Methods of treating cancer using immune checkpoint inhibitors

Abstract

The present invention provides a method for treating HPV-positive head and neck squamous cell carcinoma, comprising administering to the subject an immune checkpoint inhibitor, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody. The present invention also provides a method for treating HPV-negative head and neck squamous cell carcinoma, comprising administering to the subject an immune checkpoint inhibitor, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody. The subject can additionally be administered another anti-cancer agent.

Description

This application is a divisional application of Chinese patent application No. 201680052756.8 (filed on July 14, 2016, entitled "Method for Treating Cancer Using Immune Checkpoint Inhibitors").

[0001] In this application, various publications are cited in parentheses by author name and date, or by patent number or patent publication number. Full references to these publications can be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated in their entirety by reference to provide a more comprehensive description of the state of the prior art known to those skilled in the art at the date of the invention described and claimed herein. However, references to these references should not be construed as an admission that such references are prior art to the invention. Background Technology

[0002] Human cancers exhibit numerous genetic and epigenetic alterations, resulting in neoantigens that can potentially be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprising T and B lymphocytes, possesses potent anti-cancer potential, exhibiting broad capabilities and fine specificity in responding to diverse tumor antigens. Furthermore, the immune system displays considerable plasticity and a memory component. Successful utilization of all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

[0003] Until recently, cancer immunotherapy has focused primarily on protocols that enhance anti-tumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the delivery of non-specific immune stimulants such as cytokines. However, intensive efforts over the past decade to develop specific immune checkpoint pathway inhibitors have begun to offer new immunotherapeutic options for cancer treatment, including the development of the antibody (Ab) ipilimumab (YERVOY®) that binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al. (2010) N Engl J Med 363:711-23), and the development of antibodies such as nivolumab and pembrolizumab (formerly lambolizumab; USAN Council Statement (2013) Pembrolizumab: Statement on a nonproprietary name adopted by the USAN Council (ZZ-165), November 27, 2013), which specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1 / PD-1 ligand pathway (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12; Topalian et al. (2014) J Clin Oncol 32(10):1020-30; Hamid et al. (2013) N Engl J Med 369:134-144; Hamid and Carvajal (2013) Expert Opin Biol Ther 13(6):847-61; McDermott and Atkins (2013) Cancer Med 2(5):662-73.

[0004] PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively blocks the interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of anti-tumor T-cell function (US Patent No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivotoxicology in non-human primates, Cancer Imm Res, in print). Nirumab has been approved for the treatment of patients with unresectable or metastatic melanoma and for disease progression after ipilimumab, and as a BRAF inhibitor if BRAF V600 mutation positive, and for the treatment of squamous non-small cell lung cancer. Invention Overview The present invention provides a method for treating a subject suffering from a tumor derived from human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN), the method comprising administering to the subject a therapeutically effective amount of an antibody or its antigen-binding moiety thereof that specifically binds to programmed death-1 receptor (PD-1) or programmed death-ligand 1 (PD-L1) and inhibits PD-1 activity (“anti-PD-1 antibody”) or PD-L1 activity (“anti-PD-L1 antibody”).

[0005] The present invention also provides a method for treating a subject suffering from a tumor, the tumor being derived from an HPV-positive SCCHN, the method comprising: (i) measuring the HPV level in a sample of the subject, wherein the subject is HPV-positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion thereof or an anti-PD-L1 antibody or its antigen-binding portion thereof.

[0006] The present invention also provides a method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-positive, and wherein a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to the subject.

[0007] The present invention also provides a method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising: (i) measuring the HPV level in a sample of the subject, wherein the subject is HPV-positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion thereof or an anti-PD-L1 antibody or its antigen-binding portion thereof.

[0008] In some embodiments, the method further includes administering one or more additional anticancer drugs. In one particular embodiment, the anticancer drug is selected from: antibodies or their antigen-binding portions that specifically bind to and inhibit CTLA-4 activity, chemotherapy, platinum-based two-drug chemotherapy, tyrosine kinase inhibitors, anti-VEGF inhibitors, or any combination thereof.

[0009] The present invention also provides a method for treating a subject suffering from a tumor derived from human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN), the method comprising administering to the subject a therapeutically effective amount of an antibody or its antigen-binding moiety thereof that specifically binds to programmed death-1 receptor (PD-1) or programmed death-ligand 1 (PD-L1) and inhibits PD-1 activity (“anti-PD-1 antibody”) or PD-L1 activity (“anti-PD-L1 antibody”).

[0010] The present invention also provides a method for treating a subject suffering from a tumor originating from an HPV-negative SCCHN, the method comprising: (i) measuring the HPV level in a sample of the subject, wherein the subject is HPV-negative, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion thereof or an anti-PD-L1 antibody or its antigen-binding portion thereof.

[0011] The present invention also provides a method for identifying a subject suffering from a tumor derived from an HPV-negative SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-negative, and wherein a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to the subject.

[0012] The present invention also provides a method for identifying a subject suffering from a tumor derived from an HPV-negative SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising: (i) measuring the HPV level in a sample of the subject, wherein the subject is HPV-negative, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion thereof or an anti-PD-L1 antibody or its antigen-binding portion thereof.

[0013] The present invention also provides a kit for treating a subject suffering from a tumor derived from an HPV-positive SCCHN, the kit comprising: (a) an anti-PD-1 antibody or an antigen-binding portion thereof or an anti-PD-L1 antibody or an antigen-binding portion thereof; (b) instructions for determining HPV positivity of the tumor, and, if the tumor is HPV-positive, administering the anti-PD-1 antibody or an antigen-binding portion thereof or the anti-PD-L1 antibody or an antigen-binding portion thereof to the subject in the method described herein.

[0014] The present invention also provides a kit for treating a subject suffering from a tumor derived from an HPV-negative SCCHN, the kit comprising: (a) an anti-PD-1 antibody or an antigen-binding portion thereof or an anti-PD-L1 antibody or an antigen-binding portion thereof; (b) instructions for determining the HPV-negativity of the tumor, and, if the tumor is HPV-negative, administering the anti-PD-1 antibody or an antigen-binding portion thereof or the anti-PD-L1 antibody or an antigen-binding portion thereof to the subject in the method described herein. Brief description of the attached diagram Figure 1 This provides a schematic diagram of a non-comparative, two-cohort, single-arm, label-open, phase 1 / 2 study of nirumab in a subject with both virus-positive and virus-negative solid tumors, which will be performed to evaluate the safety, tolerability, and potency of nirumab in a subject with selected virus-positive and virus-negative tumors. The study is designed with two cohorts: a neoadjuvant therapy cohort (“neoadjuvant therapy”) and a metastatic / recurrent cohort (“metastatic”). Invention Details the term To facilitate a clearer understanding of this invention, certain terms are first defined. As used herein, unless otherwise expressly provided, each of the following terms shall have the following meaning. Further definitions are set forth in this application.

[0015] "Administration" means introducing a composition containing a therapeutic agent into a physical body using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration for immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to administration modalities other than enteral and local administration, typically performed by injection, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some embodiments, the immune checkpoint inhibitor (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) is administered via a non-parenteral route; in some embodiments, it is administered orally. Other non-parenteral routes include local, epidermal, or mucosal application, such as intranasal, vaginal, rectal, sublingual, or topical. Application may also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0016] As used herein, an “adverse event” (AE) is any adverse and generally unintentional or undesirable indication (including abnormal laboratory findings), symptom, or illness associated with the application of a medical treatment. For example, an adverse event may be associated with activation of the immune system in response to treatment or expansion of immune system cells (e.g., T cells). Medical treatments may have one or more associated AEs, and each AE may have the same or different levels of severity. References to methods capable of “modifying adverse events” refer to treatment regimens that reduce the incidence and / or severity of one or more AEs associated with the application of different treatment regimens.

[0017] An "antibody" (Ab) should include, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen and contain at least two heavy (H) chains and two light (L) chains linked by disulfide bonds, or their antigen-binding portions. Each H chain contains a heavy chain variable region (abbreviated as V in this document). H The heavy chain constant region contains three constant structural domains C. H1 C H2 and C H3 Each light chain contains a light chain variable region (abbreviated as V in this article). L ) and the light chain constant region. The light chain constant region contains a constant structural domain C L V H and V LThe region can be further subdivided into highly variable regions known as complementarity-determining regions (CDRs), interspersed with more conservative regions known as framing regions (FRs). Each V H and V L It contains three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0018] Immunoglobulins can be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to an antibody class or subclass (e.g., IgM or IgG1) encoded by a heavy chain constant region gene. In some embodiments, one or more amino acids in the isotype can be mutated to alter effector function. The term "antibody" includes, for example, naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or non-human Abs; fully synthetic Abs; and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless explicitly stated otherwise, and unless the context otherwise indicates, the term "antibody" also includes antigen-binding fragments or antigen-binding portions of any of the aforementioned immunoglobulins, and includes monovalent and bivalent fragments or portions, and single-chain antibodies.

[0019] "Isolated antibody" refers to an antibody that substantially does not contain other antibodies with different antigen specificities (e.g., isolated antibodies that specifically bind to PD-1 substantially do not contain antibodies that specifically bind to antigens other than PD-1). However, isolated antibodies that specifically bind to PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. Furthermore, isolated antibodies may substantially not contain other cellular material and / or chemicals.

[0020] The term "monoclonal antibody" ("mAb") refers to a non-natural preparation of an antibody molecule consisting of a single molecule (i.e., an antibody molecule whose basic sequence is substantially identical and which exhibits single binding specificity and affinity for a specific epitope). mAb is an example of an isolated antibody. mAbs can be produced using hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those skilled in the art.

[0021] A "human" antibody (HuMAb) indicates an antibody having a variable region, wherein both the frame region and the CDR region are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, then that constant region is also derived from a human germline immunoglobulin sequence. The human antibodies of this invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced through random or site-specific in vitro mutagenesis or in vivo somatic mutation). However, the term "human antibody" as used herein is not intended to include antibodies in which a germline-derived CDR sequence from another mammalian species (such as a mouse) has been grafted onto a human frame sequence. The terms "human" antibody and "fully human" antibody are used synonymously.

[0022] "Humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDR domain of a non-human antibody are replaced by corresponding amino acids derived from human immunoglobulins. In one embodiment of the humanized form of the antibody, some, most, or all of the amino acids outside the CDR domain have been replaced by amino acids from human immunoglobulins, while some, most, or all of the amino acids within one or more CDR regions remain unchanged. Minor additions, deletions, insertions, substitutions, or modifications of amino acids are permitted, as long as they do not abolish the antibody's ability to bind a specific antigen. "Humanized" antibodies retain antigen specificity similar to that of the original antibody.

[0023] "Chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species, such as an antibody in which the variable region is derived from a mouse antibody and the constant region is derived from a human antibody.

[0024] "Anti-antigen" antibodies are antibodies that specifically bind to antigens. For example, anti-PD-1 antibodies specifically bind to PD-1, and anti-CTLA-4 antibodies specifically bind to CTLA-4.

[0025] An antibody's "antigen-binding portion" (also known as an "antigen-binding fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to antigens bound by the intact antibody.

[0026] “Cancer” refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Disordered cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. As used herein, “cancer” refers to primary, metastatic, and recurrent cancer. In some embodiments, the cancer is head and neck cancer. In other embodiments, the cancer is squamous cell carcinoma of the head and neck. In some embodiments, the cancer is human papillomavirus (HPV) positive cancer. In other embodiments, the cancer is HPV negative cancer. In some embodiments, the cancer is HPV positive squamous cell carcinoma of the head and neck. In other embodiments, the cancer is HPV negative squamous cell carcinoma of the head and neck. In other embodiments, the cancer is nasopharyngeal carcinoma. In various embodiments, the cancer is Merkel cell carcinoma. In some embodiments, the Merkel cell carcinoma is polyomavirus-related. In other embodiments, the cancer is cervical cancer, vaginal cancer, or vulvar cancer. In some embodiments, the cancer is HPV-positive cervical cancer, vaginal cancer, or vulvar cancer. In other embodiments, the cancer is HPV-negative cervical cancer, vaginal cancer, or vulvar cancer. In some embodiments, the cancer is Epstein-Barr virus (EBV)-positive cancer. In other embodiments, the cancer is EBV-negative cancer. In some embodiments, the cancer is gastric cancer, including gastroesophageal junction cancer (including adenocarcinoma originating from the lower esophagus). In other embodiments, the cancer is EBV-positive gastric cancer. In other embodiments, the cancer is EBV-negative gastric cancer. In other embodiments, the cancer is EBV-positive nasopharyngeal carcinoma. In other embodiments, the cancer is EBV-negative nasopharyngeal carcinoma.

[0027] "Cytotoxic T-lymphocyte antigen-4" (CTLA-4) represents an immunosuppressive receptor belonging to the CD28 family. CTLA-4 is exclusively expressed on T cells in vivo and binds to two ligands, CD80 and CD86 (also known as B7-1 and B7-2, respectively). As used herein, the term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants of hCTLA-4, allotypes and species homologs, and analogs that share at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found in GenBank under accession number AAB59385.

[0028] As used herein, “dosing interval” refers to the amount of time elapsed between multiple doses of the disclosed formulation administered to the subject. Therefore, dosing intervals can be indicated as ranges.

[0029] The term “dosing frequency” as used herein refers to the frequency of administration of a dose of the formulation disclosed herein at a given time. Dosing frequency may be indicated as the number of doses at each given time, for example, once a week or once every two weeks.

[0030] As used herein, “EBV positive” refers to a subject with cancer that is positive for Epstein-Barr virus (EBV; also known as human herpesvirus 4). As used herein, “EBV negative” refers to a subject with cancer that is negative for EBV. In some embodiments, the EBV status of said subject is determined as follows: by using EBER (a small RNA encoding Epstein-Barr virus) in situ hybridization to detect EBV-specific small RNA, by using polymerase chain reaction (PCR) to amplify and detect EBV-specific DNA, or by using any other method known in the art. In some embodiments, more than about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% of tumor cells show nuclear staining for EBER in in situ hybridization, and the tumor is considered EBV positive. In one embodiment, more than about 5% of tumor cells show nuclear staining for EBER in in situ hybridization, and the tumor is considered EBV positive. In another embodiment, more than about 50% of tumor cells show nuclear staining for EBER in in situ hybridization, and the tumor is considered EBV positive. In other embodiments, approximately 5%, 4%, 3%, 2%, or 1% of tumor cells show nuclear staining for EBER in in situ hybridization, and the tumor is considered EBV negative.

[0031] As used herein, "polyomavirus-positive" or "polyomavirus-associated" refers to a subject with a polyomavirus-positive cancer. Polyomaviruses are small, non-enveloped DNA viruses, some of which have been found to be associated with certain types of cancer. Merkel cell polyomavirus (MCPyV) has been found in tumor cells of squamous cell carcinoma of the skin, basal cell carcinoma, Bowen's disease, non-small cell lung cancer, and cervical cancer. In some embodiments, the polyomavirus status of the subject is determined as follows: using PCR (including, but not limited to, real-time PCR and reverse transcription PCR) with primers targeting polyomavirus DNA, immunohistochemistry targeting polyomavirus-specific proteins, or any other method known in the art. In some embodiments, more than about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% of tumor cells exhibit strong and diffuse nuclear and / or cytoplasmic staining by immunohistochemistry against one or more polyomavirus-specific antigens, and the tumor is considered polyomavirus-positive. In one embodiment, more than about 5% of tumor cells exhibit strong and diffuse nuclear and / or cytoplasmic staining by immunohistochemistry against one or more polyomavirus-specific antigens, and the tumor is considered polyomavirus-positive. In another embodiment, at least about 50% of the tumor cells exhibit strong and diffuse nuclear and / or cytoplasmic staining by immunohistochemistry against one or more polyomavirus-specific antigens, and the tumor is considered polyomavirus-positive. In other embodiments, equal to or less than about 5%, about 4%, about 3%, about 2%, or about 1% of the tumor cells exhibit strong and diffuse nuclear and / or cytoplasmic staining by immunohistochemistry against one or more polyomavirus-specific antigens, and the tumor is considered polyomavirus-negative. In other embodiments, equal to or less than 5% of the tumor cells exhibit strong and diffuse nuclear and / or cytoplasmic staining by immunohistochemistry against one or more polyomavirus-specific antigens, and the tumor is considered polyomavirus-negative.

[0032] The term "flat dose" is used to describe a dose administered to a patient regardless of their weight or body surface area (BSA). Therefore, a flat dose is provided as a mg / kg dose, rather than as an absolute amount of the drug (e.g., anti-PD-1 antibody). For example, a 60 kg person and a 100 kg person would receive the same dose of antibody (e.g., 240 mg anti-PD-1 antibody).

[0033] The application of the term "fixed dose" in relation to the compositions of the present invention refers to the presence of two or more different antibodies in a single composition at a specific (fixed) ratio to each other in the composition. In some embodiments, the fixed dose is based on the weight (e.g., mg) of the antibodies. In some embodiments, the fixed dose is based on the concentration (e.g., mg / ml) of the antibodies. In some embodiments, the ratio of mg first antibody to mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, or about 1:18. 0, approximately 1:200, approximately 200:1, approximately 180:1, approximately 160:1, approximately 140:1, approximately 120:1, approximately 100:1, approximately 90:1, approximately 80:1, approximately 70:1, approximately 60:1, approximately 50:1, approximately 40:1, approximately 30:1, approximately 20:1, approximately 15:1, approximately 10:1, approximately 9:1, approximately 8:1, approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, or approximately 2:1. For example, a 3:1 ratio of primary antibody to secondary antibody could mean that the vial contains approximately 240 mg of primary antibody and 80 mg of secondary antibody, or approximately 3 mg / ml of primary antibody and 1 mg / ml of secondary antibody.

[0034] The term "weight-based dosage" as used in this article refers to the dosage administered to a patient based on the patient's weight. For example, when a patient weighing 60 kg requires 3 mg / kg of anti-PD-1 antibody and 1 mg / kg of anti-CTLA-4 antibody, an appropriate amount of anti-PD-1 antibody (i.e., 180 mg) and anti-CTLA-4 antibody (i.e., 60 mg) can be drawn at once from a fixed-dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody in a 3:1 ratio.

[0035] As used herein, "HPV" refers to Human Papillomavirus. HPV is a collection of more than 200 viruses. Low-risk HPV does not cause cancer. High-risk HPV can cause cancer. In some embodiments, the HPV subtype can be any type of HPV. In some embodiments, the HPV is HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, or any combination thereof.

[0036] As used herein, "HPV positive" refers to a subject with HPV-positive cancer. "HPV negative" refers to a subject with HPV-negative cancer. In some embodiments, determining the HPV status of a subject includes determining whether the cancerous tumor expresses one or more HPV-derived proteins or nucleotide sequences encoding said one or more proteins. In some embodiments, a tumor is considered HPV positive if more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than about 95%, more than about 99%, or more than about 100% of the tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16. In a specific embodiment, a tumor is considered HPV positive if more than about 70% of the tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16. In some embodiments, tumor cells of about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 1% exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16, and the tumor is considered HPV negative. In other embodiments, tumor cells of about 30% or less exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16, and the tumor is considered HPV negative.

[0037] The term "immunotherapy" refers to the treatment of a subject who has a disease or is at risk of infection or disease recurrence by means of methods including inducing, enhancing, suppressing, or otherwise altering an immune response. "Treatment" or "therapy" for a subject refers to any type of intervention or process performed on the subject, or the administration of an active agent to the subject, with the aim of reversing, alleviating, improving, suppressing, slowing, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, or conditions, or disease-related biochemical markers.

[0038] As used herein, "PD-L1 positive" may be used interchangeably with "at least about 1% PD-L1 expression". In one embodiment, PD-L1 expression may be used by any method known in the art. In another embodiment, PD-L1 expression is measured by automated IHC. PD-L1 positive tumors may therefore have at least about 1%, at least about 2%, at least about 5%, at least about 10%, or at least about 20% of tumor cells expressing PD-L1, as determined by automated IHC. In some embodiments, "PD-L1 positive" means the presence of at least 100 cells expressing PD-L1 on their cell surface.

[0039] “Programmed death-1 (PD-1)” refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is primarily expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term “PD-1” includes human PD-1 (hPD-1), variants, allotypes, and species homologs of hPD-1, as well as analogs that share at least one common epitope with hPD-1. The complete hPD-1 sequence can be found in GenBank under GenBank accession number U64863.

[0040] Programmed death-ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands (the other being PD-L2) that target PD-1, and which downregulates T cell activation and cytokine secretion upon binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, allotypes, and species homologs of hPD-L1, as well as analogs sharing at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found in GenBank under accession number Q9NZQ7.

[0041] The term "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0042] A “therapeuticly effective amount” or “therapeutic dose” of a drug or therapeutic agent is any amount of the drug, when used alone or in combination with another therapeutic agent, that protects a subject from the onset of disease or promotes disease remission, demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic phases, or prevention of damage or disability caused by disease suffering. The ability of a therapeutic agent to promote disease remission can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predicting efficacy for humans, or by determining the activity of the drug in in vitro assays.

[0043] As used in this article, “subtherapeutic dose” refers to a dose of a therapeutic compound (e.g., an antibody) that is below the usual or typical dose of the therapeutic compound when administered alone for the treatment of hyperproliferative diseases (e.g., cancer).

[0044] As an example, "anticancer drugs" promote cancer regression in a host or prevent further tumor growth. In some implementations, a therapeutically effective amount of the drug promotes cancer regression to the point of cancer elimination. "Promoting cancer regression" means that, alone or in combination with an antitumor agent, an effective amount of the drug results in a reduction in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of asymptomatic phases, or prevention of damage or disability caused by disease suffering. Furthermore, the terms "effective" and "efficacy" in relation to treatment include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level caused by drug administration.

[0045] As an example of its use in treating tumors, a therapeutically effective amount of anticancer drug, relative to an untreated subject, or, in some embodiments, relative to a patient treated with standard of care, can inhibit cell or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the invention, tumor regression can be observed and persist for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of treatment effectiveness, the evaluation of immunotherapeutic drugs must also consider “immune-related” response patterns.

[0046] The “immune-related” response pattern refers to a clinical response pattern frequently observed in cancer patients treated with immunotherapies that exert their antitumor effects by inducing cancer-specific immune responses or by altering innate immune processes. This response pattern is characterized by a beneficial therapeutic effect following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and synonymous with drug failure in the evaluation of conventional chemotherapy. Therefore, appropriate evaluation of immunotherapies may require long-term monitoring of the effects of these agents on the target disease.

[0047] Therapeutic effective amounts of a drug include "preventative effective amounts," which are any amounts of drug that, when administered alone or in combination with an antitumor agent to a subject at risk of developing cancer (e.g., a subject with a pre-existing condition that has worsened) or a subject at risk of cancer recurrence, inhibit the occurrence or recurrence of cancer. In some embodiments, preventative effective amounts completely prevent the occurrence or recurrence of cancer. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of cancer occurring or recurring, or completely preventing the occurrence or recurrence of cancer.

[0048] The use of alternatives (e.g., "or") should be understood to mean any one, two, or any combination of the alternatives. The indefinite articles "a" or "an" as used herein should be understood to mean "one or more / a combination of" any enumerated or listed components.

[0049] The terms “about” or “substantially comprise” mean a value or composition within an acceptable margin of error for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measuring system. For example, “about” or “substantially comprise” can mean within one or more standard deviations, as practiced in the art. Alternatively, “about” or “substantially comprise” can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the term can mean up to an order of magnitude or up to a maximum of 5 times the numerical value. When a particular value or composition is provided in this application and claims, unless otherwise stated, the meaning of “about” or “substantially comprise” should be assumed to be within an acceptable margin of error for that particular value or composition.

[0050] The terms “about once a week,” “about once every two weeks,” or any other similar dosing interval terms used herein refer to approximate values. “About once a week” can include every 7 days ± 1 day, i.e., every 6 to 8 days. “About once every two weeks” can include every 14 days ± 3 days, i.e., every 11 to 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In some embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose can be administered on any day of the first week, and then the second dose can be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a specific day of the first week (e.g., Monday), and then the second dose is administered on the same day of the sixth or twelfth week (i.e., Monday), respectively. Similar principles apply to phrases including, but not limited to, “about once every 2 weeks,” “about once a month,” etc.

[0051] As described herein, any concentration range, percentage range, ratio range, or integer range shall be understood to include the value of any integer within the enumerated range, and, where appropriate, to include fractions (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0052] Different aspects of the invention are described in more detail in the following sections.

[0053] The method of the present invention This invention provides a method for treating virus-related, virus-derived, or virus-caused cancers using one or more immune checkpoint inhibitors (e.g., anti-PD-1 antibody or its antigen-binding portion or anti-PD-L1 antibody or its antigen-binding portion) as monotherapy or in combination with other anticancer drugs. In one embodiment, the cancer is a solid tumor. In another embodiment, the cancer is primary cancer. In other embodiments, the cancer is metastatic or recurrent cancer. In some embodiments, the subject is a human patient. In some embodiments, the subject is a chemotherapy-naïve patient (e.g., a patient who has not previously received any chemotherapy). In other embodiments, the subject has received another cancer treatment (e.g., chemotherapy), but is resistant or refractory to such another cancer treatment.

[0054] In some embodiments, the present invention relates to a method for treating a subject with a tumor that is HPV-related, HPV-derived, or caused by HPV, the method comprising administering a therapeutically effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion) as a monotherapy or in combination with one or more anticancer drugs. In some embodiments, the invention includes a method for treating HPV-positive tumors, the method comprising administering an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion). HPV contributes as a pathogenic factor in several types of cancer, including cervical cancer, anal cancer, head and neck cancer (including oropharyngeal cancer), vaginal cancer, vulvar cancer, and penile cancer. HPV causes 5% of all cancers worldwide. In some embodiments, the method of the present invention relates to a method for identifying a subject with HPV-positive cancer. There are over 200 related HPV viruses in the HPV family, including subtypes 6, 11, 16, 18, 30, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 66, 68, and other unidentified subtypes. In some embodiments, the HPV subtype is HPV subtype 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, or any combination thereof. In some embodiments, the HPV subtype is HPV subtype 16. In some embodiments, the HPV subtype is HPV subtype 18. In some embodiments, more than about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% of tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16, and the tumor is considered HPV positive. In a specific embodiment, more than about 70% of tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16, and the tumor is considered HPV positive.

[0055] In some embodiments, the present invention provides a method for treating a subject with a tumor derived from HPV-positive squamous cell carcinoma of the head and neck (SCCHN), the method comprising administering a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-L1 antibody, to the subject. In some embodiments, the present invention relates to a method for treating a subject with a tumor derived from HPV-positive SCCHN, the method comprising: (i) measuring HPV levels in a sample of the subject, wherein the subject is HPV-positive, and (ii) administering a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or its antigen-binding portion, or an anti-PD-L1 antibody or its antigen-binding portion, to the subject. In some embodiments, the anti-PD-1 antibody is nilucanumab. In other embodiments, the anti-PD-1 antibody competitively binds to nilucanumab. In other embodiments, the anti-PD-1 antibody is pembrolizumab. In other embodiments, the anti-PD-1 antibody competitively binds to pembrolizumab. In other embodiments, the anti-PD-1 antibody is BGB-A317 or competitively binds to BGB-A317. In some embodiments, the PD-L1 antibody is BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C or competitively binds to BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C.

[0056] In some embodiments, the present invention relates to a method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for immune checkpoint inhibitor therapy (e.g., anti-PD-1 antibody or anti-PD-L1 antibody therapy), the method comprising measuring the HPV level in a sample of the subject, wherein the subject is HPV-positive, and wherein a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion, is administered to the subject. In some embodiments, the present invention relates to a method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for immune checkpoint inhibitor therapy (e.g., anti-PD-1 antibody or anti-PD-L1 antibody therapy), the method comprising: (i) measuring the HPV level in a sample of the subject, wherein the subject is HPV-positive, and (ii) administering a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion, to the subject.

[0057] In some embodiments, the cancer treated by the methods disclosed herein is HPV negative. In some embodiments, the present invention relates to a method for treating a subject with an HPV-negative tumor, the method comprising administering a therapeutically effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion) as a monotherapy or in combination with one or more anticancer drugs. In some embodiments, the method of the present invention relates to a method for identifying a subject with HPV-negative cancer. In some embodiments, tumors are considered HPV-negative if equal to or less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 1% of tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16. In other embodiments, tumors are considered HPV-negative if equal to or less than 30% of tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry against p16.

[0058] In some embodiments, the present invention provides a method for treating a subject with a tumor originating from an HPV-negative SCCHN, the method comprising administering a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-L1 antibody, to the subject. In some embodiments, the present invention relates to a method for treating a subject with a tumor originating from an HPV-negative SCCHN, the method comprising: (i) measuring HPV levels in a sample of the subject, wherein the subject is HPV-negative, and (ii) administering a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 antibody or its antigen-binding portion, or an anti-PD-L1 antibody or its antigen-binding portion, to the subject. In some embodiments, the anti-PD-1 antibody is nilucanumab. In other embodiments, the anti-PD-1 antibody competitively binds to nilucanumab. In other embodiments, the anti-PD-1 antibody is pembrolizumab. In other embodiments, the anti-PD-1 antibody competitively binds to pembrolizumab. In other embodiments, the anti-PD-1 antibody is BGB-A317 or competitively binds to BGB-A317. In other embodiments, the PD-L1 antibody is BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C or competitively binds to BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C.

[0059] In some embodiments, the present invention relates to a method for identifying a subject suffering from a tumor derived from an HPV-negative SCCHN, the subject being suitable for immune checkpoint inhibitor therapy (e.g., anti-PD-1 antibody or anti-PD-L1 antibody), the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-negative, and wherein a therapeutically effective amount of an immune checkpoint inhibitor therapy, such as an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion, is administered to the subject. In some embodiments, the present invention relates to a method for identifying a subject suffering from a tumor derived from an HPV-negative SCCHN, the subject being suitable for immune checkpoint inhibitor therapy (e.g., anti-PD-1 antibody or anti-PD-L1 antibody therapy), the method comprising: (i) measuring HPV levels in a sample of the subject, wherein the subject is HPV-negative, and (ii) administering a therapeutically effective amount of an immune checkpoint inhibitor therapy, such as an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion, to the subject.

[0060] In some embodiments, the HPV measurement disclosed herein includes identifying the expression of one or more HPV-derived proteins or nucleotide sequences encoding said one or more proteins. In other embodiments, said one or more HPV-derived proteins include p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7, or any combination thereof. In other embodiments, said nucleotide sequences encode p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7, or any combination thereof.

[0061] In other embodiments, one or more HPV-derived proteins are identified by immunohistochemistry, ELISA, Western blotting, or protein arrays, or any other assay known in the art. In other embodiments, nucleotide sequences are identified by in situ hybridization, DNA or RNA arrays or nucleotide hybridization, tumor sequencing, or quantitative polymerase chain reaction (PCR), or any other assay known in the art. See, for example, Burd, E., Clin. Microbiol. Rev. Jan 2003; 16(1): 1-17. In some embodiments, HPV DNA is detected using type-specific PCR, common primer PCR, or liquid hybridization. In some embodiments, mRNA is examined using an In-Cell (Invirion, Frankfurt, Mich.) viral load assay. In other embodiments, HPV measurement includes monolayer cytology or histopathology. In other embodiments, HPV measurement is performed using any assay known in the art. In some embodiments, the sample contains a primary tumor or metastatic lymph nodes.

[0062] In some embodiments, the cancer treated by this invention is EBV-positive cancer. In some embodiments, this invention relates to the use of immune checkpoint inhibitors (e.g., PD-1 antibodies or their antigen-binding portions or PD-L1 antibodies or their antigen-binding portions) as monotherapy or in combination with other anticancer drugs for the treatment of EBV-positive cancer. EBV is an enveloped virus and a member of the herpesvirus family. Cancers considered to be associated with EBV include, but are not limited to, nasopharyngeal carcinoma (NPC), gastric adenocarcinoma, high-grade lymphomas (such as Burkitt lymphoma and some large B-cell lymphomas), some Hodgkin lymphomas, lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphomas, peripheral T-cell lymphomas, NK-cell tumors, and leukemias and inflammatory pseudotumor-like follicular dendritic cell tumors. Treatment of EBV-related tumors may include the use of antiviral agents (including ganciclovir, famciclovir, acyclovir, valacyclovir, foscarnet, and cidofovir) and immunotherapy (including the use of monoclonal antibodies such as those targeting CD20). In some embodiments, EBV-positive tumors treatable by the present invention include EBV-associated gastric cancer and EBV-positive gastroesophageal junction cancer, including adenocarcinoma originating from the lower esophagus. In some embodiments of the invention, anti-PD-1 antibody or its antigen-binding portion or anti-PD-L1 antibody or its antigen-binding portion is administered to the main body of EBV-associated gastric cancer and EBV-positive gastroesophageal junction cancer as monotherapy or any combination thereof disclosed herein. Surgical resection of the cancerous tissue is the standard of care for EBV-associated gastric cancer. In one embodiment, nirumab is administered to a patient with EBV-associated gastric cancer in addition to surgical resection. In another embodiment, nirumab is administered to a patient with EBV-positive gastroesophageal junction cancer in addition to surgical resection.

[0063] In some embodiments, the cancer treated by the present invention is a polyomavirus-positive cancer. In some embodiments, the present invention relates to the use of immune checkpoint inhibitors (e.g., PD-1 antibodies or their antigen-binding portions or PD-L1 antibodies or their antigen-binding portions) as monotherapy or in combination with other anticancer drugs for the treatment of polyomavirus-positive cancers. Polyomaviruses are DNA-based, non-enveloped viruses that have been associated with a variety of tumors in humans. For example, Merkel cell polyomavirus (MCPyV) has been found in squamous cell carcinoma of the skin, basal cell carcinoma, Bowen's disease, non-small cell lung cancer, and cervical cancer. Merkel cell carcinoma (MCC), or neuroendocrine carcinoma of the skin, is a type of skin cancer that typically appears on the face, head, or neck of a patient. Standard care for patients with MCC includes surgical excision for early-stage disease, followed by radiation therapy and chemotherapy for advanced-stage disease. Chemotherapy drugs that can be used to treat MCC include, but are not limited to, etoposide and platinum-based drugs, including carboplatin. In one embodiment, an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to a subject with MCC tumor as a monotherapy or any combination thereof disclosed herein. In some embodiments, nirumab is administered to a patient with MCC tumor in addition to surgical resection, radiation therapy, chemotherapy, or combinations thereof.

[0064] Cervical cancer, vaginal cancer, and vulvar cancer can also be polyomavirus-positive and / or HPV-positive. In some embodiments, the present invention relates to the use of immune checkpoint inhibitors (e.g., PD-1 antibodies or their antigen-binding portions or PD-L1 antibodies or their antigen-binding portions) as monotherapy or in combination with other anticancer drugs for the treatment of cervical cancer, vaginal cancer, and vulvar cancer. These tumors typically affect squamous cell populations in various tissues. Cervical cancer can include squamous cell carcinoma of the cervix and adenocarcinoma of the cervix, affecting glandular and columnar cells lining the cervical opening and inner canal. In some embodiments, patients with cervical, vaginal, or vulvar tumors are given anti-PD-1 antibodies or their antigen-binding portions or anti-PD-L1 antibodies or their antigen-binding portions as monotherapy or any combination thereof disclosed herein. Standard care for patients with cervical cancer depends on the stage of the cancer but often includes radical hysterectomy (surgical removal of the uterus, cervix, and part of the vagina). In some cases, patients may receive radiation therapy in combination with chemotherapy. Standard care for vaginal and vulvar cancer depends on the stage of treatment but may include surgical resection for early-stage disease and radiation plus chemotherapy for advanced-stage tumors. Chemotherapy may include, but is not limited to, 5-FU or platinum-based drugs such as cisplatin. In some implementations, in addition to surgical resection and chemotherapy, nirumab may be administered to patients with polyomavirus or HPV-positive cervical, vaginal, or vulvar tumors.

[0065] Nasopharyngeal carcinoma (NPC) is a type of cancer that occurs in the nasopharynx. Previous exposure to Epstein-Barr virus (EBV) has been shown to increase a patient's chance of developing NPC. In some embodiments, the present invention relates to the use of immune checkpoint inhibitors (e.g., PD-1 antibodies or their antigen-binding portions or PD-L1 antibodies or their antigen-binding portions) as monotherapy or in combination with other anticancer drugs for the treatment of NPC. In one embodiment, an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to a subject with NPC as monotherapy or in any combination thereof disclosed herein. Early-stage NPC is typically treated with radiation therapy, supplemented with chemotherapy in advanced-stage tumors, most frequently including 5-FU and platinum-based drugs such as cisplatin. In some embodiments, nirumab is administered to patients with EPV-positive NPC in addition to radiation therapy and / or chemotherapy.

[0066] In other embodiments, the tumor also expresses PD-L1. The PD-L1 status of the tumor in the subject can be measured before applying any composition or utilizing any of the methods disclosed herein. In one embodiment, the PD-L1 expression level of the tumor is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 20%, or greater than at least about 20%. In another embodiment, the PD-L1 status of the tumor is at least about 1%. In other embodiments, the PD-L1 status of the subject is at least about 5%. In a particular embodiment, the PD-L1 status of the tumor is at least about 10%. Measurements of PD-L1 status can be performed using antibodies, in situ mRNA hybridization, automated IHC methods, or as described in Taube et al., “Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape,” Sci. Transl. Med. 4(127):127ra37 (2012) or U.S. Provisional Applications Nos. 62 / 152,669, 62 / 153,954, and 62 / 167,674.

[0067] In some embodiments, the therapy of the present invention (e.g., administration of an anti-PD-1 antibody or anti-PD-L1 antibody and optionally another anticancer drug) effectively increases the duration of survival of the subject. In some embodiments, the anti-PD-1 antibody therapy or anti-PD-L1 antibody therapy of the present invention increases the duration of survival of the subject compared with standard of care. In some embodiments, the therapy of the present invention increases the overall survival of the subject. In some embodiments, the subject exhibits overall survival for at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration. In some embodiments, when compared to another subject treated with standard care alone, the subject's survival or overall survival duration increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or at least about 75%. In other embodiments, when compared to another subject treated with standard care alone, the subject's survival or overall survival duration increased by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0068] In some embodiments, the therapy of the present invention effectively increases the duration of progression-free survival in subjects. For example, compared to another subject treated with standard of care alone, the subject's progression-free survival increased by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 1 year. In some embodiments, after administration of anti-PD-1 antibody or anti-PD-L1 antibody therapy, the subject exhibited an overall response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45%, or 50% compared to the response rate after administration of standard of care.

[0069] Immune checkpoint inhibitors (e.g., anti-PD-1 antibodies and anti-PD-L1 antibodies) Suitable immune checkpoint inhibitors for use in the disclosed methods include anti-PD-1 antibodies that bind to PD-1 with high specificity and affinity, block PD-L1 binding, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the treatment methods disclosed herein, the anti-PD-1 or anti-PD-L1 “antibody” includes an antigen-binding portion that binds to the PD-1 or PD-L1 receptor, respectively, and exhibits functional properties similar to those of the intact antibody in inhibiting ligand binding and upregulating the immune system. In some embodiments, the anti-PD-1 antibody or its antigen-binding portion cross-competes with nirushumab for binding to human PD-1. In other embodiments, the anti-PD-L1 antibody or its antigen-binding portion competes with BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C for binding to human PD-L1.

[0070] In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. In some embodiments relating to the treatment of a human subject, the antibody is a humanized antibody. In other embodiments relating to the treatment of a human subject, the antibody is a human antibody. Antibodies of IgG1, IgG2, IgG3, or IgG4 isotypes may be used.

[0071] In some embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding moiety thereof comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. In some other embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding moiety thereof contains an S228P mutation, which replaces a serine residue in the hinge region with a proline residue typically found at the corresponding position in IgG1 isotype antibodies. This mutation present in nirumab prevents Fab arm exchange with endogenous IgG4 antibodies while retaining low affinity for activating the Fc receptor associated with wild-type IgG4 antibodies (Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). In other embodiments, the antibody comprises a light chain constant region, which is a human κ or λ constant region. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding moiety thereof is a mAb or its antigen-binding moiety.

[0072] HuMAb that specifically binds to PD-1 with high affinity has been disclosed in U.S. Patent No. 8,008,449. Other anti-PD-1 mAbs have been described, for example, in U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509 and PCT Publication No. WO 2012 / 145493. Each anti-PD-1 HuMAb disclosed in U.S. Patent No. 8,008,449 has been shown to exhibit one or more of the following characteristics: (a) 1 x 10 -7 M or smaller K D The anti-PD-1 antibody can be: (a) bound to human PD-1, as determined by surface plasmon resonance using a Biacore biosensor system; (b) substantially unbound to human CD28, CTLA-4, or ICOS; (c) increased T-cell proliferation in a mixed lymphocyte response (MLR) assay; (d) increased interferon-γ production in an MLR assay; (e) increased IL-2 secretion in an MLR assay; (f) bound to both human PD-1 and cynomolgus monkey PD-1; (g) inhibited binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulated an antigen-specific memory response; (i) stimulated an antibody response; and (j) inhibited tumor cell growth in vivo. Anti-PD-1 antibodies useful in this invention comprise mAbs that specifically bind to human PD-1 and exhibit at least one (in some embodiments, at least five) of the aforementioned characteristics. In some embodiments, the anti-PD-1 antibody is nirumab. In one embodiment, the anti-PD-1 antibody is pembrolizumab.

[0073] In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab (also known as “OPDIVO®”; formerly known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively blocks the interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of anti-tumor T-cell function (US Patent No. 8,008,449; Wang et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates, Cancer Imm Res, 2(9):846-56 (2014)).

[0074] In another embodiment, the anti-PD-1 antibody or a fragment thereof cross-competes with nilumab. In other embodiments, the anti-PD-1 antibody or a fragment thereof binds to the same epitope as nilumab. In some embodiments, the anti-PD-1 antibody has the same CDR as nilumab.

[0075] In another embodiment, the anti-PD-1 antibody or a fragment thereof cross-competes with pembrolizumab. In some embodiments, the anti-PD-1 antibody or a fragment thereof binds to the same epitope as pembrolizumab. In some embodiments, the anti-PD-1 antibody has the same CDR as pembrolizumab. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also known as "Keytruda") ® Pembrolizumab (PD-1), lambrolizumab, and MK-3475 are humanized monoclonal IgG4 antibodies targeting the human cell surface receptor PD-1 (programmed cell death 1). Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587; see also http: / / www.cancer.gov / drugdictionarycdrid=695789 (last accessed: December 14, 2014). Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.

[0076] In other embodiments, the anti-PD-1 antibody or a fragment thereof cross-competes with MEDI0608. In other embodiments, the anti-PD-1 antibody or a fragment thereof binds to the same epitope as MEDI0608. In some embodiments, the anti-PD-1 antibody has the same CDR as MEDI0608. In other embodiments, the anti-PD-1 antibody is MEDI0608 (formerly known as AMP-514), which is a monoclonal antibody. MEDI0608 is described, for example, in U.S. Patent No. 8,609,089B2 or http: / / www.cancer.gov / drugdictionarycdrid=756047 (last accessed: December 14, 2014).

[0077] In some embodiments, the first antibody is an anti-PD-1 antagonist. An example of an anti-PD-1 antagonist is AMP-224, a B7-DC Fc fusion protein. AMP-224 is discussed in U.S. Publication No. 2013 / 0017199 or http: / / www.cancer.gov / publications / dictionaries / cancer-drugcdrid=700595 (last accessed: July 8, 2015).

[0078] In other embodiments, the anti-PD-1 antibody or a fragment thereof cross-competes with BGB-A317. In some embodiments, the anti-PD-1 antibody or a fragment thereof binds to the same epitope as BGB-A317. In some embodiments, the anti-PD-1 antibody has the same CDR as BGB-A317. In some embodiments, the anti-PD-1 antibody is BGB-A317, which is a humanized monoclonal antibody. BGB-A317 is described in U.S. Publication No. 2015 / 0079109.

[0079] Useful anti-PD-1 antibodies in the disclosed methods also include isolated antibodies that specifically bind to human PD-1 and cross-compete with nilumab for binding to human PD-1 (see, for example, U.S. Patents 8,008,449 and 8,779,105; WO 2013 / 173223). The ability of antibodies to cross-compete with an antigen indicates that these antibodies bind to the same epitope region of the antigen and spatially prevent other cross-competitive antibodies from binding to that specific epitope region. Due to their binding to the same epitope region of PD-1, these cross-competitive antibodies are expected to have functional properties very similar to nilumab. Cross-competitive antibodies can be readily identified based on their ability to cross-compete with nilumab in standard PD-1 binding assays such as Biacore assays, ELISA assays, or flow cytometry (see, for example, WO 2013 / 173223) (see, for example, WO 2013 / 173223).

[0080] In some embodiments, the antibody that cross-competes with nilumab for binding to human PD-1 or binds to the same epitope region of human PD-1 is a mAb. For administration to the human body, these cross-competitive antibodies are chimeric antibodies, humanized antibodies, or human antibodies. Such chimeric, humanized, or human mAbs can be prepared and isolated using methods well-known in the art.

[0081] The anti-PD-1 antibodies useful in the disclosed inventive methods also include the antigen-binding portion of the aforementioned antibody. It has been well demonstrated that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of binding fragments included in the term "antigen-binding portion" of an antibody include: (i) Fab fragments, i.e., fragments composed of V... L V H C L and C H1 (ii) A monovalent segment composed of structural domains; (iii) A F(ab'')2 segment, i.e., a divalent segment containing two Fab segments connected by disulfide bonds in the hinge region; H and C H1(iv) Fd fragments composed of structural domains; and (iv) V-shaped segments formed by the single arm of the antibody. L and V H Fv segments composed of structural domains.

[0082] Suitable anti-PD-1 antibodies for use in the disclosed compositions are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 “antibody” comprises an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of a full antibody in inhibiting ligand binding and upregulating the immune system. In some embodiments, the anti-PD-1 antibody or its antigen-binding portion cross-competes with nirushumab for binding to human PD-1. In other embodiments, the anti-PD-1 antibody or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. In some embodiments, the antibody is a humanized antibody. In other embodiments, the antibody is a human antibody. Antibodies of IgG1, IgG2, IgG3, or IgG4 isotypes may be used.

[0083] In some embodiments, the anti-PD-1 antibody or its antigen-binding moiety comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. In some other embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or its antigen-binding moiety contains an S228P mutation, which replaces a serine residue in the hinge region with a proline residue typically found at the corresponding position in IgG1 isotype antibodies. This mutation present in nirumab prevents Fab arm exchange with endogenous IgG4 antibodies while retaining low affinity for activating the Fc receptor associated with wild-type IgG4 antibodies (Wang et al. (2014)). In other embodiments, the antibody comprises a light chain constant region, which is a human κ or λ constant region. In other embodiments, the anti-PD-1 antibody or its antigen-binding moiety is a mAb or its antigen-binding moiety.

[0084] In some embodiments of any treatment method described herein that includes the administration of an anti-PD-1 antibody, the anti-PD-1 antibody is nirumab. In other embodiments, the anti-PD-1 antibody is pembrolizumab. In other embodiments, the anti-PD-1 antibody is selected from human antibodies 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4 described in U.S. Patent No. 8,008,449. In other embodiments, the anti-PD-1 antibody is MEDI0608 (formerly known as AMP-514), AMP-224, or BGB-A317.

[0085] The anti-PD-1 antibodies useful in the methods of the disclosed invention also include the antigen-binding portion of the above-mentioned antibodies. It has been well demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included in the term "antigen-binding portion" of an antibody include: (i) Fab fragments, i.e., fragments composed of V... L V H C L and C H1 (ii) A monovalent segment composed of structural domains; (iii) A F(ab'')2 segment, i.e., a divalent segment containing two Fab segments connected by disulfide bonds in the hinge region; H and C H1 (iv) Fd fragments composed of structural domains; and (iv) V-shaped segments formed by the single arm of the antibody. L and V H Fv segments composed of structural domains.

[0086] In some embodiments, the anti-PD-1 antibody used in the method can be replaced with another PD-1 or anti-PD-L1 antagonist. For example, because anti-PD-L1 antibodies block the interaction between PD-1 and PD-L1, thereby playing a similar role in the PD-1 signaling pathway, anti-PD-L1 antibodies can replace the use of anti-PD-1 antibodies in the methods disclosed herein. Therefore, in one embodiment, the present invention relates to a method for treating a subject suffering from a tumor originating from HPV-positive SCCHN, the method comprising administering a therapeutically effective amount of anti-PD-L1 antibody to the subject.

[0087] In some embodiments, the anti-PD-L1 antibody is BMS-936559 (formerly known as 12A4 or MDX-1105) (see, for example, U.S. Patent No. 7,943,743; WO 2013 / 173223).

[0088] In other embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as RG7446) (see, for example, Herbst et al. (2013) J Clin Oncol 31(Supplement):3000. Abstract; U.S. Patent No. 8,217,149).

[0089] In other embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as Durvalumab; Khleif (2013) see: Proceedings from the European Cancer Congress 2013; September 27–October 1, 2013; Amsterdam, The Netherlands. Abstract 802, see U.S. Patent No. 8,779,108 or US 2014 / 0356353, filed May 6, 2014).

[0090] In other embodiments, the anti-PD-L1 antibody is MSB0010718C (also known as Avelumab; see US2014 / 0341917).

[0091] Because anti-PD-1 and anti-PD-L1 target the same signaling pathway and have been shown in clinical trials to exhibit similar potency against a variety of cancers, including RCC (see Brahmer et al. (2012) N Engl J Med 366:2455-65; Topalian et al. (2012a) N Engl J Med 366:2443-54; WO 2013 / 173223), anti-PD-L1 antibodies can replace anti-PD-1 antibodies in any treatment method disclosed herein. In some embodiments, the anti-PD-L1 antibody is BMS-936559 (formerly known as 12A4 or MDX-1105) (see, for example, U.S. Patent No. 7,943,743; WO 2013 / 173223). In other embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as RG7446) (see, for example, Herbst et al. (2013) J Clin Oncol 31(Supplement):3000. Abstract; U.S. Patent No. 8,217,149) or MEDI4736 (Khleif (2013) see: Proceedings from the European Cancer Congress 2013; September 27–October 1, 2013; Amsterdam, The Netherlands. Abstract 802). In some embodiments, the antibody that cross-competes with the above-mentioned reference PD-L1 antibody for binding to human PD-L1, or that binds to the same epitope region of human PD-L1 with the above-mentioned reference PD-L1 antibody, is a mAb. For administration to a human body, these cross-competitive antibodies may be chimeric antibodies, or may be humanized or human antibodies. Such chimeric, humanized, or human mAbs can be prepared and isolated using methods well known in the art.

[0092] In some embodiments, the immune checkpoint inhibitors (e.g., anti-PD-1 antagonists) used in this invention are PD-1 Fc fusion proteins.

[0093] Combined therapy with anti-PD-1 or anti-PD-L1 antibodies In some embodiments, an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered in combination with one or more other anticancer drugs. In some embodiments, the one or more anticancer drugs have been administered to the subject before or in combination with anti-PD-1 or anti-PD-L1 antibodies. In some embodiments, the one or more anticancer drugs are not effective in treating the cancer. In some embodiments, the other anticancer drugs are any anticancer drugs described herein or known in the art. In some embodiments, the other anticancer drug is an anti-CTLA-4 antibody. In one embodiment, the other anticancer drug is chemotherapy or platinum-based two-drug chemotherapy (PT-DC). In some embodiments, the other anticancer drug is a tyrosine kinase inhibitor (TKI) targeting EGFR. In one embodiment, the other anticancer drug is an anti-VEGF antibody. In other embodiments, the anticancer drug is a platinum reagent (e.g., cisplatin, carboplatin), a mitotic inhibitor (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel, taxotere, docecad), a fluorovinca alkaloid (e.g., vinblastine, javlor), vinorelbine, vinblastine, etoposide, or pemetrexed gemcitabin. In one embodiment, the other anticancer drug is 5-fluorouracil (5-FU). In some embodiments, the other anticancer drug is any other anticancer drug known in the art. In some embodiments, two or more additional anticancer drugs are administered in combination with anti-PD-1 or anti-PD-L1 antibodies. In some embodiments, PD-1 or PD-L1 antibodies are combined with surgical resection and / or radiation therapy.

[0094] In some embodiments, anti-PD-1 antibodies or anti-PD-L1 antibodies may be combined with another immunotherapy. In some embodiments, immunotherapy involving blockade of immune checkpoints may be administered as a monotherapy. In other embodiments, immunotherapy involving blockade of immune checkpoints may be administered in combination with other therapies. In some embodiments, HPV-positive SCCHN patients may benefit from a combination of different immunotherapies.

[0095] Anti-CTLA-4 antibody In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody is combined with an anti-CTLA-4 antibody. The anti-CTLA-4 antibody useful for this combination can bind to human CTLA-4 to disrupt the interaction between CTLA-4 and the human B7 receptor. Because the CTLA-4-B7 interaction transduces signals leading to the inactivation of T cells carrying the CTLA-4 receptor, disruption of this interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing, or prolonging the immune response.

[0096] HuMAb that binds CTLA-4 with high affinity has been disclosed in U.S. Patent Nos. 6,984,720 and 7,605,238. Other CTLA-4 mAbs have been described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121. The CTLA-4 HuMAb disclosed in U.S. Patent Nos. 6,984,720 and 7,605,238 has been shown to exhibit one or more of the following characteristics: (a) binding with at least about 10 7 M -1 or about 10 9 M -1 or about 10 10 M -1 Up to 10 11 M -1 Or a higher equilibrium association constant (K) a (a) Reflects binding affinity specifically binding to human CTLA-4, as determined by Biacore analysis; (b) At least about 10 3 Approximately 10 4 Or about 10 5 m -1 s -1 The dynamic association constant (k) a (c) at least about 10 3 Approximately 10 4 Or about 10 5 m -1 s -1 The kinetic dissociation constant (k) d(d) Inhibits the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful in this invention comprise mAbs that specifically bind to human CTLA-4 and exhibit at least one, at least two, or in one embodiment at least three of the aforementioned characteristics. An exemplary clinical anti-CTLA-4 antibody is human mAb 10D1 disclosed in U.S. Patent No. 6,984,720 (now known as ipilimumab and marketed as YERVOY®). Ipilimumab is an anti-CTLA-4 antibody used in the methods disclosed herein. Another anti-CTLA-4 antibody useful in the methods of this invention is trimemumab.

[0097] An exemplary clinical anti-CTLA-4 antibody that can be used in the aforementioned combination is human mAb 10D1 disclosed in U.S. Patent No. 6,984,720 (now known as ipilimumab and marketed as YERVOY®). Ipilimumab is an anti-CTLA-4 antibody used in the methods disclosed herein. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma.

[0098] Another anti-CTLA-4 antibody that can be used in the methods of this invention is trimemumab (also known as CP-675,206). Trimemumab is a human IgG2 monoclonal anti-CTLA-4 antibody. Trimemumab is described in WO / 2012 / 122444, US Publication No. 2012 / 263677, or WO Publication No. 2007 / 113648 A2.

[0099] Useful anti-CTLA-4 antibodies in the disclosed methods also include isolated antibodies that specifically bind to human CTLA-4 and cross-competitively bind to human CTLA-4 with ipilimumab or trimemumab, or bind to the same epitope region of human CTLA-4 with ipilimumab or trimemumab. In some embodiments, the antibody that cross-competitively binds to human CTLA-4 with ipilimumab or trimemumab, or binds to the same epitope region of human CTLA-4 with ipilimumab or trimemumab, is an antibody containing a heavy chain of the human IgG1 isotype. For administration to the human body, these cross-competitive antibodies are chimeric antibodies, or humanized or human antibodies. Useful anti-CTLA-4 antibodies also include antigen-binding portions of the above antibodies, such as Fab, F(ab'')2, Fd, or Fv fragments.

[0100] Ipilimumab (YERVOY®) is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T-cell activation and improving overall survival (OS) in patients with advanced melanoma (Hodi et al. (2010) N Engl J Med 363:711-23). ​​In a phase 1 clinical trial, concomitant therapy with nirushumab and ipilimumab produced rapid and substantial tumor regression in a high proportion of patients with advanced melanoma, significantly more effective than either antibody alone (Wolchok et al. (2013) N Engl J Med 369(2):122-33; WO 2013 / 173223). However, it remains unknown whether this combination of immunomodulatory antibodies is similarly effective in other tumor types.

[0101] Anti-VEGF antibody In other embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody is combined with an anti-VEGF antagonist (e.g., an anti-VEGF antibody). Vascular endothelial growth factor (“VEGF”) is an endothelial cell-specific mitogen and angiogenesis inducer. VEGF plays a prominent role in angiogenesis and tumor growth and development. In some embodiments of the invention, an anti-PD-1 antibody is administered in combination with an anti-VEGF antagonist. In some embodiments, the anti-VEGF antagonist is an anti-VEGF antibody, its antigen-binding molecule, or a fragment thereof. In some embodiments, the anti-VEGF antibody is bevacizumab (described in U.S. Patent No. 7,169,901) or any other VEGF antibody known in the art, including ranibizumab (U.S. Patent No. 7,297,334), VGX-100 (U.S. Patent No. 7,423,125), r84 (U.S. Patent No. 8,034,905), aflibercept (U.S. Patent No. 5,952,199), IMC-18F1 (U.S. Patent No. 7,972,596), IMC-1C11 (PCT / US2000 / 02180), and ramucirumab (U.S. Patent No. 7,498,414).

[0102] Chemotherapy and platinum-based chemotherapy In some embodiments, the anti-PD-1 antibody is administered in combination with any chemotherapy known in the art. In some embodiments, the chemotherapy is a platinum-based chemotherapy. Platinum-based chemotherapy is a platinum coordination complex. In some embodiments, the platinum-based chemotherapy is a platinum-two-drug regimen chemotherapy. In one embodiment, the chemotherapy is administered at a dose approved for a specific indication. In other embodiments, the chemotherapy is administered at any dose disclosed herein. In some embodiments, the platinum-based chemotherapy is cisplatin, carboplatin, oxaliplatin, saxaplatin, pyrazinib, nedaplatin, triplatin, lipoplatin, or a combination thereof. In some embodiments, the platinum-based chemotherapy is any other platinum-based chemotherapy known in the art. In some embodiments, the chemotherapy is the nucleoside analog gemcitabine. In one embodiment, the chemotherapy is a folic acid antimetabolite. In one embodiment, the folic acid antimetabolite is pemetrexed. In some embodiments, the chemotherapy is taxane. In other embodiments, the taxane is paclitaxel. In other embodiments, the chemotherapy is a nucleoside analog. In one embodiment, the nucleoside analog is gemcitabine. In some embodiments, the chemotherapy is any other chemotherapy known in the art. In some embodiments, at least one, at least two, or more chemotherapy agents are administered in combination with an anti-PD-1 antibody, an anti-PD-L1 antibody, or an antigen-binding portion thereof. In one embodiment, an anti-CTLA-4 antibody is additionally administered.

[0103] Tyrosine kinase inhibitors In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered in combination with a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is gefitinib, erlotinib, a combination thereof, or any other tyrosine kinase inhibitor known in the art. In some embodiments, the tyrosine kinase inhibitor acts on the epidermal growth factor receptor (EGFR). In one embodiment, an anti-CTLA-4 antibody is additionally administered.

[0104] Drug composition and dosage The therapeutic agents of the present invention can be incorporated into compositions, for example, pharmaceutical compositions containing antibodies and pharmaceutically acceptable carriers. As used herein, “pharmaceutically acceptable carrier” includes any and all physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. In one embodiment, the carrier for an antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion), while the carrier for a TKI-containing composition is suitable for non-parenteral (e.g., oral) administration. The pharmaceutical compositions of the present invention may include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants.

[0105] The dosing regimen is adjusted to provide the optimal expected response, such as maximum therapeutic response and / or minimum adverse effects. In some embodiments, the method of the present invention can be used with a uniform dose or a weight-based dose. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or its antigen-binding portion is administered as a uniform dose. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or its antigen-binding portion is administered as a weight-based dose. For the administration of the anti-PD-1 antibody (as a monotherapy or in combination with another anticancer drug), the dosage may be in the following ranges: about 0.01 to about 20 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 5 mg / kg, about 1 to about 5 mg / kg, about 2 to about 5 mg / kg, about 7.5 to about 12.5 mg / kg, or about 0.1 to about 30 mg / kg body weight, or about 80 mg to at least 800 mg, about 80 mg to at least about 700 mg, about 80 mg to at least about 600 mg, about 80 mg to at least about 500 mg, about 80 mg to at least about 400 mg, about 80 mg to at least about 300 mg, about 100 mg to at least about 300 mg, or about 200 mg to about 300 mg. For example, the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10 mg / kg body weight; or about 0.3, about 1, about 2, about 3, or about 5 mg / kg body weight; or about 80 mg, about 100 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 320 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. Dosing schedules are typically designed to achieve exposure leading to sustained receptor occupancy (RO) (based on the typical pharmacokinetic properties of the antibody). An exemplary treatment regimen requires administration approximately once weekly, approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately once a month, approximately every 3-6 months, or longer. In some embodiments, an anti-PD-1 antibody, such as nirumab, is administered to the subject approximately every 2 weeks. In other embodiments, the antibody is administered approximately every 3 weeks. The dosage and scheduling may vary during treatment. For example, a dosing schedule for anti-PD-1 monotherapy may include administration of Ab: (i) approximately every 2 weeks in a cycle of approximately 6 weeks; (ii) approximately 6 doses every 4 weeks, followed by approximately every 3 months; (iii) approximately every 3 weeks; (iv) approximately 3 to approximately 10 mg / kg once, followed by approximately 1 mg / kg every 2-3 weeks.Given that IgG4 antibodies typically have a half-life of 2-3 weeks, the dosage regimen of the anti-PD-1 antibody of the present invention comprises at least about 0.3 to at least about 10 mg / kg body weight, at least about 1 to at least about 5 mg / kg body weight, or at least about 1 to at least about 3 mg / kg body weight, or at least about 80 to at least about 800 mg via intravenous administration, said antibody being administered every about 14-21 days in up to about 6-week or about 12-week cycles until a complete response or confirmed progressive disease. In some embodiments, anti-PD-1 monotherapy is administered at 3 mg / kg every 2 weeks until progressive disease or unacceptable toxicity. In other embodiments, anti-PD-1 monotherapy is administered at 240 mg every 2 weeks until progressive disease or unacceptable toxicity. In some embodiments, said antibody treatment or any combination of treatments disclosed herein lasts for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

[0106] When used in combination with other cancer agents, the dose of anti-PD-1 antibody can be reduced relative to the monotherapy dose. A dose of nirumab below the typical 3 mg / kg, but not less than 0.001 mg / kg, is a subtherapeutic dose. The subtherapeutic dose of the anti-PD-1 antibody used in the methods described herein is greater than 0.001 mg / kg and less than 3 mg / kg. In some embodiments, the subtherapeutic dose is about 0.001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg body weight. In some embodiments, the subtherapeutic dose is at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, or at least about 1.0 mg / kg body weight. In some embodiments, the uniform subtherapy dose is less than about 240 mg every 2 weeks, such as about 160 mg or about 80 mg every 2 weeks. Receptor occupancy data from 15 subjects who received nirumab dosing from 0.3 mg / kg to 10 mg / kg indicate that PD-1 occupancy appears to be dose-independent within this dose range. The mean occupancy rate was 85% (range, 70% to 97%) across all doses, and the mean plateau occupancy rate was 72% (range, 59% to 81%) (Brahmer et al. (2010) J Clin Oncol 28:3167-75). In some embodiments, dosing at 0.3 mg / kg may allow sufficient exposure to result in maximum biological activity.

[0107] In some embodiments, the dose of the anti-PD-1 antibody (or anti-PD-L1 antibody) is a fixed dose in the pharmaceutical composition. In other embodiments, the method of the present invention can be used at a uniform dose (the dose administered to the patient regardless of the patient's weight). For example, the uniform dose of nilumab may be about 240 mg. For example, the uniform dose of pembrolizumab may be about 200 mg. In one embodiment, the anti-PD-1 antibody or its antigen-binding portion is administered at a dose of about 240 mg. In another embodiment, the anti-PD-1 antibody or its antigen-binding portion is administered at a dose of about 360 mg. In yet another embodiment, the anti-PD-1 antibody or its antigen-binding portion is administered at a dose of about 480 mg. In one embodiment, 360 mg of the anti-PD-1 antibody or antigen-binding fragment is administered every 3 weeks. In another embodiment, 480 mg of the anti-PD-1 antibody or antigen-binding fragment is administered every 4 weeks.

[0108] For the administration of the anti-PD-L1 antibody (as a monotherapy or in combination with another anticancer drug), the dosage may be in the following ranges: about 0.01 to about 20 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 5 mg / kg, about 1 to about 5 mg / kg, about 2 to about 5 mg / kg, about 7.5 to about 12.5 mg / kg, or about 0.1 to about 30 mg / kg body weight, or about 80 mg to at least 800 mg, about 80 mg to at least about 700 mg, about 80 mg to at least about 600 mg, about 80 mg to at least about 500 mg, about 80 mg to at least about 400 mg, about 80 mg to at least about 300 mg, about 100 mg to at least about 300 mg, or about 200 mg to about 300 mg. For example, the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10 mg / kg body weight; or about 0.3, about 1, about 2, about 3, or about 5 mg / kg body weight; or about 80 mg, about 100 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 320 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. Dosing schedules are typically designed to achieve exposure leading to sustained receptor occupancy (RO) (based on the typical pharmacokinetic properties of the antibody). An exemplary treatment regimen requires administration approximately once weekly, approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately once monthly, approximately every 3–6 months, or longer.

[0109] Although higher nilumab monotherapy doses up to approximately 10 mg / kg every 2 weeks have been achieved without reaching the maximum tolerated dose (MTD), significant toxicities reported in other trials of checkpoint inhibitors plus anti-angiogenic therapy (see, for example, Johnson et al. (2013) Cancer Immunol Res 1:373-77; Rini et al. (2011) Cancer 117:758-67) support the option of nilumab doses below 10 mg / kg.

[0110] In some embodiments, the dose of anti-PD-1 antibody (or anti-PD-L1 antibody) is a fixed dose in the pharmaceutical composition.

[0111] Ipilimumab (YERVOY®) is approved for the treatment of melanoma (administered intravenously at 3 mg / kg for four doses every 3 weeks). In some embodiments, the dose of the anti-CTLA-4 antibody is a uniform dose administered to the patient regardless of body weight. In one specific embodiment, the uniform dose of the anti-CTLA-4 antibody is approximately 80 mg.

[0112] Therefore, in some embodiments, about 3 mg / kg is the maximum dose of ipilimumab used in combination with an anti-PD-1 antibody, although in some embodiments, anti-CTLA-4 antibodies such as ipilimumab, when combined with nirumumab, may be administered in doses ranging from about 0.3 to about 10 mg / kg, about 0.5 to about 10 mg / kg, about 0.5 to about 5 mg / kg, or about 1 to about 5 mg / kg body weight every 2 or 3 weeks. In other embodiments, ipilimumab is administered at a different dosage schedule than nirumumab. In some embodiments, ipilimumab is administered about weekly, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, or about every 15 weeks.

[0113] A dose of ipilimumab lower than the typical 3 mg / kg every 3 weeks, but not less than 0.001 mg / kg, is a subtherapeutic dose. The subtherapeutic dose of the anti-CTLA-4 antibody used in the methods described herein is greater than 0.001 mg / kg and less than 3 mg / kg. In some embodiments, the subtherapeutic dose is about 0.001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg body weight. In some embodiments, the subtherapeutic dose is at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, or at least about 1.0 mg / kg body weight. It has been demonstrated that the combined administration of nilumab at 3 mg / kg and ipilimumab at 3 mg / kg exceeds the mean dose (MTD) in the melanoma population, while combinations of nilumab at 1 mg / kg + 3 mg / kg ipilimumab, or nilumab at 3 mg / kg + 1 mg / kg ipilimumab, have been found tolerable in melanoma patients (Wolchok et al. (2013) N Engl J Med 369(2):122-33). Therefore, although nilumab is tolerated up to 10 mg / kg administered intravenously every 2 weeks, in some implementations, the dose of the anti-PD-1 antibody does not exceed approximately 3 mg / kg when combined with ipilimumab. In some embodiments, based on risk-benefit and PK-PD assessments, the dosage used comprises at least about 1 mg / kg of nilumab plus at least about 3 mg / kg of ipilimumab, at least about 3 mg / kg of nilumab plus at least about 1 mg / kg of ipilimumab, or at least about 3 mg / kg of nilumab plus at least about 3 mg / kg of ipilimumab, each administered at a dosing frequency of about every 2 to 4 weeks, and in some embodiments, at a dosing frequency of about every 2 weeks or about every 3 weeks. In some other embodiments, nilumab is administered in combination with ipilimumab at a dose of about 0.1, about 0.3, about 1, about 2, about 3, or about 5 mg / kg, at a dose of about 0.1, about 0.3, about 1, about 2, about 3, or about 5 mg / kg, at a dose of about 0.1, about 0.3, about 1, about 2, about 3, or about 5 mg / kg, about every 2 weeks, about every 3 weeks, or about every 4 weeks.In other embodiments, the dosage used comprises at least about 240 mg of nilumab + at least about 80 mg of ipilimumab, at least about 240 mg of nilumab + at least about 240 mg of ipilimumab, or at least about 80 mg of nilumab + at least about 240 mg of ipilimumab, each administered at a dosing frequency of about every 2 to 4 weeks, and in some embodiments, at a dosing frequency of about every 2 weeks or about every 3 weeks. In some other embodiments, nilumab is administered in combination with ipilimumab at doses of about 40 mg, about 80 mg, about 160 mg, about 240 mg, about 320 mg, or about 400 mg, at doses of about 40 mg, about 80 mg, about 100 mg, about 160 mg, about 20 ...30 mg,

[0114] In some embodiments, during the induction phase, the subject is given intravenously with a combination of anti-PD-1 antibody or anti-PD-L1 antibody and anti-CTLA-4 antibody approximately every 2 or 3 weeks, for 1, 2, 3, or 4 doses. In some embodiments, during the induction phase, the combination of anti-PD-1 antibody and anti-PD-L1 antibody is given intravenously approximately every 2 or 3 weeks, for approximately 4 doses. Following the induction phase is a maintenance phase, during which the subject is given only anti-PD-1 antibody or anti-PD-L1 antibody at doses of approximately 0.1, approximately 0.3, approximately 1, approximately 2, approximately 3, approximately 5, or approximately 10 mg / kg, or approximately 40 mg, approximately 80 mg, approximately 100 mg, approximately 160 mg, approximately 200 mg, approximately 240 mg, approximately 320 mg, or approximately 400 mg, approximately every 2 or 3 weeks, as long as the treatment proves effective or until uncontrollable toxicity or disease progression occurs. In some implementations, nirumab is administered approximately every 2 weeks at a dose of approximately 3 mg / kg body weight or approximately 240 mg during the maintenance phase.

[0115] In some embodiments, the dose of the anti-PD-1 antibody or anti-PD-L1 antibody is a fixed dose in the pharmaceutical composition containing a second anticancer drug. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the anti-CTLA-4 antibody are formulated as a single composition, wherein the doses of the anti-PD-1 antibody or anti-PD-L1 antibody and the dose of the anti-CTLA-4 antibody are combined in a ratio of 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:3, 1:1, 3:1, 5:1, 10:1, 20:1, 30:1, 40:1, or 50:1.

[0116] Regarding the combination of nirumab with other anticancer drugs, these agents are administered at their approved doses. Treatment continues as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs. Nevertheless, in some embodiments, these anticancer drugs are administered at doses significantly lower than the approved doses, i.e., a subtherapeutic dose of the agents administered in combination with anti-PD-1 antibodies or anti-PD-L1 antibodies. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at the dose that has been shown to produce the highest efficacy as a monotherapy in clinical trials, for example, approximately 3 mg / kg of nirumab administered approximately every 3 weeks (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12), at significantly lower doses, i.e., a subtherapeutic dose, or at a uniform dose, i.e., 240 mg. In some implementations, at least about 3 mg / kg or 240 mg of anti-PD-1 antibody is administered approximately every two weeks.

[0117] In some embodiments, anti-PD-1 antibodies or anti-PD-L1 antibodies are administered in combination with standards of care for specific cancer types. In other embodiments, anti-PD-1 antibodies or anti-PD-L1 antibodies are administered in combination with chemotherapy (including 5-FU, etoposide, and platinum-based drugs such as carboplatin or cisplatin). In some embodiments, anti-PD-1 antibodies or anti-PD-L1 antibodies are administered before, in parallel with, or after radiation therapy. In some embodiments, anti-PD-1 antibodies or anti-PD-L1 antibodies are administered before, in parallel with, or after surgical resection.

[0118] The dosage and frequency vary with the half-life of the antibody in the host. Generally, human antibodies exhibit the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic use, relatively low doses are typically administered at relatively infrequent intervals over a long period. Some patients continue treatment for the rest of their lives. In therapeutic use, sometimes relatively higher doses are required at relatively short intervals until the disease progression slows or ceases, or until the patient shows partial or complete improvement in disease symptoms. Afterward, a prophylactic regimen can be administered to the patient.

[0119] The actual dose level of one or more active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and administration mode, without undue toxicity to the patient. The selected dose level will depend on a variety of pharmacokinetic factors, including the activity of the particular composition of the present invention used, the route of administration, the time of administration, the excretion rate of the particular compound being used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition used, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical field. The compositions of the present invention can be administered via one or more routes of administration using one or more methods well known in the art. Those skilled in the art will understand that the route and / or mode of administration will vary depending on the desired outcome.

[0120] Reagent test kit Also within the scope of this invention are kits containing an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody and / or an anti-PD-L1 antibody) and optionally another anticancer agent for therapeutic use. Kits typically include a label and instructions for use, the label indicating the intended use of the kit contents. Terminology labels include any written or documented material provided on or with the kit or otherwise accompanying the kit. In some embodiments, the present invention relates to a kit for treating a subject suffering from a tumor derived from an HPV-positive SCCHN, the kit comprising: (a) an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion); (b) instructions for determining HPV positivity of the tumor, and, if the tumor is HPV-positive, administration of the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion) to the subject in the methods disclosed herein. In some embodiments, the kit also comprises an agent for determining HPV positivity of the tumor. In some embodiments, HPV positivity is measured by the expression of HPV p16. In some embodiments, the present invention relates to a kit for treating a subject suffering from a tumor derived from an HPV-negative SCCHN, the kit comprising: (a) an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion); (b) instructions for determining HPV negativity of the tumor, and, if the tumor is HPV negative, administration of the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion) to the subject in the method disclosed herein. In some embodiments, the kit further comprises an agent to determine HPV negativity of the tumor. In some embodiments, HPV negativity is measured by the expression of HPV p16. In other embodiments, the kit comprises one or more additional anticancer agents, such as anti-CTLA-4 antibodies and / or TKIs. In some embodiments, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, and / or TKIs may be co-packaged in a unit dosage form. In some embodiments for treating human patients, the kit comprises an anti-human PD-1 antibody or anti-human PD-L1 antibody disclosed herein, such as nilumumab or pembrolizumab. In other embodiments, the kit comprises an anti-human CTLA-4 antibody disclosed herein, such as ipilimumab or trimemumab.

[0121] The present invention is further illustrated by the following embodiments, which should not be construed as further limitations. All references cited in this application are expressly incorporated herein by reference.

[0122] Example 1 A non-comparative, two-group, single-arm, label-open, phase 1 / 2 study of nirumumab will be conducted in subjects with both virus-positive and virus-negative solid tumors to evaluate the safety, tolerability, and potency of nirumumab in subjects with selected virus-positive and virus-negative tumors. Subjects will receive a uniform dose of 240 mg nirumumab administered intravenously every 30 minutes for 2 weeks until progression or unacceptable toxicity. Potency will be measured by objective response rate and duration of response.

[0123] The study will include two cohorts: a neoadjuvant therapy cohort and a metastasis / recurrence cohort. The primary objective of the neoadjuvant therapy cohort will be to investigate the safety and tolerability of nirumab as neoadjuvant therapy in the following tumor types: HPV-positive squamous cell carcinoma of the head and neck (SCCHN); HPV-negative SCCHN; Merkel cell carcinoma (MCC); and cervical, vaginal, or vulvar cancer (GYN). The primary objective of the metastasis / recurrence cohort will be to evaluate the investigator-assessed objective response rate (ORR) of nirumab monotherapy (240 mg uniform dose, intravenously every 2 weeks) in subjects with the following diseases: metastatic or recurrent nasopharyngeal carcinoma (NPC); metastatic or recurrent EBV-associated gastric cancer; metastatic or recurrent Merkel cell carcinoma; metastatic or recurrent cervical, vaginal, or vulvar cancer; and metastatic or recurrent HPV-positive SCCHN.

[0124] The second objective of the neoadjuvant therapy group will be to determine the percentage change relative to baseline immune cell counts and the percentage change relative to baseline for selected immune activating / inhibiting molecules of virus-specific T cells in a tumor-specific subset of subjects treated with nirumab. The second objective of the metastasis / recurrence group will be to evaluate progression-free survival and overall survival in subjects treated with nirumab monotherapy.

[0125] Patients in the neoadjuvant therapy cohort will be evaluated for progression-free survival until one year after administration of nirumab neoadjuvant therapy. Patients will be further monitored to determine the percentage change in tumor volume relative to baseline after two uniform doses of nirumab neoadjuvant therapy (240 mg). Pathological complete response to tumor resection will also be determined in subjects undergoing surgical resection following two doses of nirumab neoadjuvant therapy in SCCHN, resectable Merkel cell carcinoma, and cervical, vaginal, or vulvar cancer.

[0126] In the metastatic / recurrent group, the safety and tolerability of nirumab monotherapy in subjects with metastatic or recurrent virus-mediated tumors will also be monitored, defined as the ratio of adverse events to toxicity for specific laboratory tests (worst CTC grade for each subject).

[0127] In both cohorts, changes in antiviral and antitumor immune responses at tumor sites will be evaluated using proliferation and / or functional assays. Study administrators will also investigate potential associations between selected biomarker measurements (including PD-L1) in peripheral blood and tumor tissue and safety and clinical efficacy measurements and pharmacokinetic activities of nirumab in peripheral blood and tumor tissue (e.g., as measured by gene expression, flow cytometry, immunohistochemistry, and soluble factor assays). Subjects will be further examined to investigate the potential association between nirumab and viral antigen-specific T-cell responsiveness in peripheral blood, and the number of tumor mutations and neoantigens with clinical efficacy measurements, as well as the presence of tumor antigen-specific T cells in the periphery. Furthermore, pre- and post-treatment Epstein-Barr virus (EBV) DNA levels will be evaluated in subjects with EBV-positive gastric and nasopharyngeal carcinoma in these patients.

[0128] In addition, all subjects will be evaluated on overall health status (e.g., as assessed by EQ-5D) and cancer-specific health-related quality of life (e.g., as assessed by EORTC QLQ-C30). In all cases, the immunogenicity and pharmacokinetics of nirumab monotherapy will be characterized, and, where feasible, exposure-response associations will be investigated.

[0129] main body All eligible patients will have histopathologically confirmed Merkel cell carcinoma; EBV-positive gastric or gastroesophageal junction cancer (including adenocarcinoma originating from the lower esophagus); nasopharyngeal carcinoma; squamous cell carcinoma of the cervix, vagina, or vulva; or SCCHN. For subjects with Merkel cell carcinoma, Merkel cell polyomavirus (MCPyV) status will be determined after recruitment. For subjects in the metastatic cohort with gastric tumor types, EBV positivity is defined by in situ hybridization of RNA encoding EBV (EBER). For subjects in the metastatic cohort with nasopharyngeal carcinoma tumor types, EBV positivity is defined by EBER in situ hybridization, and viral testing will be performed retrospectively only if results from previous testing are unavailable. For subjects in the metastatic cohort with gynecological tumors, HPV positivity is defined by in situ hybridization, real-time PCR, or immunohistochemistry (IHC). High-risk HPV positivity includes the following subtypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Viral testing will only be performed retrospectively if results from previous testing are unavailable. For subjects in the neoadjuvant and metastatic groups with viral positivity for head and neck squamous cell carcinoma, HPV positivity is defined by HPV p16 in situ hybridization, IHC, or tumor sequencing, and HPV p16 IHC should be interpreted as positive if >70% strong and diffuse nuclear and cytoplasmic staining is specific to tumor cells. HPV positivity can be obtained from the primary tumor or metastatic lymph nodes. For subjects in the neoadjuvant group with viral negativity, HPV negativity should be documented by HPV p16 in situ hybridization, IHC, or tumor sequencing.

[0130] Subjects in the neoadjuvant therapy group may include those with SCCHN for whom surgical resection is planned. These subjects must have a newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated oropharyngeal carcinoma, and the subject must have been identified as having resectable disease. Biopsy may have been obtained from the primary tumor or metastatic lymph nodes. In addition, these subjects must have a primary lesion of T2 or larger, nodular disease of N2 or larger, and a smoking history of more than 10 pack-years.

[0131] The neoadjuvant therapy group for squamous cell cervical cancer, vulvar cancer, or vaginal cancer will primarily include: those with stage II to IVA cervical cancer who have planned surgical staging or chemotherapy / radiation therapy, or those with stage II to IVA vulvar or vaginal cancer who have planned curative surgical or chemotherapy / radiation therapy.

[0132] Subjects with Merkel cell carcinoma in the neoadjuvant therapy group must have tumors suitable for pre-treatment biopsy (central needle); post-treatment biopsies will consist of surgical samples. Additionally, the subject will have a resectable tumor, characterized by: having > Stage IIA-IIIB disease with a primary tumor of any size, 2 cm in diameter or with palpable local lymph node metastases or resectable metastatic lesions; Stage IV disease with resectable limited metastases; or defined as... > Local / regional recurrent disease with a total load of 1 cm in diameter (which has resectable disease as defined by local or routine surgical practice).

[0133] Subjects in the metastatic / recurrent group will include those with progressive metastatic or recurrent disease who have been treated with no more than two prior systemic therapies. These subjects will have disease measurable by CT or MRI according to RECIST 1.1 criteria (radiographic tumor assessment must be performed within 35 days prior to the first dose). This group may also include subjects who actively refuse chemotherapy or other standard therapies for unresectable or metastatic disease (advanced stage III or IV). The subjects in the metastatic / recurrent group will be selected from those who are EBV positive and have histologically confirmed gastric or gastroesophageal junction cancer (including adenocarcinoma originating from the lower esophagus); histologically confirmed HPV positive SCCHN (oral, pharyngeal, larynx) unsuitable for curative local therapy (surgery or radiation therapy, with or without chemotherapy); histologically confirmed HPV positive cervical, vulvar, or vaginal cancer; histologically confirmed Merkel cell carcinoma, including those without prior systemic therapy; and histologically confirmed EBV positive nasopharyngeal carcinoma, excluding HPV-related nasopharyngeal carcinoma and keratinizing squamous cell carcinoma (WHO type I).

[0134] Subjects in both cohorts must be 18 years or older and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subjects must be willing to provide tumor tissue (preserved or fresh biopsy samples) for PD-L1 expression analysis and other biomarker-related studies. Biopsies should be excised, incised, or centrally needled. Fine-needle aspiration is inappropriate.

[0135] Subjects with active brain or leptomeningeal metastases will be excluded from the study unless the brain metastases have been treated and there is no evidence of progression on MRI at least 4 weeks after the end of treatment and 28 days prior to the administration of the first dose of the study drug. Furthermore, no immunosuppressive doses of systemic corticosteroids (>10 mg / day prednisone equivalent) must have been administered for at least 2 weeks prior to the administration of the study drug.

[0136] Subjects will be further excluded if any of the following applies: any serious or out-of-control medical condition that, in the researcher's opinion, could increase the risk associated with study participation or administration of the study drug, impair the subject's ability to receive the protocol therapy, or interfere with the interpretation of study results; active, known, or suspected autoimmune disease (excluding vitiligo, type 1 diabetes, residual hypothyroidism caused by an autoimmune disease requiring only hormone replacement, or a condition not expected to relapse in the absence of external triggers); or the need for corticosteroids (> daily) within 14 days of administration of the study drug (permitted doses of inhaled or topical steroids and adrenal replacement therapy in the absence of active autoimmune disease). Conditions requiring systemic therapy with a 10 mg prednisone equivalent or other immunosuppressive drugs; primary tumors or nodular metastases fixed to the carotid artery, skull matrix, or cervical spine; prior therapy with an experimental anti-tumor vaccine, any T-cell co-stimulatory or checkpoint pathway (such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibodies, including ipilimumab), or other drugs specifically targeting T cells; prior to administration of the investigational drug, toxicities attributable to prior anticancer therapy, other than alopecia and fatigue, must have regressed to Grade 1 (NCI CTCAE 4th edition) or baseline (allowing recruitment of subjects with toxicities attributable to prior anticancer therapy that are not expected to regress and result in lasting sequelae, such as neuropathy following platinum-based therapy); prior therapy with any chemotherapy, radiation therapy, or biologics targeting cancer, or investigational therapy within 28 days of the first administration of the investigational treatment (if toxicities from prior treatment have regressed to Grade 1 (NCI CTCAE 4th edition), prior to treatment < Subjects who have used a previous cytotoxic or investigational product for 4 weeks (may be eligible after discussions between the researchers and the sponsor); and a positive test for hepatitis B surface antigen (HBV sAg) or hepatitis C virus (RNA or HCV antibody) indicating acute or chronic infection; a known history of a positive human immunodeficiency virus (HIV) test or a known acquired immunodeficiency syndrome (AIDS); a history of allergic reactions to the investigational drug component, a history of severe hypersensitivity to any monoclonal antibody; women who are pregnant or lactating and likely to give birth, or women who had a positive pregnancy test at the time of recruitment prior to administration of the investigational drug.

[0137] Study design and treatment This study will be an open-label, multicenter, phase 1 / 2 trial to investigate the safety and efficacy of nirumab as a single agent in selected virus-positive and virus-negative solid tumors. The neoadjuvant therapy cohort will include 84 subjects belonging to 3 tumor types ( Figure 1 This group will be used to study the safety and tolerability of the neoadjuvant therapy nirumab.

[0138] Recruitment for each tumor type in the neoadjuvant therapy cohort will be paused after the first 10 subjects to assess safety and determine the number of subjects whose use of chemotherapy / radiation (in appropriate cases, GYN patients) or surgery (SCCHN, MCC, and GYN patients) is delayed by more than 4 weeks from the planned date. Figure 1 If the top 10 subjects of a single tumor type > If a tumor type is closed due to a delay of more than 4 weeks from the planned surgical date or the planned start date of chemoradiotherapy as specified in the label, that specific tumor group will be closed. If a tumor type is closed due to a delay in surgery (attributable to nirumab), recruitment will not be closed for the remaining tumor types in the neoadjuvant therapy group. If the top 8 patients for a single tumor type do not experience delays, then no pause in recruitment is required.

[0139] The neoadjuvant therapy cohort will recruit three tumor types: HPV-positive and HPV-negative SCCHN, HPV-positive cervical / vaginal / vulvar cancer, and polyomavirus-associated Merkel cell carcinoma. The SCCHN tumor type will require the anticipated (before study drug allocation) viral-positive test. Twenty-one viral-positive and twenty-one viral-negative SCCHN subjects will be recruited. Given the high (>85% positive) invasiveness, the other tumor types will not require the anticipated viral test for inclusion. The viral-negative group will serve as the control group for biological analysis. Subjects will have an initial biopsy and will receive two uniform doses of 240 mg nirumab via intravenous (IV) infusion over 30 minutes on days 1 and 15, followed by surgical resection or chemotherapy / radiation (…). Figure 1 (Table 1). Other preoperative surgical treatments are not permitted.

[0140] Table 1: Summary of Nirumab Dosage

[0141] Selected subjects initially treated with nirumab will receive subsequent standard of care. Following standard of care, subjects may receive a uniform dose of 240 mg nirumab intravenously every 2 weeks for relapse treatment until disease progression, toxicity, or study interruption (Table 1).

[0142] The recurrent / metastatic group will include 115 subjects belonging to 5 tumor types. Figure 1 This group will be used to evaluate the ORR of researchers assessing nirumab monotherapy.

[0143] The metastatic cohort will recruit subjects whose disease is in a metastatic or recurrent stage. This cohort will include the following five tumor types: EBV-associated gastric cancer, EBV-associated nasopharyngeal carcinoma, HPV-positive SCCHN, HPV-positive cervical / vulvar / vaginal cancer, and polyomavirus-associated Merkel cell carcinoma. SCCHN and gastric tumor types will require a positive viral test as expected. A uniform dose of 240 mg nirumab will be administered intravenously over 30 minutes every 2 weeks until unacceptable toxicity or disease progression as defined by RECIST 1.1 (Table 1).

[0144] Evaluate Baseline safety assessment will include obtaining medical history to capture relevant baseline conditions. Baseline examination should include signs and symptoms, weight, height, ECOG performance status, blood pressure (BP), heart rate (HR), temperature, respiratory rate, and oxygen saturation as determined by pulse oximetry at rest and after exertion, and should be performed within 14 days prior to the first dose. Concomitant drug therapy will also be collected from within 14 days prior to the first dose and during study treatment. Baseline safety laboratory assessment should be performed within 14 days prior to the first dose.

[0145] If the subject has already received any investigational drug, safety evaluations will be conducted on the subject. Toxicity assessments will be performed continuously throughout the treatment phase. Study assessments will be performed, including weight, height, ECOG performance status, BP, HR, temperature, respiratory rate, and oxygen saturation as determined by pulse oximetry at rest and after effort. Laboratory assessments of study safety will also be performed.

[0146] Researchers used RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria to assess efficacy via tumor imaging for ongoing research treatment decisions.

[0147] Statistical analysis Sample size determination is not based on statistical capability calculations. For the neoadjuvant therapy cohort, the SCCHN tumor type will contain 21 HPV-positive subjects and 21 HPV-negative subjects. MCC and HPV-positive cervical, vaginal, or vulvar cancer tumor types each contain 21 subjects. A sample size of 21 can detect safety events occurring at 5% and 10% incidence rates with probabilities exceeding 66% and 89%, respectively. Assuming pathological complete response rates of 10%, 15%, and 20%, a sample size of 21 can detect at least one pathological complete response with probabilities exceeding 89%, 97%, and 99%, respectively.

[0148] For the relapse / metastatic group, each specific disease or tumor type within the relapse / metastatic group will contain 23 subjects. Table 2 shows the number of responders observed at the assumed true ORR response rates of 5%, 20%, and 30%, with 0, 1, or 2 responders and > The probability of 3 respondents. Table 3 shows the 95% exact CI on both sides using the Clopper-Pearson method based on the 3rd, 4th and 5th respondents observed in 23 subjects.

[0149] Table 2: Probability of observing a response given the true ORR

[0150] Table 3: 95% exact CI on both sides using the Clopper-Pearson method based on the number of responses observed in 23 subjects.

[0151] Endpoints and analytics The primary objective of the neoadjuvant therapy cohort is safety assessment. All recorded adverse events are listed and tabulated by systemic organ category, preference, and cohort / group, and coded according to the most popular version of MedDRA. The incidence of adverse events is commented on for potential significance and clinical importance. Vital signs and clinical laboratory test results are listed and summarized by cohort / group. Any significant physical examination findings and clinical laboratory test results are listed. The incidence of infusion reactions is commented on to assess the safety and tolerability of reduced nirumab infusion frequency. The proportion of subjects in the neoadjuvant therapy cohort with a surgical delay > 4 weeks due to drug-related AEs is reported for each tumor type.

[0152] The primary objective of the metastasis / recurrence cohort is to determine the investigator-assessed objective response (ORR), defined as the number of subjects with a proven complete response (CR) or partial response (PR) divided by the number of treated subjects. BOR is defined as the best response recorded between the date of the first dose and the date of the first objectively documented tumor progression assessed by each investigator using RECIST 1.1 criteria, or the date of the last tumor assessment prior to subsequent treatment.

[0153] The investigator-assessed ORR in the metastatic cohort was summarized using binomial response rates and their corresponding 95% exact CIs (using the Clopper-Pearson method). DOR will be summarized for subjects achieving a confirmed PR, or CRDOR will be defined as the date from the first confirmed response (CR or PR) to the date of the first objectively documented tumor progression (as determined by each investigator's assessment using RECIST 1.1 criteria) or death from any cause (whichever occurs first). For subjects without progression or death, DOR will be censored on the date of their last evaluable tumor assessment. DOR is evaluated only in subjects with an objective response of CR or PR.

[0154] The time to reach the event distribution is assessed using the Kaplan-Meier technique. This will be done for PFS (based on researcher assessment) and OS. Median PFS or OS and 95% CI are constructed based on the log-log transformation of the survivor function. Ratios at some fixed time points are derived from Kaplan-Meier estimates, and corresponding confidence intervals are derived based on the Greenwood formula derived from variance and the log-log transformation applied to the survivor function.

[0155] The pharmacodynamic effects of nirumab on selected biomarkers were assessed by summarizing statistics and corresponding changes (or percentage changes) from baselines tabulated by time and group. Additionally, the time course of biomarker outcomes was graphically studied using summary plots or individual subject plots. If a meaningful indication of a pharmacodynamic trend exists, methods such as linear mixture models can be used to characterize patterns of change over time. The potential association between PD-L1 expression levels (IHC) and clinical efficacy measures was assessed using Fisher's exact test or other appropriate methods.

[0156] This study leverages data availability to investigate potential associations between various biomarker measurements and pharmacokinetic, safety, and clinical efficacy measurements. Methods such as, but not limited to, logistic regression and graphical summarization can be used to assess these associations.

[0157] This application claims the benefit of U.S. Provisional Application No. 62 / 192,396, filed July 14, 2015, which is incorporated herein by reference in its entirety. This disclosure relates to the following implementation plan: 1. A method for treating a subject suffering from a tumor, said tumor being derived from human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN), said method comprising administering to said subject a therapeutically effective amount of: Antibodies or their antigen-binding moieties that specifically bind to programmed death-1 receptor (PD-1) or programmed death-ligand 1 (PD-L1) and inhibit PD-1 activity (“anti-PD-1 antibody”) or PD-L1 activity (“anti-PD-L1 antibody”). 2. A method for treating a subject suffering from a tumor, said tumor originating from HPV-positive SCCHN, said method comprising: (i) Measure the HPV level in a sample of the subject, wherein the subject is HPV positive, and (ii) Administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject. 3. A method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-positive, and wherein a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to the subject. 4. A method for identifying a subject suffering from a tumor derived from HPV-positive SCCHN, said subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, said method comprising: (i) Measure the HPV level in a sample of the subject, wherein the subject is HPV positive, and (ii) Administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject. 5. The method according to any one of items 1-4, wherein the HPV-positive SCCHN comprises a tumor expressing one or more HPV-derived proteins or nucleotide sequences encoding one or more of the proteins. 6. The method according to any one of items 2-5, wherein the measurement includes identifying the expression of one or more HPV-derived proteins or nucleotide sequences encoding said one or more proteins. 7. The method according to claim 5 or 6, wherein the one or more HPV-derived proteins comprise p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7, or any combination thereof. 8. The method according to item 7, wherein the one or more HPV-derived proteins are identified by immunohistochemistry, ELISA, Western blotting, protein array, or any combination thereof. 9. The method according to claim 5 or 6, wherein the nucleotide sequence encodes p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7 or any combination thereof. 10. The method according to item 8 or 9, wherein the nucleotide sequence is identified by in situ hybridization, DNA or RNA array or nucleotide hybridization techniques, tumor sequencing techniques, quantitative polymerase chain reaction (PCR) or any combination thereof. 11. The method according to any one of items 1 to 10, wherein the HPV comprises HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 or any combination thereof. 12. The method according to any one of items 1 to 11, wherein more than about 70% of the tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry targeting p16. 13. The method according to any one of items 2 to 12, wherein the sample comprises a primary tumor or metastatic lymph nodes. 14. The method according to any one of items 1 to 13, wherein the tumor also expresses PD-L1. 15. The method according to any one of claims 1-14, wherein the anti-PD-1 antibody or its antigen-binding portion cross-competes with nilumab for binding to human PD-1. 16. The method according to any one of items 1-15, wherein the anti-PD-1 antibody or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. 17. The method according to any one of claims 1-16, wherein the anti-PD-1 antibody or its antigen-binding portion comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. 18. The method according to any one of items 1-17, wherein the anti-PD-1 antibody is nirumab. 19. The method according to any one of items 1-17, wherein the anti-PD-1 antibody is pembrolizumab. 20. The method according to any one of claims 1-14, wherein the anti-PD-L1 antibody or its antigen-binding portion competes with BMS-936559, MPDL3280A, MEDI4736 or MSB0010718C for binding to human PD-L1. 21. The method according to any one of items 1-14 and 20, wherein the anti-PD-L1 antibody or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. 22. The method according to any one of items 1-14 and 20-21, wherein the anti-PD-L1 antibody or its antigen-binding portion comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. 23. The method according to any one of items 1-14 and 20-22, wherein the anti-PD-L1 antibody is BMS-936559. 24. The method according to any one of items 1-14 and 20-22, wherein the anti-PD-L1 antibody is MPDL3280A. 25. The method according to any one of items 1-14 and 20-22, wherein the anti-PD-L1 antibody is MEDI4736. 26. The method according to any one of items 1-14 and 20-22, wherein the anti-PD-L1 antibody is MSB0010718C. 27. The method according to any one of items 1-26, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered at a dose in the range of at least about 80 mg to at least about 800 mg or at least about 0.1 mg / kg to at least about 10.0 mg / kg body weight. 28. The method according to claim 27, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered approximately every 2 weeks at a dose of at least approximately 3 mg / kg body weight or 240 mg. 29. The method according to any one of items 1-28, wherein the anti-PD-1 antibody or antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs. 30. The method according to any one of items 14-29, wherein the tumor has at least about 1% PD-L1 expression. 31. The method according to any one of items 14-30, wherein the tumor has at least about 5% or about 10% PD-L1 expression. 32. The method according to any one of items 1-31, wherein the subject exhibits total survival of at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after application. 33. The method according to any one of items 1-32, wherein the anti-PD-1 antibody or a portion thereof or the anti-PD-L1 antibody or a portion thereof is formulated for intravenous administration. 34. The method according to any one of items 1-33, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered at a subtherapeutic dose. 35. The method according to any one of claims 1 to 34, the method further comprising administering one or more additional anticancer drugs. 36. The method according to claim 35, wherein the anticancer drug is selected from: an antibody or antigen-binding moiety thereof that specifically binds to and inhibits CTLA-4 activity, chemotherapy, platinum-based two-drug chemotherapy, tyrosine kinase inhibitors, anti-VEGF inhibitors, or any combination thereof. 37. The method according to claim 35, wherein the anticancer drug is an antibody or its antigen-binding portion that specifically binds to CTLA-4 and inhibits CTLA-4 activity. 38. A kit for treating a subject suffering from a tumor derived from HPV-positive SCCHN, the kit comprising: (a) Anti-PD-1 antibody or its antigen-binding portion or anti-PD-L1 antibody or its antigen-binding portion; (b) The specification regarding the determination of HPV positivity of the tumor, and, if the tumor is HPV positive, the subject is given the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion in the method of item 1-37. 39. The kit according to claim 38, the kit further comprising a reagent to determine HPV positivity of the tumor. 40. The kit according to item 39, wherein the HPV positivity is measured by the expression of HPV p16. 41. A method for treating a subject suffering from a tumor, said tumor being derived from human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN), said method comprising administering to said subject a therapeutically effective amount of: Antibodies or their antigen-binding moieties that specifically bind to programmed death-1 receptor (PD-1) or programmed death-ligand 1 (PD-L1) and inhibit PD-1 activity (“anti-PD-1 antibody”) or PD-L1 activity (“anti-PD-L1 antibody”). 42. A method for treating a subject suffering from a tumor, said tumor originating from HPV-negative SCCHN, said method comprising: (i) Measure the HPV level in a sample of the subject, wherein the subject is HPV negative, and (ii) Administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject. 43. A method for identifying a subject suffering from a tumor derived from an HPV-negative SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-negative, and wherein a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to the subject. 44. A method for identifying a subject suffering from a tumor derived from HPV-negative SCCHN, said subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, said method comprising: (i) Measure the HPV level in a sample of the subject, wherein the subject is HPV negative, and (ii) Administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject. 45. The method according to any one of claims 41-44, wherein the HPV-negative SCCHN comprises a tumor expressing one or more HPV-derived proteins or nucleotide sequences encoding one or more of the proteins. 46. ​​The method according to any one of claims 42-45, wherein the measurement includes identifying the expression of one or more HPV-derived proteins or nucleotide sequences encoding said one or more proteins. 47. The method according to claim 45 or 46, wherein the one or more HPV-derived proteins comprise p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7, or any combination thereof. 48. The method according to claim 47, wherein the one or more HPV-derived proteins are identified by immunohistochemistry, ELISA, Western blotting, protein array, or any combination thereof. 49. The method according to claim 45 or 46, wherein the nucleotide sequence encodes p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7 or any combination thereof. 50. The method according to item 48 or 49, wherein the nucleotide sequence is identified by in situ hybridization, DNA or RNA array or nucleotide hybridization techniques, tumor sequencing techniques, quantitative polymerase chain reaction (PCR) or any combination thereof. 51. The method according to any one of claims 41 to 50, wherein the HPV comprises HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 or any combination thereof. 52. The method according to any one of items 41 to 51, wherein equal to or less than about 30% of tumor cells exhibit strong and diffuse nuclear and cytoplasmic staining by immunohistochemistry targeting p16. 53. The method according to any one of claims 42 to 52, wherein the sample comprises a primary tumor or metastatic lymph nodes. 54. The method according to any one of items 41 to 53, wherein the tumor also expresses PD-L1. 55. The method according to any one of claims 41-54, wherein the anti-PD-1 antibody or its antigen-binding portion cross-competes with nilumab for binding to human PD-1. 56. The method according to any one of claims 41-55, wherein the anti-PD-1 antibody or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. 57. The method according to any one of claims 41-56, wherein the anti-PD-1 antibody or its antigen-binding portion comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. 58. The method according to any one of items 41-57, wherein the anti-PD-1 antibody is nirumab. 59. The method according to any one of items 41-57, wherein the anti-PD-1 antibody is pembrolizumab. 60. The method according to any one of claims 41-54, wherein the anti-PD-L1 antibody or its antigen-binding portion competes with BMS-936559, MPDL3280A, MEDI4736 or MSB0010718C for binding to human PD-L1. 61. The method according to any one of items 41-54 and 60, wherein the anti-PD-L1 antibody or its antigen-binding portion is a chimeric, humanized, or human monoclonal antibody or a portion thereof. 62. The method according to any one of claims 41-54 and 60-61, wherein the anti-PD-L1 antibody or its antigen-binding portion comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. 63. The method according to any one of items 41-54 and 60-62, wherein the anti-PD-L1 antibody is BMS-936559. 64. The method according to any one of items 41-54 and 60-62, wherein the anti-PD-L1 antibody is MPDL3280A. 65. The method according to any one of items 41-44 and 60-62, wherein the anti-PD-L1 antibody is MEDI4736. 66. The method according to any one of items 41-54 and 60-62, wherein the anti-PD-L1 antibody is MSB0010718C. 67. The method according to any one of claims 41-66, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered at a dose in the range of at least about 80 mg to at least about 800 mg or at least about 0.1 mg / kg to at least about 10.0 mg / kg body weight. 68. The method according to claim 67, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered approximately every 2 weeks at a dose of at least approximately 3 mg / kg body weight or 240 mg. 69. The method according to any one of items 41-68, wherein the anti-PD-1 antibody or antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs. 70. The method according to any one of items 41-69, wherein the tumor has at least about 1% PD-L1 expression. 71. The method according to any one of items 41-70, wherein the tumor has at least about 5% or about 10% PD-L1 expression. 72. The method according to any one of items 41-71, wherein the subject exhibits total survival of at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after application. 73. The method according to any one of claims 41-72, wherein the anti-PD-1 antibody or a portion thereof or the anti-PD-L1 antibody or a portion thereof is formulated for intravenous administration. 74. The method according to any one of claims 41-73, wherein the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion is administered at a subtherapeutic dose. 75. The method according to any one of items 41 to 74, the method further comprising administering one or more additional anticancer drugs. 76. The method according to claim 75, wherein the anticancer drug is selected from: an antibody or antigen-binding moiety thereof that specifically binds to and inhibits CTLA-4 activity, chemotherapy, platinum-based two-drug chemotherapy, tyrosine kinase inhibitors, anti-VEGF inhibitors, or any combination thereof. 77. The method according to claim 75, wherein the anticancer drug is an antibody or its antigen-binding portion that specifically binds to CTLA-4 and inhibits CTLA-4 activity. 78. A kit for treating a subject suffering from a tumor derived from HPV-negative SCCHN, the kit comprising: (a) Anti-PD-1 antibody or its antigen-binding portion or anti-PD-L1 antibody or its antigen-binding portion; (b) A description of determining that the tumor is HPV negative, and, if the tumor is HPV negative, administering the anti-PD-1 antibody or its antigen-binding portion or the anti-PD-L1 antibody or its antigen-binding portion to the subject in the method of items 41-77. 79. The kit according to item 78, the kit further comprising a reagent to determine whether the tumor is HPV negative. 80. The kit according to item 79, wherein the HPV negative result is measured by the expression of HPV p16.

Claims

1. A method for treating a subject suffering from a tumor, said tumor being derived from human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN), said method comprising administering to said subject a therapeutically effective amount of: Antibodies or their antigen-binding moieties that specifically bind to programmed death-1 receptor (PD-1) or programmed death-ligand 1 (PD-L1) and inhibit PD-1 activity ("anti-PD-1 antibody") or PD-L1 activity ("anti-PD-L1 antibody"), respectively.

2. A method for treating a subject suffering from a tumor, said tumor originating from HPV-positive SCCHN, said method comprising: (i) Measuring HPV levels in a sample of the subject, wherein the subject is HPV positive, and (ii) administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject.

3. A method for identifying a subject suffering from a tumor derived from an HPV-positive SCCHN, the subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, the method comprising measuring HPV levels in a sample of the subject, wherein the subject is HPV-positive, and wherein a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion is administered to the subject.

4. A method for identifying a subject suffering from a tumor derived from HPV-positive SCCHN, said subject being suitable for anti-PD-1 antibody or anti-PD-L1 antibody therapy, said method comprising: (i) Measuring HPV levels in a sample of the subject, wherein the subject is HPV positive, and (ii) administer a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding portion or an anti-PD-L1 antibody or its antigen-binding portion to the subject.

5. The method according to any one of claims 1-4, wherein the HPV-positive SCCHN comprises a tumor expressing one or more HPV-derived proteins or nucleotide sequences encoding one or more of the proteins.

6. The method according to any one of claims 2-5, wherein the measurement comprises identifying the expression of one or more HPV-derived proteins or nucleotide sequences encoding said one or more proteins.

7. The method according to claim 5 or 6, wherein the one or more HPV-derived proteins comprise p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7, or any combination thereof.

8. The method of claim 7, wherein the one or more HPV-derived proteins are identified by immunohistochemistry, ELISA, Western blotting, protein array, or any combination thereof.

9. The method according to claim 5 or 6, wherein the nucleotide sequence encodes p16, Ki-67, cyclin D1, p53, ProEx C, E6, E7 or any combination thereof.

10. The method of claim 8 or 9, wherein the nucleotide sequence is identified by in situ hybridization, DNA or RNA array or nucleotide hybridization techniques, tumor sequencing techniques, quantitative polymerase chain reaction (PCR) or any combination thereof.

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