical cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC)
  • the method involves detecting expression of an IFNG polynucleotide and/or one or more of polynucleotide markers: CXCL9, CD274, LAG3, in a biological sample of the patient.
  • the present invention provides a method of treating a solid tumor in a subject, the method comprising administering an anti-PD-Ll antibody, or an antigen binding fragment thereof, to a patient identified as having increased levels of two or more polynucleotide markers selected from the group consisting of CXCL9, CD274, LAG3, and IFNG in a biological sample derived from the patient relative to a reference.
  • the present invention provides a method of treating lung cancer or bladder cancer in a subject, the method comprising administering an anti-PD-Ll antibody, or an antigen binding fragment thereof, to a patient identified by detecting increased levels of two or more polynucleotide markers selected from the group consisting of CXCL9, CD274, LAG3, and IFNG in a biological sample derived from the patient relative to a reference.
  • the present invention provides a method of identifying a subject having a solid tumor that is responsive to an anti-PD-Ll antibody, or an antigen binding fragment thereof, the method comprising detecting an increase in the expression levels of two or more polynucleotide markers selected from the group consisting of CXCL9, CD274, LAG3, and IFNG in a biological sample obtained from the subject relative to a reference, thereby identifying the solid tumor as responsive to anti-PD-Ll therapy.
  • the present invention provides a method of identifying a subject having a solid tumor that is responsive to anti-PD-Ll therapy, the method comprising detecting an increase in the expression levels of two or more polynucleotide markers selected from the group consisting of CXCL9, CD274, LAG3, and IFNG in a biological sample obtained from the subject, relative to a reference, thereby identifying the solid tumor as responsive to anti-PD-Ll therapy.
  • the present invention provides a method of identifying a subject having a lung cancer or bladder cancer that is responsive to anti-PD-Ll therapy, the method comprising detecting an increase in the expression levels of two or more polynucleotide markers selected from the group consisting of CXCL9, CD274, LAG3, and IFNG in a biological sample obtained from the subject, relative to a reference, thereby identifying the solid tumor as responsive to anti- PD-Ll therapy.
  • Devalumab an antibody or antigen binding fragment thereof that selectively binds a PD-L1 polypeptide and comprises at least a portion of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and/or at least a portion of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
  • Durvalumab (or antigen-binding fragments thereof) for use in the methods provided herein can be found in US Patent No. 8,779,108, the disclosure of which is 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).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • Durvalumab is selective for PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors.
  • Durvalumab can relieve PD-L1 -mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
  • Durvalumab 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 CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat- defined CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
  • the heavy chain variable region comprises the Kabat-defined CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5
  • the light chain variable region comprises the Kabat- defined CDRl, 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 US Patent No. 8,779,108, which is herein incorporated by reference in its entirety.
  • antigen binding fragment refers to a portion of an intact antibody and/or refers to the antigenic determining variable regions of an intact antibody. It is known that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.
  • Interferon gamma (IFNG) polypeptide is meant a protein or fragment thereof having at least about 85% amino acid sequence identity to NCBI Accession No. P01579 and having immunomodulatory activity.
  • An exemplary IFNG amino acid sequence (Uniprot Accession No. P01579) is provided as SEQ ID NO: 9.
  • IFNG polynucleotide is meant a nucleic acid molecule encoding an IFNG protein.
  • sequence of an exemplary IFNG polynucleotide is provided at NCBI Accession No.
  • NM_000619 which is reproduced as SEQ ID NO: 10.
  • anti-PD-Ll antibody 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 No. 8,779,108, which is herein incorporated by reference.
  • Durvalumab is an exemplary PD-L1 antibody. Following treatment with Durvalumab, a patient achieves disease control (DC). Disease control can be a complete response (CR), partial response (PR), or stable disease (SD). Sequences of Durvalumab are provided in a sequence listing herein below.
  • 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_001254635 (SEQ ID NO: 11) and having PD-1 and CD80 binding activity.
  • PD-L1 nucleic acid molecule is meant a polynucleotide encoding a PD-L1 polypeptide.
  • An exemplary PD-L1 nucleic acid molecule sequence is provided at NCBI
  • C-X-C motif chemokine 9 precursor (CXCL9) polypeptide is meant a polypeptide or fragment thereof having at least about 85% amino acid sequence identity to NCBI Accession No. NP_002407.1 and having chemokine activity.
  • sequence of an exemplary CXCL9 polypeptide is provided below.
  • CXCL9 polynucleotide a polynucleotide encoding a CXCL9 polypeptide.
  • sequence of an exemplary CXCL9 polynucleotide NCBI Accession No. NM_002416.2 is provided below:
  • gagatcctta tcgaaactca ttttaggcaa atgagttt tattgtccgt ttacttgtttt
  • cagagtttgt attgtgatta tcaattacca caccatctcc catgaagaaa gggaacggtg 2041 aagtactaag cgctagagga agcagccaag tcggttagtg gaagcatgat tggtgcccag
  • CD274 polypeptide also known as “PD-Ll polypeptide” is meant a polypeptide or fragment thereof having at least about 85% amino acid sequence identity to GenBank:
  • EAW58763 The sequence of an exemplary CD274 or PD-Ll polypeptide is provided below:
  • CD274 polynucleotide also known as “PD-Ll polynucleotide” is meant a polynucleotide encoding a CD274 or PD-Ll polypeptide.
  • sequence of an exemplary CD274 polynucleotide is provided at NCBI Accession No. NM_014143, which is reproduced below:
  • LAG3 polypeptide is meant a polypeptide or fragment thereof having at least about 85% amino acid sequence identity to NCBI Accession No.
  • AAH52589 (LAG3 polypeptide).
  • the sequence of an exemplary LAG3 polypeptide is provided below.
  • LAG3 polynucleotide is meant a polynucleotide encoding a LAG3 polypeptide.
  • sequence of an exemplary LAG3 polynucleotide is provided at NCBI Accession No.
  • 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-Ll 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.
  • an 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 (VL) and an antibody heavy chain variable region (VH), however, it does not necessarily have to comprise both.
  • VL antibody light chain variable region
  • VH antibody heavy chain variable region
  • Fd antibody fragment consists only of a V H domain, but still retains some antigen-binding function of the intact antibody.
  • Binding fragments of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies.
  • An antibody other than a "bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallize.
  • Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites.
  • Fab when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CHI domain of the heavy chain.
  • mAb refers to monoclonal 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.
  • biological sample is meant any tissue, cell, fluid, or other material derived from an organism.
  • a biological sample is a tumor biopsy sample.
  • a “biomarker” or “marker” as used herein generally refers to a protein, nucleic acid molecule, clinical indicator, or other analyte that is associated with a disease.
  • a 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.
  • a disease e.g., lung cancer
  • “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
  • Detect refers to identifying the presence, absence or amount of the analyte to be detected.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • 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
  • adenocarcinoma adenocarcinoma
  • large cell (undifferentiated) carcinoma adenocarcinoma
  • Other subtypes include
  • adenosquamous carcinoma and sarcomatoid carcinoma are adenosquamous carcinoma and sarcomatoid carcinoma.
  • isolated refers to material that is free to varying degrees from components which normally accompany it as found in its native state.
  • Isolate denotes a degree of separation from original source or surroundings.
  • Purify denotes a degree of separation that is higher than isolation.
  • a “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
  • Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography.
  • the term "purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel.
  • modifications for example, phosphorylation or glycosylation
  • the level of interferon gamma present in a sample from a patient that is partially responsive to a therapy of the invention is compared to the level present in a corresponding sample obtained from a patient having progressive disease.
  • responsive in the context of therapy is meant susceptible to treatment.
  • binding is meant a compound (e.g., antibody) that recognizes and binds a molecule (e.g., polypeptide), but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample.
  • a molecule e.g., polypeptide
  • two molecules that specifically bind form a complex that is relatively stable under physiologic conditions.
  • Specific binding is characterized by a high affinity and a low to moderate capacity as distinguished from nonspecific binding which usually has a low affinity with a moderate to high capacity.
  • binding is considered specific when the affinity constant KA IS higher than 10 6 M _1 , or more preferably higher than 10 s M -1 . If necessary, non-specific binding can be reduced without substantially affecting specific binding by varying the binding conditions.
  • the appropriate binding conditions such as concentration of antibodies, ionic strength of the solution,
  • concentration of a blocking agent e.g., serum albumin, milk casein, etc.
  • concentration of a blocking agent e.g., serum albumin, milk casein
  • 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 of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • treat refers to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • Figures 1A-D are Kaplan-Meier plots of Overall Response (OS) for CXCL9, IFNG, LAG3, and CD274 (PD-Ll), respectively, in NSCLC patients. Each plot is cut into high (dashed line) or low (solid line) expression using the receiver operator characteristic (ROC)-identified cut points.
  • OS Overall Response
  • IFNG IFNG
  • LAG3 LAG3
  • CD274 PD-Ll
  • Figures 1E-H are Kaplan-Meier plots of progression-free response (PFS) for CXCL9, IFNG, LAG3, and CD274 (PD-Ll) in NSCLC patients. Each plot is cut into high (dashed line) or low (solid line) expression using the ROC-identified cut points.
  • PFS progression-free response
  • Figure 2 provides correlation scatter plots of the four genes CXCL9, IFNG, LAG3, and CD274 (Spearman's coefficient) in non-small cell lung cancer (NSCLC).
  • Figure 3A is a Kaplan-Meier plot of Overall Response (OS) for the four genes CXCL9, IFNG, LAG3, and CD274 signature in NSCLC patients. Each plot is cut into high (dashed line) or low (solid line) expression using the ROC-identified cut point.
  • OS Overall Response
  • Figure 3B is a Kaplan-Meier plot of progression-free response (PFS) for the four genes CXCL9, IFNG, LAG3, and CD274 signature in NSCLC patients. Each plot is cut into high (dashed line) or low (solid line) expression using the ROC-identified cut point.
  • PFS progression-free response
  • Figure 4 shows the on-treatment effects by durvalumab for gene signature in NSCLC before and after dosing.
  • Figure 5A shows the progression-free response of the four gene signature in bladder cancer patients. Each plot is cut into high (dashed line) or low (solid line) expression using the upper tertile cut point.
  • Figure 5B shows the progression-free response of IFNG gene signature in bladder cancer patients. Each plot is cut into high (dashed line) or low (solid line) expression using the upper tertile cut point.
  • the present invention provides methods for selecting patients as having a solid tumor (e.g., bladder cancer, ovarian cancer, colorectal cancer, head and neck cancer, cervical cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC)) that is responsive to treatment with an anti-PD-Ll antibody, and methods of treating such patients.
  • a solid tumor e.g., bladder cancer, ovarian cancer, colorectal cancer, head and neck cancer, cervical cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • the invention is based, at least in part, on the discovery that patients having lung cancer (e.g., non-squamous cell or squamous cell non-small cell lung cancer) or bladder cancer that is responsive to treatment with an anti-PD-Ll antibody may be identified by detecting increased levels of CXCL9, CD274, LAG3, and IFNG mRNA in a tumor or blood sample of a subject.
  • the patients may be identified by detecting increased levels of one or more of CXCL9, CD274, LAG3, and IFNG mRNA in a tumor or blood sample of the patient.
  • the patient is identified by detecting increased levels of the combination of CXCL9, CD274, LAG3, and IFNG mRNA in a tumor or blood sample of the patient.
  • the invention provides methods for identifying subjects that have a solid tumor (e.g., breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), pancreatic cancer, melanoma) that is likely to respond to anti-PD-Ll antibody treatment based on an increase in the level of one or more of CXCL9, CD274, LAG3, and IFNG mRNA in a subject tumor or blood sample.
  • a solid tumor e.g., breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), pancreatic cancer, melanoma
  • the invention provides methods for identifying subjects that have lung cancer or bladder cancer that is likely to respond to anti-PD-Ll antibody treatment based on an increase in the level of the combination of CXCL9, CD274, LAG3, and IFNG mRNAs in a subject tumor or blood sample.
  • aspects of the present invention provide methods for treating lung cancer (e.g., non- squamous cell or squamous cell non- small cell lung cancer) with an anti-PD-Ll antibody in a patient identified by detecting an increase in the level of one or more of CXCL9, CD274, LAG3, and IFNG polynucleotides in a tumor or blood sample of the patient.
  • the patient is identified by detecting an increase in the levels of a combination of CXCL9, CD274, LAG3, and IFNG polynucleotides in a tumor or blood sample of the patient.
  • aspects of the present invention provide methods for treating bladder cancer with an anti- PD-L1 antibody in a patient identified by detecting an increase in the level of one or more of CXCL9, CD274, LAG3, and IFNG polynucleotides in a tumor or blood sample of the patient.
  • the patient is identified by detecting an increase in the levels of a
  • CXCL9, CD274, LAG3, and IFNG polynucleotides in a tumor or blood sample of the patient.
  • B7-H1 also known as CD274 and PD-L1
  • CD274 and PD-L1 is a type I transmembrane protein of approximately 53kDa in size.
  • 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.
  • DC myeloid dendritic cells
  • 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-1, is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-1 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-Ll activity e.g., binding to PD-1 and/or
  • CD80 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- Hl to the PD-1 and CD80 receptors.
  • Durvalumab 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-Ll and/or PD-1 (AB or other).
  • 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 No. 8,779, 108, which is herein incorporated by reference in its entirety.
  • a solid tumor e.g., breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), pancreatic cancer, melanoma
  • NSCLC non-small cell lung cancer
  • HCC hepatocellular cancer
  • pancreatic cancer pancreatic cancer, melanoma
  • the level of expression of one or more of CXCL9, CD274, LAG3 and IFNG polynucleotides is measured in different types of biologic samples (e.g., tumor, blood, and/or lymph node samples).
  • the polynucleotide expression of one or more of polynucleotide markers CXCL9, CD274, LAG3 and IFNG is higher in a tumor or blood sample obtained from a subject that is responsive to anti-PD-Ll antibody than the level of expression in a non-responsive subject (e.g., a subject with progressive disease).
  • levels of polynucleotide markers IFNG and CXCL9 are measured.
  • levels of polynucleotide markers IFNG and CD274 are measured.
  • levels of polynucleotide markers IFNG and LAG3 are measured.
  • levels of polynucleotide markers IFNG, CXCL9, and either LAG3 or CD274 are measured.
  • an alteration in expression is calculated using cycle threshold (Ct) values.
  • Ct cycle threshold
  • the Ct value of an IFNG gene is obtained and from that value the Ct value of a reference gene (e.g., B2M, ACTB, GAPDH) is subtracted from the mean Ct value for each gene to obtain a Delta-Ct value.
  • the final gene expression score is defined as (20 - ACt).
  • expression of a marker of the invention is increased by at least about 2, 3, 4, 5 or 10-fold in a responsive patient relative to the level in a non-responsive subject (e.g., a subject with progressive disease).
  • CXCL9, CD274, LAG3 and IFNG polynucleotide fold change values are determined using any method known in the art, including but not limited to quantitative PCR, RT-PCR, Northern blotting, in situ hybridization, fluorescence in situ hybridization (FISH), microarray, and/or RN A- sequencing.
  • Subjects suffering a solid tumor may be tested for one or more of CXCL9, CD274, LAG3 and IFNG polynucleotide expression in the course of selecting a treatment method.
  • a solid tumor e.g., breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), pancreatic cancer, melanoma
  • NSCLC non-small cell lung cancer
  • HCC hepatocellular cancer
  • pancreatic cancer pancreatic cancer
  • Patients characterized as having high expression (e.g., as defined by Ct score) or increased expression relative to a reference level are identified as responsive to anti-PD-Ll treatment.
  • Patients identified as having tumors or blood samples that express one or more of CXCL9, CD274, LAG3 and IFNG polynucleotides particularly at high levels, are likely to be responsive to anti-PD-Ll antibody therapy.
  • Such patients are administered an anti-PD-Ll antibody, such as Durvalumab, or an antigen-binding fragment thereof.
  • the anti-PD-Ll antibody, such as 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • the methods provided herein can decrease or retard tumor growth.
  • 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.
  • a patient achieves disease control (DC).
  • Disease control can be a complete response (CR), partial response (PR), or stable disease (SD).
  • CR complete response
  • 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.
  • administering can increase progression-free survival (PFS).
  • PFS progression-free survival
  • administering can increase overall survival (OS).
  • 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
  • B7-H1 levels are reduced by at least 80%. In some embodiments, B7-H1 levels are reduced by at least 90%. In some embodiments, B7-H1 levels are reduced by at least 95%. In some embodiments, B7-H1 levels are reduced by at least 99%. In some embodiments, B7-H1 levels are eliminated following administration of Durvalumab or an antigen-binding fragment thereof. In some embodiments, 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. Kits
  • kits for characterizing the responsiveness of a subject to anti-PD- Ll antibody treatment includes a therapeutic composition containing an effective amount of an antibody that specifically binds a PD-Ll polypeptide in unit dosage form.
  • a diagnostic kit of the invention provides a reagent (e.g., TaqMan primers/ probes for one or more of CXCL9, CD274, LAG3 and IFNG polynucleotide and housekeeping reference genes) for measuring relative expression of CXCL9, CD274, LAG3 and IFNG polynucleotides.
  • a reagent e.g., TaqMan primers/ probes for one or more of CXCL9, CD274, LAG3 and IFNG polynucleotide and housekeeping reference genes
  • the kit comprises a sterile container which contains a therapeutic and/or diagnostic composition; such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • a sterile container which contains a therapeutic and/or diagnostic composition
  • Such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • a kit of the invention comprises reagents for measuring
  • kits further comprises instructions for measuring
  • lung cancer e.g., squamous cell or non-squamous cell carcinoma non-small cell lung cancer
  • bladder cancer selected as responsive to anti-PD-Ll antibody treatment.
  • the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment or prevention of a solid tumor, bladder cancer or lung cancer (e.g., non-small cell lung cancer, small cell lung cancer) or symptoms thereof; precautions; warnings; indications; counter- indications; over dosage information;
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • Example 1 CXCL9, CD274, LAG3 and IFNG correlate with the objective response rate (ORR) in NSCLC
  • RNA sequencing data was generated on patient tumors with available clinical data, where 30 had pre/post NSCLC patient tumor pair as well as 30 bladder patient tumors pre-treatment with available clinical data and subjected to bioinformatics analysis.
  • the following genes were evaluated: CXCL9, PD-Ll (CD274), LAG-3, IFNG, PD-1 (PDCDl), NKG7, CD8A, SLAMF7, PD-L2 (PDCD1LG2), TIM-3 (HAVCR2), CD80, CD86, CTLA-4, CD2, TLR8, GZMK,
  • TNFRSF4 TNFRSF4, FOXP3, CD276, B7-H4 (VTCN1), and CD37.
  • ROC receiver operator characteristic
  • AUC area under the curve
  • PH Cox proportional hazards
  • the 21 candidate genes were subsequently correlated with objective response rate (ORR), both without and with adjustment for age, gender, previous therapy lines, smoking status and histology (squamous or non-squamous). Results are presented in Tables 1 and 2, where the top 4 genes in each (ranked by area under the curve (AUC) or p-value) include CXCL9, CD274,
  • Example 2 CXCL9, CD274, LAG3 and IFNG are correlated with the overall response (OS) or progression-free response (PFS) in NSCLC
  • OS overall response
  • PFS progression-free response
  • Figures 1A-H Kaplan Meier estimator
  • Figures 1A-D show the overall response plots for CXCL9, IFNG, LAG3, and CD274 (PDLl) in NSCLC patients. Each plot is cut into high or low expression using the ROC- identified cut points.
  • Figures 1E-H show the progression free survival plots for CXCL9, IFNG, LAG3, and CD274 (PDLl) in NSCLC patients. Each plot is cut into high or low expression using the ROC -identified cut points.
  • NSCLC Patients are stratified into high or low groups using the upper tertile of expression.
  • Example 4 IFNG and CXCL9 showed the highest correlation Pretreatment levels of each of the four genes, CXCL9, CD274, LAG3 and IFNG, were correlated with each other to show shared information.
  • Figure 2 shows Correlation scatter plot of four genes (Spearman's coefficient) in NSCLC.
  • the Spearman's coefficient is a nonparametric measure of statistical dependence between two variables.
  • Each x and y axis for a plot indicates the specific gene regressed against one of the four other genes.
  • Each data point is a NSCLC patient tumor sample at baseline.
  • Example 5 A composite signature from the four genes CXCL9, CD274, LAG3 and IFNG in NSCLC
  • a gene signature was calculated using the median expression of the four genes CXCL9, CD274, LAG3 and IFNG and the previous analyses were repeated using this signature as a predictor of objective response rate (ORR) and overall response/progression free survival.
  • Results are shown in Tables 4 and 5 and Figure 3.
  • the gene signature is shown to be highly correlated with both objective response as well as overall (Figure 3A) and progression- free (Figure 3B) survival in NSCLC.
  • the y-axis indicates probability of overall survival while the x-axis indicates time in days.
  • the dashed line indicates patients with expression of the gene signature at the upper tertile of expression.
  • the four gene signature was cut into low or high groups using the upper tertile of expression (top 33%) and subsequently correlated with objective response rate. Due to the small sample size, the adjusted model was not calculated. Results for all comers, IFNG alone, and the four gene signature are presented in Table 6. The enrichment of responders is apparent in both the IFNG group and the gene signature positive group in bladder cancer patients treated with durvalumab, as was demonstrated in the NSCLC patient cohort.
  • Example 7 Correlation of gene signature and IFNG with progression free survival in bladder cancer
  • Tissues were homogenized in 600 ⁇ RLT lysis buffer (Qiagen, Valencia, CA) supplemented with ⁇ -mercaptoethanol ( ⁇ -me) using PowerGen 500 cryogenic homogenizer (Fisher Scientific, Pittsburgh, PA). Homogenized tissue lysates were centrifuged for 3 min at 13,000 x g at room temperature to remove insoluble tissue debris. The supernatant was transferred into a fresh microcentrifuge tube and 1 volume of 100% ethanol was added to the supernatant. The supernatant-ethanol mixture was applied to a Zymo-Spin IC column (Zymo Research, Irvine, CA) for the binding of RNA.
  • RNA-seq libraries were prepared using the TruSeq Stranded Total RNA Prep Kit according to the manufacturer's instructions (Illumina, San Diego, CA). Ribosomal RNAs were depleted from total RNA (150 ng per sample) using the Ribo-Zero Gold rRNA removal solution containing biotinylated probes targeting eukaryotic cytoplasmic and mitochondrial rRNAs. The rRNA-probe complexes were removed from the sample using streptavidin-coated magnetic beads and the resulting rRNA-depleted sample was subjected to thermal RNA fragmentation prior to cDNA synthesis.
  • the first strand cDNA was synthesized using Superscript III reverse transcriptase (Thermo Fisher Scientific, Waltham MA) and random primers, followed by second strand cDNA synthesis.
  • a single adenylate (A) residue was added to 3' end of the double- stranded cDNA molecules and the resulting A-tailed double stranded cDNAs were ligated to 3'- dT-tailed Illumina TruSeq paired-end adaptors containing unique index barcode sequences.
  • the ligated products were purified and enriched with 15 cycles of Polymerase Chain Reaction (PCR) using the primers provided in the Illumina library prep kit.
  • RNA-seq libraries The size distribution of the RNA-seq libraries was analyzed on a 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA) and the library concentrations were determined using Kapa Library Quantification kit (Kapa Biosystems, Woburn, MA). Each library was normalized to 4 nM in 10 mM Tris-HCl, pH 8.0 and denatured in 0. IN NaOH for 5 min prior to the final dilution. Paired-end sequencing runs (2 x 100 cycles) were performed on either HiSeq 2000 or
  • NextSeq 500 sequencing instruments (Illumina, San Diego, CA).
  • denatured libraries (12 pM final concentration) were clustered on a TruSeq v3 Paired-End with a cBot system and sequenced using TruSeq v3 SBS reagents (Illumina, San Diego, CA).
  • Sequencing runs on NextSeq 500 system was carried out with 1.8 pM denatured libraries loaded onto a NextSeq 500/550 v2 flowcell and reagents (Illumina, San Diego, CA).
  • CP1108/NCT01693562 is a nonrandomized, open-label, multicenter phase 1/2 clinical trial evaluating safety and clinical activity of durvalumab in multiple advanced solid tumors.
  • RNA sequencing data was generated on 97 NSCLC patient tumors with available clinical data, where 30 had pre/post NSCLC patient tumor pair as well as 30 bladder patient tumors pre- treatment with available clinical data.
  • ROC receiver operator characteristic
  • AUC area under the curve
  • PH Cox proportional hazards
  • gagatcctta tcgaaactca ttttaggcaa atgagttt tattgtccgt ttacttgtttt

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Abstract

La présente invention concerne des procédés de sélection de patients comme ayant une tumeur solide (par exemple, un cancer de la vessie, un cancer des ovaires, un cancer colorectal, un cancer de la tête et du cou, un cancer du col de l'utérus, un carcinome des cellules rénales et un cancer du poumon non à petites cellules (NSCLC)) qui est sensible au traitement par un anticorps anti-PD-L1, et des méthodes de traitement de tels patients. Le procédé comprend la détection de l'expression d'un polynucléotide IFNG et/ou d'un ou plusieurs des marqueurs polynucléotidiques : CXCL9, CD274 et LAG3, dans un échantillon biologique du patient.
PCT/US2017/052246 2016-09-20 2017-09-19 Compositions et procédés pour caractériser la réactivité de tumeurs solides à une monothérapie d'anticorps anti-pd-l1 WO2018057506A1 (fr)

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US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
WO2023064784A1 (fr) * 2021-10-12 2023-04-20 Foundation Medicine, Inc. Réarrangements de cd274 en tant que prédicteurs de réponse à une thérapie par inhibiteur de point de contrôle immunitaire
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
EP4010022A4 (fr) * 2019-08-09 2024-01-17 The Regents Of Univ Of California Compositions et procédés de diagnostic et de traitement du cancer de la vessie

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WO2016034718A1 (fr) * 2014-09-05 2016-03-10 Medimmune Limited Méthodes d'identification de patients sensibles à un traitement aux anticorps anti-pd-l1 à l'aide de marqueurs (cxcl9, krt8.trim29, et ifngamma.)

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Publication number Priority date Publication date Assignee Title
WO2018222718A1 (fr) * 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Traitement de tumeurs positives pour lag-3
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
EP4010022A4 (fr) * 2019-08-09 2024-01-17 The Regents Of Univ Of California Compositions et procédés de diagnostic et de traitement du cancer de la vessie
WO2023064784A1 (fr) * 2021-10-12 2023-04-20 Foundation Medicine, Inc. Réarrangements de cd274 en tant que prédicteurs de réponse à une thérapie par inhibiteur de point de contrôle immunitaire

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