US20180291074A1 - Determinants of cancer response to immunotherapy by pd-1 blockade - Google Patents

Determinants of cancer response to immunotherapy by pd-1 blockade Download PDF

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US20180291074A1
US20180291074A1 US15/528,385 US201515528385A US2018291074A1 US 20180291074 A1 US20180291074 A1 US 20180291074A1 US 201515528385 A US201515528385 A US 201515528385A US 2018291074 A1 US2018291074 A1 US 2018291074A1
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cancer
neoepitope
composition
mutation
immune checkpoint
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Timothy A. Chan
Naiyer A. RIZVI
Matthew D. Hellmann
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Memorial Sloan Kettering Cancer Center
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    • A—HUMAN NECESSITIES
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    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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    • 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
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • 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
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • Cancer immunotherapy involves the attack of cancer cells by a patient's immune system. Regulation and activation of T lymphocytes depends on signaling by the T cell receptor and also cosignaling receptors that deliver positive or negative signals for activation. Immune responses by T cells are controlled by a balance of costimulatory and inhibitory signals, called immune checkpoints.
  • Immunotherapy with immune checkpoint inhibitors is revolutionizing cancer therapy.
  • anti-CTLA4 and anti-PD1 antibodies have offered a remarkable opportunity for long-term disease control in the metastatic setting.
  • the present invention encompasses the discovery that the likelihood of a favorable response to cancer immunotherapy can be predicted.
  • the present invention particularly comprises the discovery that, for certain cancers, mutation burden can correlate with responsiveness to particular therapy.
  • the present invention provides the finding that certain cancer cells may harbor somatic mutations that result in neoepitopes that are recognizable by a patient's immune system as non-self, and that presence and/or identity of such neoepitopes may correlate with responsiveness to particular therapy.
  • the identification of multiple mutations in a cancer sample as described herein is useful for determining which cancer patients are likely to respond favorably to immunotherapy, in particular, treatment with an immune checkpoint modulator.
  • the present disclosure defines certain characteristics of particular tumor cells that can be detected to predict responsiveness to immunotherapy, and particularly to therapy with immune checkpoint modulators.
  • the present disclosure provides tools and technologies that can be practically applied to define, characterize, and/or detect “signatures” of tumor responsiveness.
  • the present disclosure provides tools and technologies that provide effective prediction or assessment of the likelihood that a particular tumor will respond to a particular therapy.
  • the present disclosure provides tools for defining or detecting particular features of cancer cells that may act as a proxy for underlying aspects of biology that support the natural correlation.
  • the present disclosure demonstrates, for example, that particular, limited, signatures can be defined that are useful to define or detect such features, and provides detection formats that utilize these signatures.
  • the present disclosure demonstrates that provided formats are more effective and/or informative, in at least some contexts, than are other methodologies for applying the biological correlation.
  • the invention provides methods for identifying a subject as likely to respond to treatment with an immune checkpoint modulator.
  • the methods comprise steps of detecting a marker of high mutations in a cancer sample from a subject; and identifying the subject as a candidate for treatment with an immune checkpoint modulator.
  • the step of detecting comprises sequencing one or more exomes from the cancer sample.
  • the number of mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator. In some embodiments, a high number of mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator. In some embodiments, a high number of nonsynonymous mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator.
  • the ratio of transition mutations to transversion mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator. In some embodiments, the ratio comprises the molecular smoking signature.
  • the somatic mutation comprises a neoepitope recognized by a T cell.
  • the number of neoepitopes identifies the subject as a candidate for treatment with an immune checkpoint modulator.
  • neoepitopes identify the subject as a candidate for treatment with an immune checkpoint modulator.
  • the neoepitopes are associated with high mutation rate.
  • high mutations are present in genes encoding proteins involved in DNA repair. In some embodiments, high mutations are present in genes encoding proteins involved in cell signal transduction.
  • the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding epitope that does not have a mutation.
  • MHC major histocompatibility complex
  • the somatic mutation comprises a neoepitope comprising a nonamer that is not expressed in the same cell type that does not have a somatic mutation.
  • the neoepitope shares a consensus sequence with an infectious agent.
  • the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma. In some embodiments, the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.
  • the immune checkpoint modulator interacts with cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) or its ligands, lymphocyte activation gene-3 (LAG3), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), indoleamine (2,3)-dioxygenase (IDO), adenosine A2a receptor, neuritin, B- and T-lymphocyte attenuator (BTLA), killer immunoglobulin-like receptors (KIR), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), inducible T cell costimulator (ICOS), CD27, CD28, CD40, CD137, or combinations thereof.
  • CTL4 cytotoxic T-lymphocyte antigen 4
  • PD-1 programmed death 1
  • LAG3 lymphocyte activation gene-3
  • B7-H3 B7 homolog 3
  • B7-H4 B7 homolog 4
  • IDO indo
  • the immune checkpoint modulator is an antibody agent.
  • the antibody agent is or comprises a monoclonal antibody or antigen binding fragment thereof.
  • the antibody is pembrolizumab.
  • the subject has not previously been treated with a cancer therapeutic. In some embodiments, the subject has not previously been treated with a cancer immunotherapeutic.
  • the method of identifying a subject for treatment with an immune checkpoint modulator further comprises a step of administering pembrolizumab to the subject.
  • the invention provides methods for detecting a low number of mutations in a cancer sample from a subject; and identifying the subject as a poor candidate for treatment with an immune checkpoint modulator.
  • the invention provides methods for determining a subject has a cancer comprising a marker of high mutations, wherein the mutations comprises a neoepitope comprising a nonamer, and selecting for the subject a cancer treatment comprising an immune checkpoint modulator.
  • the cancer comprises lung carcinoma.
  • the invention provides methods for improving efficacy of cancer therapy with an immune checkpoint modulator, the method comprising a step of: selecting for receipt of the therapy a subject identified as having a cancer with markers of high mutation comprising a neoepitope recognized by a T cell.
  • the invention provides methods for treating cancer by administering immune checkpoint modulator therapy, the improvement that comprises: administering the therapy to a subject identified as having a cancer with one or more markers of high mutation comprising a neoepitope recognized by a T cell.
  • the invention provides methods for treating a cancer selected from the group consisting of carcinoma, sarcoma, myeloma, leukemia, or lymphoma, the method comprising a step of: administering immune checkpoint modulator therapy to a subject identified as having a cancer with a marker of high mutations comprising a neoepitope recognized by a T cell.
  • the cancer is or comprises lung carcinoma.
  • the invention provides methods for defining a mutation signature that correlates with responsiveness to therapy with an immune checkpoint modulator, the method comprising: determining one or more mutation characteristics in a plurality of samples of tumors sharing a response characteristic to immune checkpoint modulator therapy; comparing the determined one or more mutation characteristics with those in a plurality of samples of tumors that do not share the response characteristic; and identifying a set of mutation characteristics whose presence correlates with the response characteristic.
  • the one or more mutation characteristics include a mutation characteristic selected from the group consisting of mutation burden, nonsynonymous mutation burden, neoantigen burden, transversion burden, transition burden, relative transversion vs transition burden, mutation burden in genes associated with DNA repair, presence of mutation in one or more particular genes associated with DNA repair, identity of mutation in one or more particular genes associated with DNA repair, and combinations thereof.
  • the determined burden is or comprises rate or number.
  • the genes associated with DNA repair are or include a genes selected from the group consisting of POLD1, PRKDC, DNA-PK, RAD17, POLE, and MSH2.
  • genes not associated with DNA repair that harbor mutation characteristics include genes selected from the group consisting of POLR2A, KEAP1, PAPPA2, PXDNL, RYR1, SCN8A, SLIT3 and KRAS.
  • the response characteristic is or comprises a characteristic selected from the group consisting of partial or stable response lasting longer than 6 months (“durable clinical benefit”; “DCB”), a reduction in tumor size for more than 4 weeks (“objective response rate”; “ORR”); no disease progression for more than 9 weeks (“progression-free survival”; “PFS”), and combinations thereof.
  • DCB durable clinical benefit
  • ORR objective response rate
  • PFS progression-free survival
  • the invention provides methods for characterizing a tumor sample by determining presence of a set of mutation characteristics that correlates with a response characteristic to immune checkpoint modulator therapy.
  • the step of determining comprises detecting at least one of the mutation characteristics by nucleic acid sequencing.
  • the nucleic acid sequencing is or comprises whole exome sequencing.
  • FIGS. 1A-1G shows Nonsynonymous mutation burden predicts clinical benefit with anti-PD-1 therapy.
  • Cut-off of ⁇ 178 nonsynonymous mutations is designated by triangle.
  • FIGS. 1A, 1C, and 1F median and interquartile ranges of total nonsynonymous mutations are shown, with individual values for each tumor shown with dots.
  • FIGS. 2A-2B show smoking and response to pembrolizumab in NSCLC.
  • FIG. 3 shows mutation burden, clinical response, and factors contributing to mutation burden.
  • Columns are shaded to indicate durable response (DCB, green; NDB, red; not reached 6 months follow-up (NR), blue).
  • the cohort identification (D, discovery; V, validation), best objective response (PR, partial response; SD, stable disease; POD, progression of disease), and progression-free survival (censored at the time of data lock) are reported in the table.
  • Those with ongoing progression-free survival are labeled with ++.
  • the presence of the molecular smoking signature is displayed with TH cases (purple) and TL cases (orange).
  • the presence of deleterious mutations in specific DNA repair/replication genes is noted by the arrows.
  • FIGS. 4A-4E show candidate neoantigens, neoantigen-specific T-cell response, and response to pembrolizumab.
  • FIG. 4B shows higher
  • FIG. 4C shows representative computed tomography (CT) images of a liver metastasis prior to and at days after initiating treatment, as indicated.
  • Middle panel of FIG. 4C shows decline of tumor burden.
  • the bottom panel of FIG. 4C shows the anti-HERC1 P>S CD8+ T-cell response measured in peripheral blood.
  • FIG. 4D shows a CD8+ T-cell population in serially-collected autologous PBLs recognizing the HERC1 P>S neoantigen (ASNASSAAK) was detected after beginning pembrolizumab, represented by the events in the double positive position indicated in black. Percentages indicate the number of CD8+ MHC multimer+ cells out of total CD8 cells.
  • T-cell co-stains for IFN ⁇ and CD8, TNF ⁇ , CD107a, and MIP1 ⁇ , respectively, are displayed for the Day 63 and Day 297 time points.
  • FIG. 5 coverage and depth of target exome sequence. Coverage and depth of sequenced exomes is similar in discovery compared to validation cohorts and is similar in those with durable clinical benefit (DCB) compared to those with no durable benefit (NDB).
  • DCB durable clinical benefit
  • NDB no durable benefit
  • FIG. 6 shows an exome analysis pipeline.
  • FIGS. 7A-7B show median and interquartile range of mutations in the current study and in published series of NSCLC (13, 14).
  • FIG. 7A shows somatic nonsynonymous mutation burden.
  • FIG. 7B shows total exonic mutations.
  • FIG. 8 shows a pattern of nucleotide changes in tumors sequenced.
  • the spectrum and frequency of nucleotide changes in the pembrolizumab-treated NSCLCs is typical of non-small cell lung cancers.
  • FIG. 10 shows a neoantigen analysis pipeline. ⁇ All steps are executed for predicted wild type and mutant. *MHC Class I prediction by NetMHCv3.4.
  • FIG. 11 shows HLA type and benefit to pembrolizumab. There was no evident association between the presence of any specific HLA allele and benefit from pembrolizumab.
  • FIG. 12 depicts neoantigens and best objective response.
  • FIGS. 13A-13D demonstrate that following expansion, stimulation of peripheral blood mononuclear cells with wild type or mutant peptide versus no stimulation control shows a polyfunctional CD8+ T cell response to the mutant peptide only.
  • FIG. 13A shows neoantigen-induced IFN ⁇ production by CD3+CD8+ T-cells at day 63 and day 297 after initiation of therapy.
  • FIG. 13B shows co-staining of CD107a in CD3+CD8+IFN ⁇ + cells when stimulated with mutant peptide versus no stimulation or wild type.
  • FIG. 13C shows co-staining of MIP-1 ⁇ in CD3+CD8+IFN ⁇ + cells when stimulated with mutant peptide versus no stimulation or wild type.
  • FIG. 13D shows co-staining of TNF- ⁇ in CD3+CD8+IFN ⁇ + cells when stimulated with mutant peptide versus no stimulation or wild type.
  • FIGS. 14A-14Q show the DNA quality metrics.
  • FIG. 15 depicts a table summarizing clinical and genomic charateristics.
  • FIG. 16 depicts a table demonstrating nonsynonymous, total exonic mutation burden, and association with clinical efficacy to pembrolizumab.
  • Clinical efficacy strongly correlates with nonsynonymous mutation burden in the overall set of sequenced NSCLCs.
  • High total exonic mutation burden less strongly correlates with improved clinical efficacy.
  • FIG. 17 depicts a table of detailed clinical and genomic characteristics of individual patients.
  • FIG. 18 depicts a table of quality metrics for all samples.
  • FIG. 19A-19B depict the correlation of molecular smoking signature, nonsynonymous mutation burden, and neoantigen burden.
  • FIG. 19A shows a hive plot that displays the relationship between molecular smoking signature, mutation and neoantigen burden for each tumor. Red lines depict transversion low tumors; blue lines depict transversion high tumors. Transversion low tumors have significantly lower mutation and neoantigen burden compared to transversion high tumors (Mann Whitney p ⁇ 0.0001 for both). Nonsynonymous mutation burden correlates with neoantigen burden (Spearman ⁇ 0.91, 95% CI 0.83-0.96, p ⁇ 0.0001). In FIG.
  • this hive plot displays the relationship between pack-years of tobacco consumption, mutation and neoantigen burden for each tumor.
  • FIG. 20 depicts the immunophenotype of neoantigen-specific T-cells.
  • peripheral blood lymphocytes PBLs
  • ASNASSAAK peripheral blood lymphocytes
  • Neoantigen-specific T-cells are represented by the events in the double positive position.
  • Flow cytometry dot plots of staining of HERC1 P3278S neoantigen-specific T-cells (Top panels) and bulk CD8+ T-cells (Bottom panels) show expression of indicated phenotypic markers.
  • FIG. 21 depicts neoepitope sequences.
  • FIG. 21 includes, among other things, a listing of immunogenic mutations, HLA typesm neoantigens and predicted MHC binding.
  • administration refers to the administration of a composition to a subject. Administration may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal and vitreal.
  • affinity is a measure of the tightness with a particular ligand binds to its partner. Affinities can be measured in different ways. In some embodiments, affinity is measured by a quantitative assay. In some such embodiments, binding partner concentration may be fixed to be in excess of ligand concentration so as to mimic physiological conditions. Alternatively or additionally, in some embodiments, binding partner concentration and/or ligand concentration may be varied. In some such embodiments, affinity may be compared to a reference under comparable conditions (e.g., concentrations).
  • amino acid in its broadest sense, refers to any compound and/or substance that can be incorporated into a polypeptide chain.
  • an amino acid has the general structure H2N—C(H)(R)—COOH.
  • an amino acid is a naturally occurring amino acid.
  • an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an 1-amino acid.
  • Standard amino acid refers to any of the twenty standard 1-amino acids commonly found in naturally occurring peptides.
  • Nonstandard amino acid refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source.
  • synthetic amino acid encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and/or substitutions.
  • Amino acids, including carboxy- and/or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, protecting groups, and/or substitution with other chemical groups that can change the peptide's circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond.
  • Amino acids may comprise one or posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.).
  • chemical entities e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.
  • amino acid is used interchangeably with “amino acid residue,” and may refer to a free amino acid and/or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a
  • antibody agent refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide with immunoglobulin structural elements sufficient to confer specific binding. Suitable antibody agents include, but are not limited to, human antibodies, primatized antibodies, chimeric antibodies, bi-specific antibodies, humanized antibodies, conjugated antibodies (i.e., antibodies conjugated or fused to other proteins, radiolabels, cytotoxins), Small Modular ImmunoPharmaceuticals (“SMIPsTM”), single chain antibodies, cameloid antibodies, and antibody fragments.
  • SMIPsTM Small Modular ImmunoPharmaceuticals
  • antibody agent also includes intact monoclonal antibodies, polyclonal antibodies, single domain antibodies (e.g., shark single domain antibodies (e.g., IgNAR or fragments thereof)), multispecific antibodies (e.g. bi-specific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
  • the term encompasses stapled peptides.
  • the term encompasses one or more antibody-like binding peptidomimetics.
  • the term encompasses one or more antibody-like binding scaffold proteins.
  • the term encompasses monobodies or adnectins.
  • an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as a complementarity determining region (CDR); in some embodiments an antibody agent is or comprises a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and/or at least one light chain CDR) that is substantially identical to one found in a reference antibody. In some embodiments an included CDR is substantially identical to a reference CDR in that it is either identical in sequence or contains between 1-5 amino acid substitutions as compared with the reference CDR.
  • CDR complementarity determining region
  • an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR.
  • an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR.
  • an antibody agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain.
  • an antibody agent is a polypeptide protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.
  • antibody polypeptide As used herein, the terms “antibody polypeptide” or “antibody”, or “antigen-binding fragment thereof”, which may be used interchangeably, refer to polypeptide(s) capable of binding to an epitope.
  • an antibody polypeptide is a full-length antibody, and in some embodiments, is less than full length but includes at least one binding site (comprising at least one, and preferably at least two sequences with structure of antibody “variable regions”).
  • the term “antibody polypeptide” encompasses any protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.
  • antibody polypeptides encompasses polypeptides having a binding domain that shows at least 99% identity with an immunoglobulin binding domain.
  • antibody polypeptide is any protein having a binding domain that shows at least 70%, 80%, 85%, 90%, or 95% identity with an immuglobulin binding domain, for example a reference immunoglobulin binding domain.
  • An included “antibody polypeptide” may have an amino acid sequence identical to that of an antibody that is found in a natural source.
  • Antibody polypeptides in accordance with the present invention may be prepared by any available means including, for example, isolation from a natural source or antibody library, recombinant production in or with a host system, chemical synthesis, etc., or combinations thereof.
  • an antibody polypeptide may be monoclonal or polyclonal.
  • An antibody polypeptide may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE.
  • an antibody may be a member of the IgG immunoglobulin class.
  • the terms “antibody polypeptide” or “characteristic portion of an antibody” are used interchangeably and refer to any derivative of an antibody that possesses the ability to bind to an epitope of interest.
  • the “antibody polypeptide” is an antibody fragment that retains at least a significant portion of the full-length antibody's specific binding ability.
  • antibody fragments include, but are not limited to, Fab, Fab′, F(ab′) 2 , scFv, Fv, dsFv diabody, and Fd fragments.
  • an antibody fragment may comprise multiple chains that are linked together, for example, by disulfide linkages.
  • an antibody polypeptide may be a human antibody. In some embodiments, the antibody polypeptides may be a humanized.
  • Humanized antibody polypeptides include may be chimeric immunoglobulins, immunoglobulin chains or antibody polypeptides (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
  • antibody polyeptides for use in accordance with the present invention bind to particular epitopes of on immune checkpoint molecules.
  • an “antigen” is a molecule or entity to which an antibody binds.
  • an antigen is or comprises a polypeptide or portion thereof.
  • an antigen is a portion of an infectious agent that is recognized by antibodies.
  • an antigen is an agent that elicits an immune response; and/or (ii) an agent that is bound by a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody (e.g., produced by a B cell) when exposed or administered to an organism.
  • an antigen elicits a humoral response (e.g., including production of antigen-specific antibodies) in an organism; alternatively or additionally, in some embodiments, an antigen elicits a cellular response (e.g., involving T-cells whose receptors specifically interact with the antigen) in an organism.
  • a particular antigen may elicit an immune response in one or several members of a target organism (e.g., mice, rabbits, primates, humans), but not in all members of the target organism species.
  • an antigen elicits an immune response in at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the members of a target organism species.
  • an antigen binds to an antibody and/or T cell receptor, and may or may not induce a particular physiological response in an organism.
  • an antigen may bind to an antibody and/or to a T cell receptor in vitro, whether or not such an interaction occurs in vivo.
  • an antigen may be or include any chemical entity such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer [in some embodiments other than a biologic polymer (e.g., other than a nucleic acid or amino acid polymer)] etc.
  • an antigen is or comprises a polypeptide.
  • an antigen is or comprises a glycan.
  • an antigen may be provided in isolated or pure form, or alternatively may be provided in crude form (e.g., together with other materials, for example in an extract such as a cellular extract or other relatively crude preparation of an antigen-containing source).
  • antigens utilized in accordance with the present invention are provided in a crude form.
  • an antigen is or comprises a recombinant antigen.
  • Burden refers to the number or rate (e.g., of mutations or neoantigens) in a sample or cohort, in some embodiments relative to that observed in an appropriate reference sample or cohort.
  • Combination therapy refers to those situations in which two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
  • two or more different agents may be administered simultaneously or separately.
  • This administration in combination can include simultaneous administration of the two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, two or more agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents can be simultaneously administered, wherein the agents are present in separate formulations.
  • a first agent can be administered just followed by one or more additional agents.
  • two or more agents may be administered a few minutes apart, or a few hours apart, or a few days apart.
  • Comparable is used herein to describe two (or more) sets of conditions, circumstances, individuals, or populations that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.
  • relative language used herein e.g., enhanced, activated, reduced, inhibited, etc
  • Consensus sequence refers to a core sequence that elicits or drives a physiological phenomenon (e.g., an immune response). It is to be understood by those of skill in the art that a a cancer cell that shares a “consensus sequence” with an antigen of an infectious agent shares a portion of amino acid sequence that affects the binding affinity of the antigen to an MHC molecule (either directly or allosterically), and/or facilitates recognition by T cell receptors.
  • a consensus sequence is a tetrapeptide.
  • a consensus sequence is a nonapeptide.
  • a consensus sequence is betwene four and nine amino acids in length.
  • a consesnsus sequence is greater than nine amino acids in length.
  • diagnostic information is any information that is useful in determining whether a patient has a disease or condition and/or in classifying the disease or condition into a phenotypic category or any category having significance with regard to prognosis of the disease or condition, or likely response to treatment (either treatment in general or any particular treatment) of the disease or condition.
  • diagnosis refers to providing any type of diagnostic information, including, but not limited to, whether a subject is likely to have a disease or condition (such as cancer), state, staging or characteristic of the disease or condition as manifested in the subject, information related to the nature or classification of a tumor, information related to prognosis and/or information useful in selecting an appropriate treatment.
  • Selection of treatment may include the choice of a particular therapeutic (e.g., chemotherapeutic) agent or other treatment modality such as surgery, radiation, etc., a choice about whether to withhold or deliver therapy, a choice relating to dosing regimen (e.g., frequency or level of one or more doses of a particular therapeutic agent or combination of therapeutic agents), etc.
  • a particular therapeutic e.g., chemotherapeutic
  • other treatment modality e.g., surgery, radiation, etc.
  • dosing regimen e.g., frequency or level of one or more doses of a particular therapeutic agent or combination of therapeutic agents
  • Dosing regimen is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • a dosing regimen is or has been correlated with a desired therapeutic outcome, when administered across a population of patients.
  • Durable clinical benefit As used herein, the term “durable clinical benefit” (DCB), has its art-understood meaning, referring to a clinical benefit that lasts for a relevant period of time.
  • a clinical benefit is or comprises reduction in tumor size, increase in progession free survival, increase in overall survival, decrease in overall tumor burden, decrease in the symptoms caused by tumor growth such as pain, organ failure, bleeding, damage to the skeletal system, and other related sequelae of metastatic cancer and combinations thereof.
  • the relevant period of time is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or longer. In some particular embodiments, the relevant period of time is 6 months.
  • favorable response refers to a reduction in frequency and/or intensity of one or more symptoms, reduction in tumor burden, full or partial remission, or other improvement in disease pathophysiology. Symptoms are reduced when one or more symptoms of a particular disease, disorder or condition is reduced in magnitude (e.g., intensity, severity, etc.) and/or frequency. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom. Many cancer patients with smaller tumors have no symptoms. It is not intended that the present invention be limited only to cases where the symptoms are eliminated.
  • the present invention specifically contemplates treatment such that one or more symptoms is/are reduced (and the condition of the subject is thereby “improved”), albeit not completely eliminated.
  • a favorable response is established when a particular therapeutic regimen shows a statistically significant effect when administered across a relevant population; demonstration of a particular result in a specific individual may not be required.
  • a particular therapeutic regimen is determined to have a favorable response when its administration is correlated with a relevant desired effect.
  • homology refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules.
  • polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical.
  • polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similar.
  • identity refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes).
  • the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence.
  • the nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.
  • Immune checkpoint modulator refers to an agent that interacts directly or indirectly with an immune checkpoint.
  • an immune checkpoint modulator increases an immune effector response (e.g., cytotoxic T cell response), for example by stimulating a positive signal for T cell activation.
  • an immune checkpoint modulator increases an immune effector response (e.g., cytotoxic T cell response), for example by inhibiting a negative signal for T cell activation (e.g. disinhibition).
  • an immune checkpoint modulator interferes with a signal for T cell anergy.
  • an immune checkpoint modulator reduces, removes, or prevents immune tolerance to one or more antigens.
  • a long term benefit refers to a desirable clinical outcome, e.g., observed after administration of a particular treatment or therapy of interest, that is maintained for a clinically relevant period of time.
  • a long term benefit of cancer therapy is or comprises (1) no evidence of disease (“NED”, for example upon radiographic assessment) and/or (2) stable or decreased volume of diseases.
  • NED no evidence of disease
  • a clinically relevant period of time is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months or more.
  • a clinically relevant period of time is at least six months.
  • a clinically relevant period of time is at least 1 year.
  • a marker refers to an agent whose presence or level is a characteristic of a particular tumor or metastatic disease thereof.
  • the term refers to a gene expression product that is characteristic of a particular tumor, tumor subclass, stage of tumor, etc.
  • a presence or level of a particular marker correlates with activity (or activity level) of a particular signaling pathway, for example that may be characteristic of a particular class of tumors.
  • the statistical significance of the presence or absence of a marker may vary depending upon the particular marker.
  • detection of a marker is highly specific in that it reflects a high probability that the tumor is of a particular subclass.
  • markers with a high degree of sensitivity may be less specific that those with lower sensitivity. According to the present invention a useful marker need not distinguish tumors of a particular subclass with 100% accuracy.
  • Modulator is used to refer to an entity whose presence in a system in which an activity of interest is observed correlates with a change in level and/or nature of that activity as compared with that observed under otherwise comparable conditions when the modulator is absent.
  • a modulator is an activator, in that activity is increased in its presence as compared with that observed under otherwise comparable conditions when the modulator is absent.
  • a modulator is an inhibitor, in that activity is reduced in its presence as compared with otherwise comparable conditions when the modulator is absent.
  • a modulator interacts directly with a target entity whose activity is of interest.
  • a modulator interacts indirectly (i.e., directly with an intermediate agent that interacts with the target entity) with a target entity whose activity is of interest.
  • a modulator affects level of a target entity of interest; alternatively or additionally, in some embodiments, a modulator affects activity of a target entity of interest without affecting level of the target entity.
  • a modulator affects both level and activity of a target entity of interest, so that an observed difference in activity is not entirely explained by or commensurate with an observed difference in level.
  • mutations refers to permanent change in the DNA sequence that makes up a gene.
  • mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.
  • mutations can include missense mutations, frameshift mutations, duplications, insertions, nonsense mutation, deletions and repeat expansions.
  • a missense mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
  • a nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein.
  • an insertion changes the number of DNA bases in a gene by adding a piece of DNA.
  • a deletion changes the number of DNA bases by removing a piece of DNA.
  • small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes.
  • a duplication consists of a piece of DNA that is abnormally copied one or more times.
  • frameshift mutations occur when the addition or loss of DNA bases changes a gene's reading frame.
  • a reading frame consists of groups of 3 bases that each code for one amino acid.
  • a frameshift mutation shifts the grouping of these bases and changes the code for amino acids.
  • insertions, deletions, and duplications can all be frameshift mutations.
  • a repeat expansion is another type of mutation.
  • nucleotide repeats are short DNA sequences that are repeated a number of times in a row.
  • a trinucleotide repeat is made up of 3-base-pair sequences
  • a tetranucleotide repeat is made up of 4-base-pair sequences.
  • a repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated.
  • Neoepitope is understood in the art to refer to an epitope that emerges or develops in a subject after exposure to or occurrence of a particular event (e.g., development or progression of a particular disease, disorder or condition, e.g., infection, cancer, stage of cancer, etc).
  • a neoepitope is one whose presence and/or level is correlated with exposure to or occurrence of the event.
  • a neoepitope is one that triggers an immune response against cells that express it (e.g., at a relevant level).
  • a neopepitope is one that triggers an immune response that kills or otherwise destroys cells that express it (e.g., at a relevant level).
  • a relevant event that triggers a neoepitope is or comprises somatic mutation in a cell.
  • a neoepitope is not expressed in non-cancer cells to a level and/or in a manner that triggers and/or supports an immune response (e.g., an immune response sufficient to target cancer cells expressing the neoepitope).
  • a neoepitope is a neoantigen.
  • no benefit is used to refer to absence of detectable clinical benefit (e.g., in response to administration of a particular therapy or treatment of interest).
  • absence of clinical benefit refers to absence of statistically significant change in any particular symptom or characteristic of a particular disease, disorder, or condition.
  • absence of clinical benefit refers to a change in one or more symptoms or characteristics of a disease, disorder, or condition, that lasts for only a short period of time such as, for example, less than about 6 months, less than about 5 months, less than about 4 months, less than about 3 months, less than about 2 months, less than about 1 month, or less.
  • no benefit refers to no durable benefit.
  • the phrase “objective response” refers to size reduction of a cancerous mass by a defined amount.
  • the cancerous mass is a tumor.
  • confirmed objective response is response confirmed at least four (4) weeks after treatment.
  • ORR object response rate
  • response duration usually measured from the time of initial response until documented tumor progression.
  • ORR involves the sum of partial responses plus complete responses.
  • a patient refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disorder or condition. In some embodiments, a patient has been diagnosed with one or more disorders or conditions. In some embodiments, the disorder or condition is or includes cancer, or presence of one or more tumors. In some embodiments, the disorder or condition is metastatic cancer.
  • Polypeptide As used herein, a “polypeptide”, generally speaking, is a string of at least two amino acids attached to one another by a peptide bond. In some embodiments, a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides sometimes include “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain, optionally.
  • Prognostic and predictive information are used interchangeably to refer to any information that may be used to indicate any aspect of the course of a disease or condition either in the absence or presence of treatment. Such information may include, but is not limited to, the average life expectancy of a patient, the likelihood that a patient will survive for a given amount of time (e.g., 6 months, 1 year, 5 years, etc.), the likelihood that a patient will be cured of a disease, the likelihood that a patient's disease will respond to a particular therapy (wherein response may be defined in any of a variety of ways). Prognostic and predictive information are included within the broad category of diagnostic information.
  • Progression free survival As used herein, the term “progression free survival” (PFS) has its art-understood meaning relating to the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In some embodiments, measuring the progression-free survival is utilized as an assessment of how well a new treatment works. In some embodiments, PFS is determined in a randomized clinical trial; in some such embodiments, PFS refers to time from randomization until objective tumor progression and/or death.
  • Protein refers to a polypeptide (i.e., a string of at least two amino acids linked to one another by peptide bonds). Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete polypeptide chain as produced by a cell (with or without a signal sequence), or can be a characteristic portion thereof. Those of ordinary skill will appreciate that a protein can sometimes include more than one polypeptide chain, for example linked by one or more disulfide bonds or associated by other means.
  • Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc.
  • proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.
  • the term “peptide” is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids.
  • a determined value or characteristic of interest is compared with an appropriate reference.
  • a reference value or characteristic is one determined for a comparable cohort, individual, population, or sample.
  • a reference value or characteristic is tested and/or determined substantially simultaneously with the testing or determination of the characteristic or value of interest.
  • a reference characteristic or value is or comprises a historical reference, optionally embodied in a tangible medium.
  • a reference value or characteristic is determined under conditions comparable to those utilized to determine or analyze the characteristic or value of interest.
  • a response may refer to an alteration in a subject's condition that occurs as a result of or correlates with treatment.
  • a response is or comprises a beneficial response.
  • a beneficial response may include stabilization of the condition (e.g., prevention or delay of deterioration expected or typically observed to occur absent the treatment), amelioration (e.g., reduction in frequency and/or intensity) of one or more symptoms of the condition, and/or improvement in the prospects for cure of the condition, etc.
  • “response” may refer to response of an organism, an organ, a tissue, a cell, or a cell component or in vitro system.
  • a response is or comprises a clinical response.
  • presence, extent, and/or nature of response may be measured and/or characterized according to particular criteria; in some embodiments, such criteria may include clinical criteria and/or objective criteria.
  • techniques for assessing response may include, but are not limited to, clinical examination, positron emission tomography, chest X-ray CT scan, MRI, ultrasound, endoscopy, laparoscopy, presence or level of a particular marker in a sample, cytology, and/or histology.
  • a response of interest is or comprises response of a tumor to therapy
  • those of ordinary skill will be aware of a variety of established techniques for assessing such response, including, for example, for determining tumor burden, tumor size, tumor stage, etc.
  • certain technologies for assessing response of solid tumors to treatment are discussed in Therasse et. al., “New guidelines to evaluate the response to treatment in solid tumors”, European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada, J. Natl. Cancer Inst., 2000, 92(3):205-216.
  • sample typically refers to a biological sample obtained or derived from a source of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • processing e.g., by removing one or more components of and/or by adding one or more agents to
  • a primary sample For example, filtering using a semi-permeable membrane.
  • Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Specific binding refers to an interaction (typically non-covalent) between a target entity (e.g., a target protein or polypeptide) and a binding agent (e.g., an antibody, such as a provided antibody).
  • a target entity e.g., a target protein or polypeptide
  • a binding agent e.g., an antibody, such as a provided antibody.
  • an interaction is considered to be “specific” if it is favored in the presence of alternative interactions.
  • an interaction is typically dependent upon the presence of a particular structural feature of the target molecule such as an antigenic determinant or epitope recognized by the binding molecule.
  • an antibody is specific for epitope A
  • the presence of a polypeptide containing epitope A or the presence of free unlabeled A in a reaction containing both free labeled A and the antibody thereto will reduce the amount of labeled A that binds to the antibody.
  • specificity need not be absolute.
  • numerous antibodies cross-react with other epitopes in addition to those present in the target molecule. Such cross-reactivity may be acceptable depending upon the application for which the antibody is to be used.
  • an antibody specific for receptor tyrosine kinases has less than 10% cross-reactivity with receptor tyrosine kinase bound to protease inhibitors (e.g., ACT).
  • protease inhibitors e.g., ACT
  • One of ordinary skill in the art will be able to select antibodies having a sufficient degree of specificity to perform appropriately in any given application (e.g., for detection of a target molecule, for therapeutic purposes, etc.). Specificity may be evaluated in the context of additional factors such as the affinity of the binding molecule for the target molecule versus the affinity of the binding molecule for other targets (e.g., competitors). If a binding molecule exhibits a high affinity for a target molecule that it is desired to detect and low affinity for non-
  • Stage of cancer refers to a qualitative or quantitative assessment of the level of advancement of a cancer. Criteria used to determine the stage of a cancer include, but are not limited to, the size of the tumor and the extent of metastases (e.g., localized or distant).
  • subject refers to any organism upon which embodiments of the invention may be used or administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.).
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • an individual who is “suffering from” a disease, disorder, or condition e.g., a cancer
  • a disease, disorder, or condition e.g., a cancer
  • an individual who is suffering from cancer has cancer, but does not display any symptoms of cancer and/or has not been diagnosed with a cancer.
  • an individual who is “susceptible to” a disease, disorder, or condition is at risk for developing the disease, disorder, or condition.
  • an individual who is susceptible to a disease, disorder, or condition does not display any symptoms of the disease, disorder, or condition.
  • an individual who is susceptible to a disease, disorder, or condition has not been diagnosed with the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, or condition is an individual who displays conditions associated with development of the disease, disorder, or condition.
  • a risk of developing a disease, disorder, and/or condition is a population-based risk.
  • Target cell or target tissue refers to any cell, tissue, or organism that is affected by a condition described herein and to be treated, or any cell, tissue, or organism in which a protein involved in a condition described herein is expressed.
  • target cells, target tissues, or target organisms include those cells, tissues, or organisms in which there is a detectable amount of immune checkpoint signaling and/or activity.
  • target cells, target tissues, or target organisms include those cells, tissues or organisms that display a disease-associated pathology, symptom, or feature.
  • therapeutic regimen refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. It may include a treatment or series of treatments designed to achieve a particular effect, e.g., reduction or elimination of a detrimental condition or disease such as cancer.
  • the treatment may include administration of one or more compounds either simultaneously, sequentially or at different times, for the same or different amounts of time.
  • the treatment may include exposure to radiation, chemotherapeutic agents, hormone therapy, or surgery.
  • a “treatment regimen” may include genetic methods such as gene therapy, gene ablation or other methods known to reduce expression of a particular gene or translation of a gene-derived mRNA.
  • therapeutic agent refers to any agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect.
  • therapeutically effective amount refers to an amount of an agent (e.g., an immune checkpoint modulator) that confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the “therapeutically effective amount” refers to an amount of a therapeutic agent or composition effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease.
  • a therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses.
  • a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents.
  • the specific therapeutically effective amount (and/or unit dose) for any particular patient may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific pharmaceutical agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific fusion protein employed; the duration of the treatment; and like factors as is well known in the medical arts.
  • treatment refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition (e.g., cancer).
  • a substance e.g., provided compositions
  • Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • Wild-type As used herein, the term “wild-type” has its art-understood meaning that refers to an entity having a structure and/or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).
  • the present invention encompasses the discovery of particular signatures and/or characteristics that can be detected in certain tumors or tumor samples and that predict or correlate with responsiveness to immune checkpoint modulator therapy.
  • the present disclosure demonstrates that a high mutational load can correlate with such responsiveness.
  • the present disclosure also particularly demonstrates that presence (e.g., number and/or rate) and/or identity of somatic neoepitopes (e.g., which may result from tumor mutations) can contribute to, and therefore may correlate with, such responsiveness.
  • the present disclosure defines certain mutation and/or neoepitope characteristics of relevant tumors that correlate with and/or can be used to predict responsiveness to immune checkpoint modulator therapy.
  • the present disclosure also provides technologies for defining and/or detecting certain mutation “signatures” useful in predicting and/or characterizing such responsiveness.
  • the overall number and/or rate of mutation and/or of neoepitopes in cancer cells can be predictive of clinical response to immunotherapy, and particularly to immune checkpoint modulator therapy.
  • those individuals whose tumors show high mutation burden and/or high neoepitope burden are predisposed to benefit from immunotherapy as described herein compared to those individuals with reltaively lower such burdens.
  • neoepitopes in cancer cells can be associated with increased binding affinity to MHC class I molecules and/or with improved recognition by cytotoxic T cells.
  • neoepitopes useful in predicting responsiveness to therapy as described herein are those that in fact show increased binding affinity to MHC class I molecules and/or improved recognition by cytotoxic T cells, for example relative to a parent protein that is otherwise identical but lacks the neoepitope.
  • the present disclosure relates to characterizing tumor responsiveness to immunotherapy, and particularly to immune checkpoint modulator therapy.
  • such therapy involves blockade of programmed cell death 1 (PD-1).
  • PD-1 programmed cell death 1
  • such therapy involves treatement with an agent that interferes with an interaction involving PD-1 (e.g., with PD-L1).
  • such therapy involves administration of an antibody agent that specifically interacts with PD-1 or with PD-L1.
  • such therapy involves administration of one or more of nivolumab (BMS-936558, MDX-1106, ONO-4538, a fully human Immunoglobulin G4 (IgG4) monoclonal PD-1 antibody), pembrolizumab (MK-3475, a humanized monoclonal IgG4 anti-PD-1 antibody), BMS-936559 (a fully human IgG4 PD-L1 antibody), MPDL3280A (a humanized engineered IgG1 monoclonal PD-L1 antibody) and/or MEDI4736 (a humanized engineered IgG1 monoclonal PD-L1 antibody).
  • BMS-936558 a fully human Immunoglobulin G4 (IgG4) monoclonal PD-1 antibody
  • MK-3475 a humanized monoclonal IgG4 anti-PD-1 antibody
  • BMS-936559 a fully human IgG4 PD-L1 antibody
  • MPDL3280A a humanized engineered
  • the present invention provides, among other things, technologies for defining, characterizing, and/or detecting burden (e.g., number, level, and/or rate) of somatic mutations and/or neoepitopes present in cancer cells and/or for defining, characterizing, and/or detecting particular mutation and/or neoepitope “signatures” that predict responsiveness to immunotherapy, and particularly to immune checkpoint modulator therapy.
  • burden e.g., number, level, and/or rate
  • somatic mutations and/or neoepitopes present in cancer cells and/or for defining, characterizing, and/or detecting particular mutation and/or neoepitope “signatures” that predict responsiveness to immunotherapy, and particularly to immune checkpoint modulator therapy.
  • the present invention provides methods and/or reagents for identifying cancer patients that are likely to respond favorably to treatment with immunotherapy (e.g., with an immune checkpoint modulator) and/or for selecting patients to receive such
  • the present invention provides methods and/or reagents for treating patients with an immune checkpoint modulator that have been identified to have cancer harboring a particular mutation burden, neoepitope burden, and/or mutation or neoepitope signature as described herein.
  • the present invention defines and provides tools and kits for detecting or determining whether a particular cancer patient does or does not have the relevant mutational landscape or signature for responding to immunotherapy (e.g., PD-1 blockade).
  • the present invention demonstrates that certain particular mutational landscapes or signatures are more useful and effective in predicting responsiveness.
  • the present disclosure demonstrates that high mutational loads can predict responsiveness of cancers to immunotherapy. Furthermore, the disclosure also teaches that high neoepitope loads can predict responsiveness of cancers to immunotherapy. Moreover, the present disclosure demonstrates that particular mutational and/or neoepitope signatures can predict responsiveness of cancers to immunotherapy. Specifically, the present disclosure establishes that signatures including information from DNA repair genes and/or signal transduction genes can predict responsiveness of cancers to immunotherapy. The present disclosure further establishes that signatures that, alternatively or additionally, include characteristics of the established molecular smoking signature, can predict responsiveness of cancers to immunotherapy.
  • Acquired (or somatic) mutations can occur in the DNA of cells at some time during an individual's life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, carcinogens in chemicals or cigarette smoke, or can occur if a mistake is made during DNA replication. Cancer cells from cancers such as lung cancer or melanoma, which are often the result of chronic exposure to environmental factor or mutagens, often possess multiple mutations of varying types.
  • NSCLC non small cell lung carcinoma
  • smokers have a much greater mutation burden compared to never-smokers.
  • immunotherapy e.g., PD-1 blockade
  • highly mutable cancers are more susceptible to attack from the immune system.
  • Mutations of certain genes correlate with higher (hyper) levels of mutations in cancer cells.
  • the present disclosure demonstrates that mutations in genes associated with DNA repair correlated with cancer cells possessing higher numbers of mutations.
  • the present disclosure demonstrates a that high mutation load can predict clinical efficacy of immunotherapy treatment for certain cancers.
  • the present disclosure establishes that, in certain cases, individuals with higher somatic mutation loads are more likely to respond positively to immunotherapy than individuals with significantly lower mutation burdens.
  • the present disclosure demonstrates that, for certain cancers, patients with high numbers of mutations are more likely to benefit from treatment with immune checkpoint modulators than those patients with lower mutation loads.
  • patients with higher numbers of somatic mutations respond better to PD-1 (programmed cell death 1) blockade than those patients with significantly lower overall mutations.
  • individuals with high numbers of mutations respond better to treatment with anti-PD-1 antibodies than those individuals with low numbers of mutations.
  • the overall number of mutations has a greater correlation with positive response to immunotherapy than the specific mutational signatures.
  • the type of somatic mutation correlates with response to treatment.
  • the present disclosure teaches that individuals with a lower transition to transversion ratio (Ti/Tv) also experienced greater likelihood of positive response to immunotherapy.
  • the present disclosure encompasses the insight that meaningful limits can be imposed on mutational analysis of cancer cells and, moreover, that use of such limits surprisingly defines and/or provides signature formats that effectively predict responsiveness to treatment.
  • the ⁇ mutation signatures as described herein correlate with and/or predict response to immunotherapy (e.g., PD-1 blockade).
  • the genes that are mutated (for example, DNA repair) as well as the exact type of mutation (for example, transversions rather than transitions) correlate with and/or are predictive of positive response to immunotherapy.
  • the present disclosure demonstrates that such signatures can be detected and effectively utilized to predict tumor responsiveness.
  • the present disclosure provides technologies for defining mutation signatures that predict responsiveness to immunotherapy, and particularly to immune checkpoint modulator therapy.
  • the present disclosure defines one or more characteristics or attributes of useful signatures.
  • the present disclosure describes and/or establishes effective use of such signatures in predicting therapeutic responsiveness.
  • the present disclosure demonstrates that mutational landscape of particular tumors can predict the likelihood of clinical benefit from immunotherapy (e.g., PD-1 blockade).
  • immunotherapy e.g., PD-1 blockade
  • high mutation load can predict likelihood of positive response to immunotherapy.
  • nature of the somatic mutations present can predict response to immunotherapy.
  • individuals with neoepitope signatures consistent with mutations of genes associated with DNA repair and signaling e.g., KRAS signaling
  • KRAS signaling also correlated with a positive outcome for immune checkpoint modulation.
  • the present dislcosure particularly demonstrates, surprisingly, that the established “smoking signature” can be effectively utilized to predict responsiveness of certain tumors to immunotherapy, and particularly to immune checkpoint modulator therapy (e.g., PD-1 blockade).
  • immune checkpoint modulator therapy e.g., PD-1 blockade.
  • individuals possessing (or whose tumor(s) possess) one or more features of the molecular smoking signature and suffering from a smoking-related cancer are more likely to repond to immunotherapy than are non-smoking individuals and/or individuals that do not posess (or whose tumor(s) do not possess) the one or more features.
  • cancer types to which the present disclosure applied include one or more of lung cancer (e.g., small cell or non-small-cell carcinoma [“NSCLC”), bladder cancer, renal carcinoma, head and neck cancers, and melanoma respond to immunotherapy.
  • lung cancer reponds to PD-1 blockade.
  • expression of PD-L1 is an indicator of positive response to therapy.
  • smoking related cancers are more likely to respond to immunotherapy treatment.
  • the present disclosure demonstrates that those individuals possessing (or whose tumor(s) possess) one or more features or characteristics of the established molecular smoking signature are more likely to respond to immunotherapy treatment.
  • the present disclosure establishes that, for those individuals suffering from NSCLC, those with the smoking signature experienced greater clinical benefit from treatment with PD-1 blockade than their non-smoker counterparts.
  • a cancer cell comprising a neoepitope is selected from a carcinoma, sarcoma, melanoma, myeloma, leukemia, or lymphoma. In some embodiments, a cancer cell comprising a neoepitope is a melanoma. In some embodiments, a cancer cell comprising a neoepitope is a non-small-cell lung carcinoma.
  • teachings of the present disclosure predict responsiveness to immunomodulatory therapeutic modalities or regimens, and particularly to therapeutic modalities or regimens targeting immune checkpoint regulators.
  • the present disclosure demonstrates the mutational landscape of tumors correlates with responsiveness to immune checkpoint regulators.
  • high somatic mutation load correlates with an increased likelihood of clinical efficacy from immune checkpoint regultors for those cancers responsive to immunotherapy (e.g., PD-1 blockade).
  • PD-1 blockade e.g., PD-1 blockade.
  • such therapy involves blockade of programmed cell death 1 (PD-1).
  • PD-1 programmed cell death 1
  • such therapy involves treatement with an agent that interferes with an interaction involving PD-1 (e.g., with PD-L1).
  • such therapy involves administration of an antibody agent that specifically interacts with PD-1 or with PD-L1.
  • such therapy involves administration of one or more of nivolumab (BMS-936558, MDX-1106, ONO-4538, a fully human Immunoglobulin G4 (IgG4) monoclonal PD-1 antibody), pembrolizumab (MK-3475, a humanized monoclonal IgG4 anti-PD-1 antibody), BMS-936559 (a fully human IgG4 PD-L1 antibody), MPDL3280A (a humanized engineered IgG1 monoclonal PD-L1 antibody) and/or MEDI4736 (a humanized engineered IgG1 monoclonal PD-L1 antibody).
  • Somatic mutations comprise DNA alterations in non-germline cells and commonly occur in cancer cells. It has been discovered herein that certain somatic mutations in cancer cells result in the expression of neoepitopes, that in some embodiments transition a stretch of amino acids from being recognized as “self” to “non-self”. According to the present invention, a cancer cell harboring a “non-self” antigen is likely to elicit an immune response against the cancer cell. Immune responses against cancer cells can be enhanced by an immune checkpoint modulator. The present invention teaches that cancers expressing neoepitopes may be more responsive to therapy with immune checkpoint modulator.
  • the present invention provides strategies for improving cancer therapy by permitting identification and/or selection of particular patients to receive (or avoid) therapy.
  • the present invention also provides technologies for defining neoeptiopes, or sets thereof, whose presence is indicative of a particular clinical outcome of interest (e.g., responsiveness to therapy, for example with a particular immune checkpoint modulator and/or risk of developing a particular undesirable side effect of therapy).
  • the present invention defines and/or permits definition of one or more neoepitope “signatures” associated with beneficial (or undesirable) response to immune checkpoint modulator therapy.
  • a somatic mutation results in a neoantigen or neoepitope.
  • the present disclosure demonstrates the existence of neoepitopes, arising from somatic mutation, whose presence is associated with a particular response to immune checkpoint modulator therapy.
  • high numbers of neoepitopes are associated with a positive response to immunotherapy.
  • a neoepitope is or comprises a tetrapeptide, for example that contributes to increased binding affinity to MHC Class I molecules and/or recognition by cells of the immune system (i.e. T cells) as “non-self”.
  • a neoepitope shares a consensus sequence with an antigen from an infectious agent.
  • a neoepitope signature of interest in accordance with the present invention is or comprises a neoepitope or set thereof whose presence in a tumor sample correlates with a particular clinical outcome.
  • neoepitopes of genes associated with DNA repair correlate with a positive response to immune checkpoint modulation.
  • neoepitopes of genes associated with signal transduction correlate with a positive response to immune checkpoint therapy.
  • the present disclosure provides technologies for defining and/or detecting neoepitopes, and particulary those relevant to immune checkpoint modulator therapy.
  • the present disclosure demonstrates definition of neoepitopes and neoepitope signatures associated with a particular response or response feature (e.g., responsiveness to therapy or risk of side effect) of immune checkpoint modulator therapy.
  • a particular response or response feature e.g., responsiveness to therapy or risk of side effect
  • such definition is achieved by comparing genetic sequence information from a first plurality of tumor samples, which first plurality contains samples that share a common response feature to immune checkpoint modulator therapy, with that obtained from a second plurality of tumor samples, which second plurality contains samples that do not share the common response feature but are otherwise comparable to those of the first set, so that the comparison defines genetic sequence elements whose presence is associated or correlates with the common response feature.
  • the present disclosure specifically demonstrates that increased mutational burden can correlate with a response feature (e.g., with responsiveness to therapy), but also demonstrates that such increased mutational burden alone may not be sufficient to predict the response feature.
  • the present disclosure demonstrates that, when such somatic mutation generates neoepitopes, a useful neoeptiope signature associated with the response feature can be defined.
  • the present disclosure provides specific technologies for defining and utilizing such signatures.
  • Immune checkpoints refer to inhibitory pathways of the immune system that are responsible for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses.
  • Certain cancer cells thrive by taking advantage of immune checkpoint pathways as a major mechanism of immune resistance, particularly with respect to T cells that are specific for tumor antigens.
  • certain cancer cells may overexpress one or more immune checkpoint proteins responsible for inhibiting a cytotoxic T cell response.
  • immune checkpoint modulators may be administered to overcome the inhibitory signals and permit and/or augment an immune attack against cancer cells.
  • Immune checkpoint modulators may facilitate immune cell responses against cancer cells by decreasing, inhibiting, or abrogating signaling by negative immune response regulators (e.g. CTLA4), or may stimulate or enhance signaling of positive regulators of immune response (e.g. CD28).
  • Immunotherapy agents targeted to immune checkpoint modulators may be administered to encourage immune attack targeting cancer cells.
  • Immunotherapy agents may be or include antibody agents that target (e.g., are specific specific for) immune checkpoint modulators.
  • Examples of immunotherapy agents include antibody agents targeting one or more of CTLA-4, PD-1, PD-L1, GITR, OX40, LAG-3, KIR, TIM-3, CD28, CD40; and CD137.
  • antibody agents may include monoclonal antibodies.
  • Certain monoclonal antibodies targeting immune checkpoint modulators are available. For instance, ipilumimab targets CTLA-4; tremelimumab targets CTLA-4; pembrolizumab targets PD-1, etc.
  • Cancers may be screened to detect mutations and/or neoepitopes (e.g., to detect mutation load/burden and/or neoepitope load/burden, and/or to detect a particular signature) as described herein using any of a variety of known technologies.
  • particular mutations or neoepitopes, or expression thereof is/are detected at the nucleic acid level (e.g., in DNA or RNA).
  • such mutations or neopeitopes, or expression thereof is detected at the protein level (e.g., in a sample comprising polypeptides from cancer cells, which sample may be or comprise polypeptide complexes or other higher order structures including but not limited to cells, tissues, or organs).
  • detection involves nucleic acid sequencing. In some embodiments, detection involves whole exome sequencing. In some embodiments, detection involves immunoassay. In some embodiments, detection involves use of amicroarray. In some embodiments, detection involves massively parallel exome sequencing sequencing. In some embodiments, mutations and/or neoepitopes may be detected by genome sequencing. In some embodiments, detection involves RNA sequencing. In some embodiments, detection involves standard DNA or RNA sequencing. In some embodiments, detection involves mass spectrometry.
  • detection involves next generation sequencing (DNA and/or RNA). In some embodiments, detection involves genome sequencing, genome resequencing, targeted sequencing panels, transcriptome profiling (RNA-Seq), DNA-protein interactions (ChIP-sequencing), and/or epigenome characterization. In some embodiments, re-sequencing of a patient's genome may be utilized, for example to detect genomic variations.
  • detection involves using a technique such as ELISA, Western Tranfer, immunoassay, mass spectrometry, microarray analysis, etc.
  • the invention provides methods for identifying cancer patients that are likely to respond favorably to treatment with an immune checkpoint modulator. In some embodiments, the invention provides methods for identifying a cancer patient that is likely to respond favorably to treatment with an immune checkpoint modulator and treating the patient with an immune checkpoint modulator. In some embodiments, the invention provides methods of treating a cancer patient with an immune checkpoint modulator who has previously been identified as likely to respond favorably to treatment with an immune checkpoint modulator. In some embodiments, the invention provides methods for identifying a cancer patient that is not likely to respond favorably to treatment with an immune checkpoint modulator and not treating the patient with an immune checkpoint modulator.
  • the invention provides methods for identifying a cancer patient who is likely to suffer one or more autoimmune complications if administered an immune checkpoint modulator. In some embodiments, the invention provides methods for treating a cancer patient with an immunosuppressant who has previously identified as likely to suffer one or more autoimmune complications if treated with an immune checkpoint modulator. In some embodiments, the immunosuppressant is administered to the patient prior to or concomitantly with an immune checkpoint modulator.
  • an immune checkpoint modulator is or has been administered to an individual.
  • treatment with an immune checkpoint modulator is utilized as a sole therapy.
  • treatement with an immune checkpoint modulator is used in combination with one or more other therapies.
  • Example 5 presents certain approved dosing information for ipilumimab, an anti-CTL-4 antibody.
  • an immune checkpoint modulator is administered in accordance with the present invention according to such an approved protocol.
  • the present disclosure provides certain technologies for identifying, characterizing, and/or selecting particular patients to whom immune checkpoint modulators may desirably be administered.
  • insights provided by the present disclosure permit dosing of a given immune checkpoint modulator with greater frequency and/or greater individual doses (e.g., due to reduced susceptibiloity to and/or incidence or intensity of undesirable effects) relative to that recommended or approved based on population studies that include both individuals identified as described herein (e.g., expressing neoepitopes) and other individuals.
  • insights provided by the present disclosure permit dosing of a given immune checkpoint modulator with reduced frequency and/or reduced individual doses (e.g., due to increased responsiveness) relative to that recommended or approved based on population studies that include both individuals identified as described herein (e.g., expressing neoepitopes) and other individuals.
  • an immune system modulator is administered in a pharmaceutical composition that also comprises a physiologically acceptable carrier or excipient.
  • a pharmaceutical composition is sterile.
  • a pharmaceutical composition is formulated for a particular mode of administration.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions (e.g., NaCl), saline, buffered saline, alcohols, glycerol, ethanol, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, sugars such as mannitol, sucrose, or others, dextrose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidone, etc., as well as combinations thereof.
  • a pharmaceutical preparation can, if desired, comprise one or more auxiliary agents (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like) which do not deleteriously react with the active compounds or interference with their activity.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like
  • a water-soluble carrier suitable for intravenous administration is used.
  • a pharmaceutical composition or medicament can contain an amount (typically a minor amount) of wetting or emulsifying agents, and/or of pH buffering agents.
  • a pharmaceutical composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • a pharmaceutical composition canbe formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharine, cellulose, magnesium carbonate, etc.
  • a pharmaceutical composition can be formulated in accordance with the routine procedures as a pharmaceutical composition adapted for administration to human beings.
  • a composition for intravenous administration typically is a solution in sterile isotonic aqueous buffer.
  • acomposition may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • an immune checkpoint modulator can be formulated in a neutral form; in some embodiments it may be formulated in a salt form.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • compositions for use in accordance with the present invention may be administered by any appropriate route.
  • a pharmaceutical composition is administered intravenously.
  • a pharmaceutical composition is administered subcutaneously.
  • a pharmaceutical composition is administered by direct administration to a target tissue, such as heart or muscle (e.g., intramuscular), or nervous system (e.g., direct injection into the brain; intraventricularly; intrathecally).
  • a pharmaceutical composition is administered parenterally, transdermally, or transmucosally (e.g., orally or nasally). More than one route can be used concurrently, if desired.
  • Immune checkpoint modulators can be administered alone, or in conjunction with other immune checkpoint modulators.
  • the term, “in conjunction with,” indicates that a first immune checkpoint modulator is administered prior to, at about the same time as, or following another immune checkpoint modulator.
  • a first immune checkpoint modulator can be mixed into a composition containing one or more different immune checkpoint modulators, and thereby administered contemporaneously; alternatively, the agent can be administered contemporaneously, without mixing (e.g., by “piggybacking” delivery of the agent on the intravenous line by which the immune checkpoint modulator is also administered, or vice versa).
  • the immune checkpoint modulator can be administered separately (e.g., not admixed), but within a short time frame (e.g., within 24 hours) of administration of the immune checkpoint modulator.
  • subjects treated with immune checkpoint modulators are administered one or more immunosuppressants.
  • one or more immunosuppressants are administered to decrease, inhibit, or prevent an undesired autoimmune response (e.g., enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and/or endocrinopathy), for example, hypothyroidism.
  • exemplary immunosuppressants include steroids, antibodies, immunoglobulin fusion proteins, and the like.
  • an immunosuppressant inhibits B cell activity (e.g. rituximab).
  • an immunosuppressant is a decoy polypeptide antigen.
  • immune checkpoint modulators are administered in a therapeutically effective amount (e.g., a dosage amount and/or according to a dosage regimen that has been shown, when administered to a relevant population, to be sufficient to treat cancer, such as by ameliorating symptoms associated with the cancer, preventing or delaying the onset of the cancer, and/or also lessening the severity or frequency of symptoms of cancer).
  • a therapeutically effective amount e.g., a dosage amount and/or according to a dosage regimen that has been shown, when administered to a relevant population, to be sufficient to treat cancer, such as by ameliorating symptoms associated with the cancer, preventing or delaying the onset of the cancer, and/or also lessening the severity or frequency of symptoms of cancer.
  • long term clinical benefit is observed after treatment with immune checkpoint modulators, including, for example, PD-1 blockers such as pembrolizumab, and/or other agents.
  • a dose which will be therapeutically effective for the treatment of cancer in a given patient may depend, at least to some extent, on the nature and extent of cancer, and can be determined by standard clinical techniques.
  • one or more in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges.
  • a particular dose to be employed in the treatment of a given individual may depend on the route of administration, the extent of cancer, and/or one or more other factors deemed relevant in the judgment of a practitioner in light of patient's circumstances.
  • effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems (e.g., as described by the U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research in “Guidance for Industry: Estimating Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”, Pharmacology and Toxicology, July 2005.
  • a therapeutically effective amount of an immune check point modulator can be, for example, more than about 0.01 mg/kg, more than about 0.05 mg/kg, more than about 0.1 mg/kg, more than about 0.5 mg/kg, more than about 1.0 mg/kg, more than about 1.5 mg/kg, more than about 2.0 mg/kg, more than about 2.5 mg/kg, more than about 5.0 mg/kg, more than about 7.5 mg/kg, more than about 10 mg/kg, more than about 12.5 mg/kg, more than about 15 mg/kg, more than about 17.5 mg/kg, more than about 20 mg/kg, more than about 22.5 mg/kg, or more than about 25 mg/kg body weight.
  • a therapeutically effective amount can be about 0.01-25 mg/kg, about 0.01-20 mg/kg, about 0.01-15 mg/kg, about 0.01-10 mg/kg, about 0.01-7.5 mg/kg, about 0.01-5 mg/kg, about 0.01-4 mg/kg, about 0.01-3 mg/kg, about 0.01-2 mg/kg, about 0.01-1.5 mg/kg, about 0.01-1.0 mg/kg, about 0.01-0.5 mg/kg, about 0.01-0.1 mg/kg, about 1-20 mg/kg, about 4-20 mg/kg, about 5-15 mg/kg, about 5-10 mg/kg body weight.
  • a therapeutically effective amount is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, about 10.0 mg/kg, about 11.0 mg/kg, about 12.0 mg/kg, about 13.0 mg/kg, about 14.0 mg/kg, about 1
  • the therapeutically effective amount is no greater than about 30 mg/kg, no greater than about 20 mg/kg, no greater than about 15 mg/kg, no greater than about 10 mg/kg, no greater than about 7.5 mg/kg, no greater than about 5 mg/kg, no greater than about 4 mg/kg, no greater than about 3 mg/kg, no greater than about 2 mg/kg, or no greater than about 1 mg/kg body weight or less.
  • the administered dose for a particular individual is varied (e.g., increased or decreased) over time, depending on the needs of the individual.
  • a loading dose (e.g., an initial higher dose) of a therapeutic composition may be given at the beginning of a course of treatment, followed by administration of a decreased maintenance dose (e.g., a subsequent lower dose) of the therapeutic composition.
  • a loading dose may clear out an initial and, in some cases massive, accumulation of undesirable materials (e.g., fatty materials and/or tumor cells, etc) in tissues (e.g., in the liver), and maintenance dosing may delay, reduce, or prevent buildup of fatty materials after initial clearance.
  • undesirable materials e.g., fatty materials and/or tumor cells, etc
  • a loading dose and maintenance dose amounts, intervals, and duration of treatment may be determined by any available method, such as those exemplified herein and those known in the art.
  • a loading dose amount is about 0.01-1 mg/kg, about 0.01-5 mg/kg, about 0.01-10 mg/kg, about 0.1-10 mg/kg, about 0.1-20 mg/kg, about 0.1-25 mg/kg, about 0.1-30 mg/kg, about 0.1-5 mg/kg, about 0.1-2 mg/kg, about 0.1-1 mg/kg, or about 0.1-0.5 mg/kg body weight.
  • a maintenance dose amount is about 0-10 mg/kg, about 0-5 mg/kg, about 0-2 mg/kg, about 0-1 mg/kg, about 0-0.5 mg/kg, about 0-0.4 mg/kg, about 0-0.3 mg/kg, about 0-0.2 mg/kg, about 0-0.1 mg/kg body weight.
  • a loading dose is administered to an individual at regular intervals for a given period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months) and/or a given number of doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more doses), followed by maintenance dosing.
  • a maintenance dose ranges from 0-2 mg/kg, about 0-1.5 mg/kg, about 0-1.0 mg/kg, about 0-0.75 mg/kg, about 0-0.5 mg/kg, about 0-0.4 mg/kg, about 0-0.3 mg/kg, about 0-0.2 mg/kg, or about 0-0.1 mg/kg body weight.
  • a maintenance dose is about 0.01, 0.02, 0.04, 0.06, 0.08, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, or 2.0 mg/kg body weight.
  • maintenance dosing is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months.
  • maintenance dosing is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years.
  • maintenance dosing is administered indefinitely (e.g., for life time).
  • a therapeutically effective amount of an immune checkpoint modulator may be administered as a one-time dose or administered at intervals, depending on the nature and extent of the cancer, and on an ongoing basis.
  • Administration at an “interval,” as used herein indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose).
  • the interval can be determined by standard clinical techniques.
  • an immune checkpoint modulator is administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, or daily.
  • the administration interval for a single individual need not be a fixed interval, but can be varied over time, depending on the needs and rate of recovery of the individual.
  • the term “bimonthly” means administration once per two months (i.e., once every two months); the term “monthly” means administration once per month; the term “triweekly” means administration once per three weeks (i.e., once every three weeks); the term “biweekly” means administration once per two weeks (i.e., once every two weeks); the term “weekly” means administration once per week; and the term “daily” means administration once per day.
  • the invention additionally pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising an immune checkpoint modulator, as described herein, in a container (e.g., a vial, bottle, bag for intravenous administration, syringe, etc.) with a label containing instructions for administration of the composition for treatment of cancer.
  • a container e.g., a vial, bottle, bag for intravenous administration, syringe, etc.
  • This example illustrates analysis of the mutational landscape of cancer, and demonstrates its effectiveness in defining useful hallmarks of patients that respond favorably or poorly to an immune checkpoint modulator.
  • the example particularly exemplifies analysis of lung cancer patients treated with PD-1 blockade (e.g. pembrolizumab), and defines exemplary mutational characteristics in such patients.
  • PD-1 blockade e.g. pembrolizumab
  • the overall quantity and range of nonsynonymous and exonic mutation burden were similar to published series of NSCLCs (13, 14) ( FIGS. 7A & 7B ).
  • the transition/transversion ratio (Ti/Tv) was 0.74 ( FIG. 8 ), also similar to previously described NSCLCs (13-15).
  • targeted resequencing with an orthogonal method was performed using 376 randomly selected variants and mutations were confirmed in 357 (95%).
  • the validation cohort included an independent set of 18 NSCLC samples from patients treated with pembrolizumab; three patients currently on therapy have not yet reached six months of follow up and are therefore not included in calculations of DCB.
  • the clinical characteristics of the validation cohort were similar to the discovery cohort, although there were more never-smokers in the validation cohort ( 5/18 vs 1/16).
  • POLD1 Glu374 lies in the exonuclease proofreading domain of Pol ⁇ (17), and mutation of this residue may contribute to low fidelity replication of the lagging DNA strand.
  • genes that harbored deleterious mutations common to four or more DCB patients and not present in NDB patients included POLR2A, KEAP1, PAPPA2, PXDNL, RYR1, SCN8A, and SLIT3. Mutations in KRAS were found in 7/14 tumors from patients with DCB compared to 1/17 in the NDB group, a finding that may be explained by the previously reported association between smoking and presence of KRAS mutations in NSCLC (21). There were no mutations or copy number alterations in antigen presentation pathway-associated genes or CD274 (encoding programmed cell death ligand-1, PD-L1) that associated with response or resistance.
  • CD274 encoding programmed cell death ligand-1, PD-L1
  • Predicted HLA-A restricted peptides were synthesized and used to screen for autologous T-cells using a validated high-throughput MHC multimer screening strategy (26, 27) to assess neoantigen-specific reactivity ex vivo in serially collected peripheral blood lymphocytes (PBLs) (Day 0, 21, 44, 63, 256, and 297, where Day 0 is the first date of treatment).
  • PBLs peripheral blood lymphocytes
  • This analysis revealed a dominant CD8+ T-cell response against a neoantigen resulting from a HERC1 P3278S mutation (ASNASSAAK) ( FIGS. 4C ).
  • this T-cell response was below the level of detection at start of therapy (level of detection of 0.005%), but increased to readily detectable levels within 3 weeks post therapy initiation (0.040% of CD8+ T-cells) and was maintained at Day 44 (0.044% of Cd8+ T-cells).
  • This rapid induction of T cell reactivity correlated with tumor regression and returned to levels just above background in the subsequent months as tumor regression plateaued ( FIGS. 4D ).
  • HERC1 P3278S-multimer reactive T-cells from PBLs collected on day 44 were characterized by a CD45RA-CCR7-HLA-DR+LAG-3-phenotype, consistent with an activated effector population ( FIG. 20 ).
  • This example demonstrates the in vitro validation of immunogenic peptides.
  • T-cell checkpoint therapies in a number of cancers (2-5) has confirmed the ability to re-establish a tumor-directed effector T-cell response.
  • NSCLCs treated with pembrolizumab elevated nonsynonymous mutation burden is strongly predictive of clinical efficacy and can be used to identify patients with high likelihood of benefit.
  • clinical efficacy correlates with a molecular signature characteristic of tobacco carcinogen-related mutagenesis, certain DNA repair mutations, and with the burden of neoantigens.
  • cancer exome data from a lung cancer patient to identify an autologous neoantigen-specific peripheral blood T-cell response that correlated temporally with a rapid and durable response to pembrolizumab.
  • T-cell recognition of cancers relies upon presentation of tumor-specific antigens on MHC molecules by cancer cells and professional antigen presenting cells (29).
  • a few elegant pre-clinical (30-33, 66-68) and clinical (25, 34-36, 69) reports have demonstrated that neoantigen-specific effector T-cell response can recognize and shrink established tumors (36).
  • Our finding that nonsynonymous mutation burden was more predictive of clinical benefit with anti-PD-1 therapy compared to total exonic mutation burden suggests the importance of neoantigens in dictating response.
  • the temporal association between the expansion of neoantigen-specific T-cells in peripheral blood with radiographic response to anti-PD-1 therapy is shown.
  • T-cell checkpoint inhibitors have begun to transform the treatment landscape for patients with a number of high prevalence malignancies. These findings impact our understanding of response to anti-PD-1 therapy and on its application in the clinic. The ability to identify those patients most likely to benefit from these therapies, as demonstrated here by analysis of nonsynonymous mutation burden, will contribute to maximizing the clinical value of these novel therapies.
  • NSCLC non-small cell lung cancer
  • All patients initiated therapy in 2012-2013 and were treated at 10 mg/kg every 2-3 weeks, except for 5 patients treated at 2 mg/kg every 3 weeks.
  • the overall response rate and progression-free survival are reported to be similar across dose and schedules (6).
  • All patients had consented to Institutional Review Board-approved protocols permitting tissue collection and sequencing.
  • PD-L1 expression was assessed prospectively by immunohistochemistry using a previously validated murine anti-human anti-PD-L1 antibody (clone 22C3, Merck & Co., Inc.).
  • Membranous expression of PD-L1 on tumor cells and infiltrating immune cells were scored. 31 (91%) scored at least 1% positive for PD-L1 expression; 2 patients were PD-L1 negative; and 1 was unknown. Smoking status was evaluated using previously completed self-reported smoking questionnaires executed as standard of care at MSKCC or review of medical records at UCLA. Patients eligible for this analysis all received at least two doses of study therapy and were evaluable for response to pembrolizumab, and did not prematurely discontinue therapy due to toxicity or withdrawal of consent.
  • tumor tissue used for sequencing was obtained prior to dosing with pembrolizumab, except for one non-responder in whom post-treatment tissue was used (study ID DM123062).
  • Tumor samples used for whole exome sequencing were paraffin-embedded (FFPE).
  • FFPE paraffin-embedded
  • Peripheral blood was collected and DNA isolated from all patients (Nucleospin Blood L, Machery-Nagel). Presence of tumor tissue in the sequenced samples was confirmed by examination of a representative hematoxylin and eosin-stained slide by thoracic pathologists (N.R. or A.M). DNA extraction was performed using the DNEasy kit (Qiagen).
  • HLA typing was performed at the MSKCC HLA typing lab New York Blood Center by high resolution SeCore HLA sequence-based typing method (HLA-SBT) (Invitrogen).
  • HLA-SBT high resolution SeCore HLA sequence-based typing method
  • ATHLATES http://www.broadinstitute.org/scientific-community/science/projects/viral-genomics/athlates (38) was also used for HLA typing and confirmation.
  • Raw sequencing data were aligned to the hg37 genome build using the Burrows-Wheeler Aligner (BWA) version 0.7.10 (39) ( FIG. 6 ). Further indel realignment, base-quality score recalibration and duplicate-read removal were performed using the Genome Analysis Toolkit (GATK) version 3.2.2 (40). Mutations were annotated using SnpEffect version 3.5d (build Mar. 5, 2014) (41). Somatic Sniper version 1.0.0 (42), VarScan version 2.2.3 (43), Strelka version 1.0.13 (44) and MuTect version 1.4 (45) were used to generate single nucleotide variant (SNV) calls using default parameters. VarScan and Strelka were used to generate indel calls.
  • GTK Genome Analysis Toolkit
  • Baseline filters depth of 7 ⁇ coverage in tumor specimens, >97% normal allelic fraction, >10% tumor allelic fraction were chosen.
  • Known single nucleotide polymorphisms SNPs were eliminated by comparison to 1000 Genomes Project, ESP6500 (National Heart, Lung and Blood Institute [NHLBI] GO Exome Sequencing Project) and dbSNP132 (46-48).
  • Single nucleotide polymorphisms SNPs that were rare in the SNP data bases and present in tumors with an allelic fraction of zero in the normal DNA were manually reviewed using Integrative Genomics Viewer (IGV) and included as somatic SNVs (49).
  • the mutation spectrum in each sample was calculated by analyzing nonsynonymous exonic single nucleotide substitutions within their trinucleotide sequence context. That is, for each sample the percentage of each of the six possible single nucleotide changes (C>A:G>T, C>G:G>C, C>T:G>A, T>A:A>T, T>C:A>G, T>G:A>C, with the pyrimidine of the Watson-Crick base pair referenced first) within each of the 16 possible combinations of flanking nucleotides was calculated to generate a 96-feature vector that is used to represent the mutation spectrum for that sample.
  • HLA-A restricted candidate neoantigens were synthesized in-house (Netherlands Cancer Institute) and HLA-multimers containing these peptides were produced by micro-scale parallel UV-induced peptide exchange reactions as previously described (26, 58). Briefly, peptide-MHC complexes loaded with UV-sensitive peptide were subjected to 366-nm UV light (CAMAG) for one hour at 4° C. in the presence of candidate neoantigen peptide in a 384-well plate. pMHC multimers were generated using a total of 11 different fluorescent streptavidin (SA) conjugates (Invitrogen). For each pMHC monomer, conjugation was performed with two of these fluorochromes.
  • SA fluorescent streptavidin
  • HERC1 P3278S MHC multimers were stained with HERC1 P3278S MHC multimers in two colors (qdot 625 (Invitrogen) and PerCPeFluor710 (ebioscience)) plus anti-CD45RA Ab (Invitrogen), anti-CCR7 Ab (BD Bioscience), anti-HLA-DR Ab (BD Bioscience), and anti-LAG-3 Ab (R&D systems).
  • the immunophenotype of HERC1 P3278S reactive and bulk CD8+ T-cells were analyzed. Data were acquired using an LSR II flow cytometer (Becton Dickson) with FASCDiva 6 software.
  • HERC1 P>S mutant and wild type peptides of 9 amino acids in length were synthesized (GenScript Piscataway, N.J.).
  • 1.5 ⁇ 106 patient PBMCs were cultured with 1.5 ⁇ 106 autologous PBMCs pulsed with HERC1 P>S mutant peptide in RPMI media containing 10% pooled human serum (PHS), 10 mM HEPES, 2 mM L Glutamine, and 50 ⁇ M ⁇ -mercaptoethanol supplemented with IL-15 (10 ng/ml) and IL-2 (10 IU/ml), using methods previously described (59).
  • Cells were harvested at day 12, stained with 3 ⁇ L PE-Cy5-CD107a (BD Pharmingen), and either left unstimulated, or stimulated by the addition of (a) mutant peptide or (b) wild type peptide for 2 hours. Cells were then treated with lx Brefeldin A and monensin (BioLegend) for 4 hours, and subsequently stained with 1 ⁇ L Alexa Fluor 405-CD3 (Invitrogen), 3 ⁇ L APC-H7-CD8 (BD Bioscience), and 1 ⁇ L ECD-CD4 (Beckman Coulter).
  • Alexa Fluor 405-CD3 Invitrogen
  • 3 ⁇ L APC-H7-CD8 BD Bioscience
  • ECD-CD4 Beckman Coulter
  • the cells were stained with the following antibodies to intracellular cytokines: 3 ⁇ L Alexa Fluor 647-IFN- ⁇ (Biolegend), 3 ⁇ L PE-MIP-1 ⁇ , and 1 ⁇ L PE-Cy7-TNF- ⁇ (BD Pharmingen). Data were acquired by flow cytometry (using CYAN flow cytometer, Summit software, Dako Cytomation California Inc., Carpinteria, Calif.). Analysis was done by FlowJo version 10.1, TreeStar, Inc. CD3+ single cell lymphocytes were gated for analysis (SS vs. FS [low, mid], FS vs. Pulse Width [all, low], and CD3 vs. “dump” channel [high, low]).
  • This example provides instructions for treatment of a cancer (melanoma) with an antibody immunotherapy (pembrolizumab), as approved by the United States Food & Drug Administration for the treatment of metastatic melanoma.
  • pembrolizumab an antibody immunotherapy
  • long term clinical benefit is observed after pembrolizumab treatment.
  • KEYTRUDA is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1)
  • PD-1 programmed death receptor-1
  • Immune-mediated adverse reactions Administer corticosteroids based on the severity of the reaction. (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)
  • Immune-mediated hepatitis Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue. (5.3)
  • Immune-mediated nephritis Monitor for changes in renal function. Withhold for moderate, and permanently discontinue for severe or life-threatening nephritis. (5.5)
  • Embryofetal Toxicity may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. (5.8)
  • KEYTRUDA® pembrolizumab
  • pembrolizumab is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor [see Clinical Studies (14)].
  • This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • Reconstituted KEYTRUDA is a clear to slightly opalescent, colorless to slightly yellow solution. Discard reconstituted vial if extraneous particulate matter other than translucent to white proteinaceous particles is observed.
  • the product does not contain a preservative.
  • the median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1-34) followed by a corticosteroid taper.
  • Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients.
  • Pneumonitis completely resolved in seven of the nine patients with Grade 2-3 pneumonitis.
  • Colitis occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1.
  • the median time to onset of colitis was 6.5 months (range 2.3-9.8).
  • the median duration was 2.6 months (range 0.6 weeks-3.6 months).
  • All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4-41), followed by a corticosteroid taper.
  • KEYTRUDA One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life threatening (Grade 4) colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
  • Hepatitis occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1.
  • the time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months.
  • the patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event. Monitor patients for changes in liver function.
  • hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1.
  • the median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks-19 months). All but two of the patients with hypothyroidism were treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism.
  • Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
  • KEYTRUDA For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
  • KEYTRUDA may cause fetal harm when administered to a pregnant woman.
  • Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102674A1 (en) * 2018-11-15 2020-05-22 Personal Genome Diagnostics Inc. Method of improving prediction of response for cancer patients treated with immunotherapy
WO2020121226A1 (en) * 2018-12-12 2020-06-18 Medimmune, Llc Blood-based tumor mutation burden predicts overall survival in non-small cell lung cancer
US10993998B2 (en) 2014-11-21 2021-05-04 Memorial Sloan Kettering Cancer Center Determinants of cancer response to immunotherapy by PD-1 blockade
US11279767B2 (en) * 2016-02-29 2022-03-22 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US11300570B2 (en) 2016-10-06 2022-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US20220112556A1 (en) * 2020-10-14 2022-04-14 Shenzhen Neocura Biotechnology Corporation Method and system for calculating tumor neoantigen burden
WO2022099004A1 (en) * 2020-11-06 2022-05-12 The General Hospital Corporation Methods for characterizing biological samples
US11674962B2 (en) 2017-07-21 2023-06-13 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US11725247B2 (en) 2016-02-29 2023-08-15 Foundation Medicine, Inc. Methods of treating cancer
US11896800B2 (en) * 2016-03-01 2024-02-13 North Carolina State University Enhanced cancer immunotherapy by microneedle patch-assisted delivery

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835812A (zh) 2008-12-09 2022-08-02 霍夫曼-拉罗奇有限公司 抗-pd-l1抗体及它们用于增强t细胞功能的用途
ME03527B (me) 2013-12-12 2020-04-20 Shanghai hengrui pharmaceutical co ltd Pd-1 antitijelo, njegov fragment koji se vezuje na antigen, i njegova medicinska primjena
IL251464B2 (en) 2014-10-29 2023-03-01 Five Prime Therapeutics Inc Combination therapy for cancer
GB201516047D0 (en) 2015-09-10 2015-10-28 Cancer Rec Tech Ltd Method
IL259931B2 (en) 2015-12-16 2024-02-01 Gritstone Bio Inc Identification of neo-antigens, preparation, and use
PT3424518T (pt) 2016-03-02 2021-09-22 Toray Industries Indutor de imunidade
WO2017205721A1 (en) 2016-05-27 2017-11-30 Agenus Inc. Anti-tim-3 antibodies and methods of use thereof
JP6910653B2 (ja) * 2016-07-01 2021-07-28 国立大学法人東北大学 免疫チェックポイント阻害薬使用における免疫関連副作用の予測方法
KR20200003294A (ko) * 2016-08-25 2020-01-08 난토믹스, 엘엘씨 면역요법 마커들 및 그 용도들
CA3039402A1 (en) * 2016-10-07 2018-04-12 Omniseq, Inc. Methods and systems for determining personalized therapies
WO2018132753A1 (en) * 2017-01-13 2018-07-19 Nantbio, Inc. Validation of neoepitope-based treatment
US20200232040A1 (en) * 2017-01-18 2020-07-23 Vinod P. Balachandran Neoantigens and uses thereof for treating cancer
WO2018144775A1 (en) 2017-02-01 2018-08-09 Modernatx, Inc. Immunomodulatory therapeutic mrna compositions encoding activating oncogene mutation peptides
JP7162600B2 (ja) * 2017-02-06 2022-10-28 ノヴァルティス アーゲー 免疫療法に対する応答を予測する方法
CN109642259A (zh) * 2017-02-17 2019-04-16 阿姆斯特丹自由大学医学中心基金会 使用肿瘤教育的血小板的针对癌症的群智能增强的诊断和治疗选择
SG11201908530QA (en) * 2017-03-20 2019-10-30 Genocea Biosciences Inc Treatment methods
WO2018183928A1 (en) * 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
GB201710815D0 (en) * 2017-07-05 2017-08-16 Francis Crick Inst Ltd Method
CN111148996A (zh) * 2017-07-28 2020-05-12 百时美施贵宝公司 用于检查点抑制剂的预测性外周血生物标志物
CN111479586A (zh) * 2017-09-13 2020-07-31 戊瑞治疗有限公司 用于胰腺癌的组合抗csf1r和抗pd-1抗体的组合疗法
WO2019055860A1 (en) * 2017-09-15 2019-03-21 The Texas A&M University System METHODS FOR IMPROVING IMMUNOTHERAPY IN THE TREATMENT OF CANCER
JP2020535230A (ja) 2017-09-25 2020-12-03 メモリアル スローン ケタリング キャンサー センター 腫瘍変異負荷
US20200362418A1 (en) * 2017-10-02 2020-11-19 Curematch, Inc. Method of prediction of tumor-derived neo-peptide antigenicity and/or immunogenicity using mutational signature patterns
CN111465989A (zh) 2017-10-10 2020-07-28 磨石肿瘤生物技术公司 使用热点进行的新抗原鉴别
AU2018348249A1 (en) 2017-10-12 2020-04-16 Nantomics, Llc Cancer score for assessment and response prediction from biological fluids
WO2019075468A1 (en) * 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
WO2019090156A1 (en) 2017-11-03 2019-05-09 Guardant Health, Inc. Normalizing tumor mutation burden
AU2018367925A1 (en) * 2017-11-17 2020-07-02 Gmdx Co Pty Ltd Systems and methods for predicting the efficacy of cancer therapy
JP2021503897A (ja) 2017-11-22 2021-02-15 グリットストーン オンコロジー インコーポレイテッド 新生抗原のためのジャンクションエピトープ提示の低減
KR20200093438A (ko) * 2017-12-01 2020-08-05 일루미나, 인코포레이티드 체성 돌연변이 클론형성능을 결정하기 위한 방법 및 시스템
CN112088220B (zh) 2018-05-03 2024-04-19 豪夫迈·罗氏有限公司 替代标志物及用于肿瘤突变负荷测定的方法
KR20210006405A (ko) * 2018-05-04 2021-01-18 메르크 파텐트 게엠베하 암의 치료를 위한 PD-1/PD-L1, TGFβ 및 DNA-PK의 조합 억제
EP3827100A2 (en) 2018-07-23 2021-06-02 Guardant Health, Inc. Methods and systems for adjusting tumor mutational burden by tumor fraction and coverage
EP3830296A1 (en) 2018-07-27 2021-06-09 F. Hoffmann-La Roche AG Method of monitoring effectiveness of immunotherapy of cancer patients
EP3845236A4 (en) * 2018-08-29 2022-07-27 Tokyo Metropolitan Institute of Medical Science ANTI-TUMOR AGENT TARGETING AN HGF-REGULATED TYROSINE KINASE (HGS) SUBSTRATE
EP3844761A1 (en) 2018-08-31 2021-07-07 Guardant Health, Inc. Microsatellite instability detection in cell-free dna
EP3982954A4 (en) * 2019-06-14 2024-01-03 Univ Columbia NT5C2 INHIBITORS FOR THE TREATMENT OF CHEMOTHERAPY-RESISTANT ACUTE LYMPHOBLASTIC LEUKEMIA
GB202003669D0 (en) * 2020-03-13 2020-04-29 Univ Oxford Innovation Ltd Method for identifying neo-antigens
JP2023523450A (ja) 2020-04-28 2023-06-05 ジェネンテック， インコーポレイテッド 非小細胞肺がん免疫療法のための方法及び組成物
WO2022235482A1 (en) * 2021-05-03 2022-11-10 Rutgers, The State University Of New Jersey Immunotherapy for inflammatory bowel disease and/or cancer
CN113030475B (zh) * 2021-05-25 2021-08-10 泛肽生物科技(浙江)有限公司 一种基于细胞线粒体质量评估的t细胞pd-1检测方法
CN113355424B (zh) * 2021-07-14 2022-03-25 江苏先声医学诊断有限公司 Pcdh11x突变在预测非小细胞肺癌患者对免疫检查点抑制剂疗法敏感性中的应用

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040033497A1 (en) 2002-08-13 2004-02-19 Alarcon-Riquelme Marta E. Polymorphisms of PD-1
TWI477602B (zh) 2006-02-09 2015-03-21 Educational Foundation Jichi Medical Univ Novel viral vector
EP2499486A4 (en) * 2009-11-13 2013-11-27 Infinity Pharmaceuticals Inc COMPOSITIONS, KITS, AND METHODS FOR IDENTIFICATION, EVALUATION, PREVENTION, AND THERAPY OF CANCER
GB201004551D0 (en) * 2010-03-19 2010-05-05 Immatics Biotechnologies Gmbh NOvel immunotherapy against several tumors including gastrointestinal and gastric cancer
US9169325B2 (en) * 2010-04-13 2015-10-27 Celldex Therapeutics, Inc. Antibodies that bind human CD27 and uses thereof
ES2788863T3 (es) * 2010-05-14 2020-10-23 Massachusetts Gen Hospital Composiciones de neoantígenos específicos de un tumor para uso en el tratamiento de tumores
SG11201406592QA (en) 2012-05-04 2014-11-27 Pfizer Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2014052707A2 (en) * 2012-09-28 2014-04-03 The University Of Connecticut Identification of tumor-protective epitopes for the treatment of cancers
PE20161344A1 (es) * 2014-01-02 2016-12-23 Memorial Sloan Kettering Cancer Center Determinantes de respuesta del cancer a la inmunoterapia
SG10201914022QA (en) * 2014-11-13 2020-03-30 Univ Johns Hopkins Checkpoint blockade and microsatellite instability
MA40737A (fr) 2014-11-21 2017-07-04 Memorial Sloan Kettering Cancer Center Déterminants de la réponse d'un cancer à une immunothérapie par blocage de pd-1
JP2020535230A (ja) * 2017-09-25 2020-12-03 メモリアル スローン ケタリング キャンサー センター 腫瘍変異負荷

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10993998B2 (en) 2014-11-21 2021-05-04 Memorial Sloan Kettering Cancer Center Determinants of cancer response to immunotherapy by PD-1 blockade
US11279767B2 (en) * 2016-02-29 2022-03-22 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US11725247B2 (en) 2016-02-29 2023-08-15 Foundation Medicine, Inc. Methods of treating cancer
US11896800B2 (en) * 2016-03-01 2024-02-13 North Carolina State University Enhanced cancer immunotherapy by microneedle patch-assisted delivery
US11300570B2 (en) 2016-10-06 2022-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US11674962B2 (en) 2017-07-21 2023-06-13 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2020102674A1 (en) * 2018-11-15 2020-05-22 Personal Genome Diagnostics Inc. Method of improving prediction of response for cancer patients treated with immunotherapy
WO2020121226A1 (en) * 2018-12-12 2020-06-18 Medimmune, Llc Blood-based tumor mutation burden predicts overall survival in non-small cell lung cancer
US20220112556A1 (en) * 2020-10-14 2022-04-14 Shenzhen Neocura Biotechnology Corporation Method and system for calculating tumor neoantigen burden
US11967399B2 (en) * 2020-10-14 2024-04-23 Shenzhen Neocura Biotechnology Corporation Method and system for calculating tumor neoantigen burden
WO2022099004A1 (en) * 2020-11-06 2022-05-12 The General Hospital Corporation Methods for characterizing biological samples

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