Methods and Compositions for Combination Therapy

Abstract

The present disclosure provides compositions and methods for treating a disease, such as a cancer or a tumor, comprising administering to a subject sequential doses of an anti-PD-1 antibody composition comprising an anti-PD-1 antibody, such as pembrolizumab or a pembrolizumab variant, or an antigen-binding fragment thereof, and administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a DR IL-18 polypeptide, thereby improving the subject's condition, e.g., causing immunotherapy-induced regression of the disease in the subject, such as immunotherapy-induced regression of the cancer or tumor.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 481,214, filed January 24, 2023, 63 / 488,384, filed March 3, 2023, 63 / 488,473, filed March 3, 2023, and 63 / 511,404, filed June 30, 2023, each of which is incorporated by reference in its entirety.

[0002] Reference to an electronically submitted sequence listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on January 12, 2024, is named "ST-011-WO1_seq_list.xml", and is 35kb in size. [Background technology]

[0003] PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B, and NKT cells and is upregulated by T / B cell receptor signaling on lymphocytes, monocytes, and myeloid cells (Non-Patent Document 1).

[0004] Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. For example, in large sample sets of ovarian cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, PD-L1 expression has been shown to correlate with poor prognosis and reduced overall survival, regardless of subsequent treatment (Non-Patent Documents 2-13).

[0005] Similarly, PD-1 expression on tumor-infiltrating lymphocytes has been found to indicate dysfunctional T cells in breast cancer and melanoma (Non-Patent Documents 14 and 15) and to correlate with poor prognosis in renal cancer (Non-Patent Document 16). Therefore, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to impaired immune responses against tumors.

[0006] Immune checkpoint therapy targeting the PD-1 axis has led to dramatic improvements in clinical responses in multiple human cancers (Non-Patent Documents 17-25). Immunotherapies targeting the PD-1 axis include monoclonal antibodies directed against the PD-1 receptor (KEYTRUDA® (pembrolizumab), Merck Sharp & Dohme LLC., Rahway, NJ, USA; OPDIVO® (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ, USA; and LIBTAYO® (cemiplimab), Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), as well as PD-L1 ligands (MPDL3280A; TECENTRIQ® (atezolizumab), Genentech, San Francisco, CA, USA; IMFINZI® (durvalumab), AstraZeneca Pharmaceuticals LP, Wilmington, DE; BAVENCIO® (avelumab), Merck KGaA, Darmstadt, Germany; and JEMPERLI® (dostarimab), GlaxoSmithKline Biologics LLC, Philadelphia, PA, USA. Both therapeutic approaches have demonstrated antitumor efficacy in multiple cancer types. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Sharpe et al.,The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection.Nature Immunology,8:239-245(2007) [Non-licensed document 2] Dong et al., Nat Med.8(8):793-800(2002) [Non-licensed document 3] Yang et al.Invest Ophthalmol Vis Sci.49:2518-2525(2008)

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[0008] Interleukin-18 (IL-18) is a proinflammatory cytokine capable of stimulating T cells, NK cells, and myeloid cells. IL-18 has been proposed as an immunotherapeutic agent for the treatment of cancer, given its ability to stimulate antitumor cells. However, the clinical efficacy of IL-18 has been limited.

[0009] Thus, there is a need for compositions and methods that provide effective IL-18 signaling activity to treat and prevent cancer and other diseases and disorders. Summary of the Invention

[0010] One aspect of the present disclosure is a method of treating a disease in a subject in need thereof, comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; and (b) administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, thereby causing immunotherapy-induced regression of the disease in the subject.

[0011] One aspect of the disclosure provides a method of treating a disease in a subject in need thereof, the method comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; and (b) administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:41.

[0012] In some embodiments, the method further comprises administering cytokine release syndrome (CRS) prophylaxis to the subject with or before the sequential doses of the DR IL-18 composition. In some embodiments, the method further comprises administering a dose of a CRS prophylactic agent to the subject with or before the sequential doses of the DR IL-18 composition. In some embodiments, the method comprises administering CRS prophylaxis to the subject with or before each dose of the sequential doses of the DR IL-18 composition. In some embodiments, the method further comprises administering a dose of a CRS prophylactic agent to the subject with or before each dose of the sequential doses of the DR IL-18 composition. In some embodiments, the dose of CRS prophylaxis comprises at least one of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid administered to the subject. In some embodiments, CRS prophylaxis comprises administering to a subject at least an NSAID and acetaminophen, at least an NSAID and an H1 antagonist, at least an acetaminophen and an H1 antagonist, or at least an NSAID, acetaminophen, and an H1 antagonist. In some embodiments, the CRS prophylaxis dose is administered to a subject orally or intravenously.

[0013] In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject Q3W. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject Q3W. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject about every 21 days. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition comprises a fixed dose of 200 mg pembrolizumab. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition comprises about 2 mg / kg pembrolizumab per kg of subject body weight. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject Q3W as a fixed dose of 200 mg pembrolizumab. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject about every 21 days as about 200 mg pembrolizumab. In some embodiments, each dose of the sequential doses of the anti-PD-1 antibody composition is administered Q3W at a dose of about 2 mg / kg of pembrolizumab per kg of the subject's body weight. In some embodiments, each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject about every 21 days at a dose of about 2 mg / kg of pembrolizumab per kg of the subject's body weight. In some embodiments, each dose of the sequential doses of the DR IL-18 composition is administered to the subject weekly. In some embodiments, each dose of the sequential doses of the DR IL-18 composition is administered to the subject about every 7 days. In some embodiments, the next dose of the DR IL-18 composition is administered to the subject at least 6 days after the previous dose of the DR IL-18 composition. In some embodiments, the next dose of the DR IL-18 composition is administered to the subject up to 9 days after the previous dose of the DR IL-18 composition. In some embodiments, the polypeptide is at a concentration of about 30 mg / mL. In some embodiments, the dose of the DR IL-18 composition comprises at least about 15 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 20 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 30 μg of polypeptide per kg of subject body weight.In some embodiments, the dose of the DR IL-18 composition comprises at least about 90 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 180 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 360 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 600 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 900 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises at least about 1200 μg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition is at least one of the initial dose, first dose, or lowest dose administered to the subject. In some embodiments, each dose of the DR IL-18 composition comprises about 15 μg / kg to about 1200 μg / kg of polypeptide per kg of subject body weight, hi some embodiments, the dose of the DR IL-18 composition is about 15 μg / kg, about 30 μg / kg, about 90 μg / kg, about 180 μg / kg, about 360 μg / kg, about 600 μg / kg, about 900 μg / kg, or about 1200 μg / kg of subject body weight. In some embodiments, a dose of a DR IL-18 composition comprises about 15 μg / kg to about 30 μg / kg, about 30 μg / kg to about 90 μg / kg, about 90 μg / kg to about 180 μg / kg, about 180 μg / kg to about 360 μg / kg, about 360 μg / kg to about 600 μg / kg, about 600 μg / kg to about 900 μg / kg, or about 900 μg / kg to about 1200 μg / kg of polypeptide per kg of the subject's body weight. In some embodiments, a subsequent dose of a DR IL-18 composition comprises a greater amount of polypeptide per kg of the subject's body weight than the amount of polypeptide previously administered to the subject. In some embodiments, the previous amount of polypeptide was tolerated by the subject.In some embodiments, a subsequent dose of a DR IL-18 composition comprises a greater amount of polypeptide per kg of subject body weight than the amount of polypeptide in a previous dose of the DR IL-18 composition. In some embodiments, the previous dose was tolerated by the subject. In some embodiments, a subsequent dose of a DR IL-18 composition comprises the same or equivalent amount of polypeptide per kg of subject body weight as the amount of polypeptide previously administered to the subject. In some embodiments, the amount of polypeptide is associated with a recorded treatment-emergent adverse event in the subject. In some embodiments, the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. In some embodiments, the recorded treatment-emergent adverse event is associated with no or minimal medical intervention, support, or therapy being provided to the subject. In some embodiments, the amount is the maximum tolerated dose. In some embodiments, a subsequent dose of a DR IL-18 composition comprises the same or equivalent amount of polypeptide per kg of subject body weight as the amount of polypeptide in a previous dose of the DR IL-18 composition. In some embodiments, the previous dose is associated with causing a recorded treatment-emergent adverse event in the subject. In some embodiments, the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. In some embodiments, the recorded treatment-emergent adverse event is associated with providing the subject with no or minimal medical intervention, support, or therapy. In some embodiments, the previous dose is the maximum tolerated dose. In some embodiments, a subsequent dose of a DR IL-18 composition comprises a lower amount of polypeptide per kg of subject body weight than the amount of polypeptide previously administered to the subject.In some embodiments, the subject did not tolerate the previously administered amount of polypeptide. In some embodiments, the previously administered amount of polypeptide is associated with dose-limiting toxicity (DLT). In some embodiments, the subsequent dose is a previously tolerated dose. In some embodiments, the subsequent dose of the DR IL-18 composition contains a lower amount of polypeptide per kg of the subject's body weight than the amount of polypeptide in the previous dose of the DR IL-18 composition. In some embodiments, the previous dose was not tolerated by the subject. In some embodiments, the previous dose is associated with dose-limiting toxicity (DLT). In some embodiments, the subsequent dose is a previously tolerated dose. In some embodiments, the anti-PD-1 and DR IL-18 compositions are administered to the subject in a series of cycles, each cycle comprising about 21 days. In some embodiments, the anti-PD-1 antibody composition is administered once per cycle. In some embodiments, the DR IL-18 composition is administered once, twice, or three times during each cycle. In some embodiments, the series of cycles comprises a current cycle and a next cycle, wherein the next cycle is performed consecutively to the current cycle. In some embodiments, the series of cycles includes a first cycle, and the first cycle includes the first day. In some embodiments, a dose of an anti-PD-1 antibody composition comprising 200 mg of pembrolizumab is administered to the subject on the first day of the first cycle. In some embodiments, a dose of a DR IL-18 composition comprising 30 μg / kg of the polypeptide is administered to the subject on the first day of the first cycle. In some embodiments, the series of cycles includes at least 8 cycles. In some embodiments, the series of cycles includes 35 or fewer cycles. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered for at least 24 weeks. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject has received at least 8 doses of the anti-PD-1 antibody composition.In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 24 weeks or has received at least 8 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 8 cycles. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been administered at least 8 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences at least about 24 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences intervention-related toxicity designated as grounds for permanent discontinuation. In some embodiments, the intervention-related toxicity is at least one of a Grade 4, Grade 3, or recurrent Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the treatment-emergent adverse event is associated with a significant or severe limitation in the subject's activities. In some embodiments, the treatment-emergent adverse event is life-threatening or requires significant medical intervention or hospitalization. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered for up to about 2 years. In some embodiments, the subject is administered up to 35 doses of the anti-PD-1 antibody composition. In some embodiments, a dose of the anti-PD-1 antibody composition is administered to the subject at least about 60 minutes before a dose of the DR IL-18 composition is administered to the subject. In some embodiments, a dose of the DR IL-18 composition is administered to the subject at least about 60 minutes after a dose of the anti-PD-1 antibody composition is administered to the subject. In some embodiments, (a) and (b) are performed sequentially. In some embodiments, (a) is performed before (b). In some embodiments, (b) is performed before (a). In some embodiments, (a) and (b) are performed simultaneously.In some embodiments, one dose of the anti-PD-1 antibody composition is administered to the subject by intravenous infusion. In some embodiments, each dose of the anti-PD-1 antibody composition is administered to the subject by intravenous infusion. In some embodiments, one dose of the DR IL-18 composition is administered to the subject by subcutaneous injection. In some embodiments, each dose of the DR IL-18 composition is administered to the subject by subcutaneous injection. In some embodiments, the disease comprises cancer or a solid tumor. In some embodiments, the cancer or solid tumor is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin's lymphoma (cHL), or primary mediastinal tumor. The cancer or solid tumor is associated with large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient (dMMR) cancer, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof. In some embodiments, the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. In some embodiments, the cancer or solid tumor is associated with melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutations / fusions), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. In some embodiments, the cancer or solid tumor is associated with platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.

[0014] Another aspect of the present disclosure provides a method of treating a disease in a human patient, comprising administering to the patient an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a decoy-resistant (DR) IL-18 composition comprising a polypeptide to the subject, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, and the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) comprising the amino acid sequence set forth in SEQ ID NOs: 1, 2, and 3, and a heavy chain CDR comprising the amino acid sequence set forth in SEQ ID NOs: 6, 7, and 8.

[0015] Another aspect of the present disclosure provides a method of treating a disease in a human patient, comprising administering to the patient an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a decoy-resistant (DR) IL-18 composition comprising a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:41, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) comprising the sequence of amino acids set forth in SEQ ID NOs:1, 2, and 3, and a heavy chain CDR comprising the sequence of amino acids set forth in SEQ ID NOs:6, 7, and 8. In some embodiments, the method further comprises administering CRS prophylaxis to the subject with or before administering the DR IL-18 composition. In some embodiments, the CRS prophylaxis comprises at least one of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid administered to the subject. In some embodiments, CRS prophylaxis comprises administering to a subject at least an NSAID and acetaminophen, at least an NSAID and an H1 antagonist, at least an acetaminophen and an H1 antagonist, or at least an NSAID, acetaminophen, and an H1 antagonist. In some embodiments, CRS prophylaxis is administered to a subject orally or intravenously.

[0016] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is administered to the subject at a dose of about 200 mg once every three weeks. In some embodiments, the anti-PD-1 monoclonal antibody is administered to the subject at a dose of about 400 mg once every six weeks. In some embodiments, the anti-PD-1 monoclonal antibody is administered to the subject by IV infusion. In some embodiments, the anti-PD-1 monoclonal antibody is administered to the patient by IV infusion over about 30 minutes on day 1 of each treatment cycle. In some embodiments, the anti-PD-1 or antigen-binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is a pembrolizumab variant. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition comprising 130 mg / mL of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition comprising 165 mg / mL of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0017] Another aspect of the disclosure provides for the use of an anti-PD-1 antibody or antigen-binding fragment thereof in a method of treating cancer.

[0018] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0019] The following detailed description of the invention will be better understood when read in conjunction with the accompanying drawings, in which: It is understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. [Brief explanation of the drawings]

[0020] [Figure 1] 1 shows substantially reduced CT26 (colorectal) tumor growth in mice treated with a combination of decoy-resistant (DR) IL-18 polypeptide and an anti-PD-1 immune checkpoint inhibitor (ICI) antibody. The Y-axis is tumor growth in cubic millimeters (mm3), and error bars represent standard deviation. [Figure 2] Figure 1 shows reduced MC38 (colorectal) tumor growth in mice treated with a combination of DR IL-18 polypeptide and anti-PD-1 ICI antibody compared to either DR IL-18 polypeptide or anti-PD-1 ICI monotherapy. The Y-axis is tumor growth in mm3, and error bars represent standard deviation. The inset provides a magnification of the tumor growth area between 0 and 1000 mm3. [Figure 3] The amino acid sequences of the light and heavy chains of exemplary anti-PD-1 monoclonal antibodies useful in the invention are shown (SEQ ID NOs: 5 and 10, respectively). The light and heavy chain variable regions are underlined (SEQ ID NOs: 4 and 9, respectively), and the CDRs are in bold. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0023] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting.

[0024] As used herein, quantitatively, the term "about" refers to plus or minus 10% of the value it modifies (if the value is not divisible, such as the number of molecules or nucleotides, it is rounded up to the nearest integer).

[0025] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., the range "50 mg to 500 mg" includes the endpoints 50 mg and 500 mg, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values; they are sufficiently imprecise to include values ​​that approximate these ranges and / or values.

[0026] As used herein, the term "comprising" can include the embodiments "consisting of" and "consisting essentially of." As used herein, the terms "comprise(s)," "include(s)," "having," "has," "may," "contain(s)," and variations thereof, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified ingredients / steps and allow for the presence of other ingredients / steps. However, such descriptions should also be construed to describe compositions or processes as "consisting of" and "consisting essentially of" the listed ingredients, which allows for the presence of only the specified ingredients or compounds, along with any acceptable carriers or fluids, and excludes other ingredients or compounds.

[0027] As used herein, the terms "at least one" item or "one or more" items each include a single item selected from a list, as well as a mixture of two or more items selected from a list.

[0028] The terms "administration" or "administer" refer to the act of injecting or otherwise physically delivering an exogenous substance (e.g., an anti-PD-1 antibody) to a patient or subject, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0029] As used herein, the term "subject" (alternatively, "patient") refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovines (e.g., dairy cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), and Procyon lotor (e.g., raccoons). In certain embodiments, the subject is a human.

[0030] As used herein, the term "subject in need thereof" refers to a subject diagnosed with or suspected of having cancer, as defined herein.

[0031] As used herein, the term "antibody" refers to any form of immunoglobulin molecule exhibiting the desired biological or binding activity. It is therefore used in the broadest sense and specifically encompasses, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies, and may include post-translational modifications thereof (e.g., C-terminal lysine clipping in the heavy chain, conversion of glutamine or glutamic acid to pyroglutamic acid) that may occur when the antibody is recombinantly expressed in host cells (e.g., CHO cells) or during purification / storage. A "parent antibody" is an antibody obtained by exposing the immune system to an antigen prior to modification of the antibody for its intended use, such as humanizing the antibody for use as a human therapeutic. As used herein, the term "antibody" encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, fusion proteins containing antigen-binding fragments thereof that specifically compete with the intact antibody.

[0032] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair containing one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region of approximately 100-110 amino acids primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody generally has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Human heavy chains are further classified as mu, delta, gamma, alpha, or epsilon, which define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 or more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)).

[0033] As used herein, "variable region" or "V region" or "V chain" refers to the segment of an IgG chain that is variable in sequence among different antibodies. The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, alone or in combination. The variable domain of the heavy chain is referred to as the "V H The variable domain of the light chain is sometimes referred to as "V L "It is sometimes referred to as ".

[0034] Typically, both heavy and light chain variable regions contain three hypervariable regions located within relatively conserved framework regions (FRs), also called complementarity-determining regions (CDRs). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. Generally, from the N-terminus to the C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As referred to herein, the light chain CDRs are CDRL1, CDRL2, and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2, and CDRH3, respectively. The assignment of amino acids to each domain generally follows Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991), Kabat (1978) Adv. Prot. Chem. 32:1-75, Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616, Chothia, et al., (1987) J Mol. Biol. 196:901-917, or Chothia, et al., (1989) Nature 342:878-883.

[0035] "CDR" is antibody V H One of the three hypervariable regions (H1, H2, or H3) within the non-framework regions of the β-sheet framework, or antibody V LCDR refers to one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the β-sheet framework. Thus, CDR is a variable region sequence interspersed within the framework region sequence. CDR regions are well known to those skilled in the art, and are defined, for example, by Kabat as the most hypervariable region within an antibody variable domain. CDR region sequences are also structurally defined by Chothia as residues that are not part of the conserved β-sheet framework and can therefore adopt different conformations. Both terms are well recognized in the art. CDR region sequences are also defined by AbM, Contact, and IMGT. The location of CDRs within canonical antibody variable regions has been determined by comparing numerous structures (Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Because the number of residues within hypervariable regions varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered a, b, c, etc. next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is similarly well known to those of skill in the art. For example, correspondence between numbering systems, including Kabat numbering and the IMGT unique numbering system, is well known to those of skill in the art and is shown in Table 1 below. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In still other embodiments, the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In still other embodiments, the CDRs are as defined by the Contact numbering system. [Table 1]

[0036] A "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular species (e.g., human) or contains sequences belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species (e.g., mouse) or belongs to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0037] A "human antibody" refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. If produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, a human antibody may contain mouse carbohydrate chains. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0038] "Humanized antibody" refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulins. Generally, humanized antibodies contain substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FR regions being those of a human immunoglobulin. A humanized antibody will also optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefixes "hum," "hu," or "h" may be added to antibody clone names when necessary to distinguish the humanized antibody from the parent rodent antibody. Humanized forms of rodent antibodies generally contain the same CDR sequences as the parent rodent antibody, but certain amino acid substitutions may be included to improve affinity, increase the stability of the humanized antibody, or for other reasons.

[0039] "Monoclonal antibody" or "mAb" or "Mab," as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present disclosure may be produced by the hybridoma method described in Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0040] As used herein, unless otherwise indicated, "antibody fragment" or "antigen-binding fragment" refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., a fragment that retains one or more CDR regions, and that retains the ability to specifically bind to an antigen. An antibody that "specifically binds" to PD-1 is one that exhibits preferential binding to PD-1 (optionally) relative to other proteins, although this specificity does not require absolute binding specificity. An antibody is considered "specific" for its intended target if its binding determines the presence of the target protein in a sample without producing undesirable results, such as false positives. An antibody, or a binding fragment thereof, binds to a target protein with an affinity that is at least 2-fold, preferably at least 10-fold, more preferably at least 20-fold, and most preferably at least 100-fold higher than its affinity for a non-target protein.

[0041] Antigen-binding portions include, for example, Fab, Fab', F(ab')2, Fd, Fv, fragments containing the CDRs, and single-chain variable fragment antibodies (scFv), as well as polypeptides containing at least a portion of an immunoglobulin sufficient to confer specific antigen binding to an antigen (e.g., PD-1). Antibodies include antibodies of any class, such as IgG, IgA, or IgM (or subclasses thereof); antibodies need not be of any particular class. Depending on the amino acid sequence of the constant region of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant regions corresponding to the various classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0042] An "antigen" is a structure to which an antibody can selectively bind. A target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on or within a cell, e.g., a cancer cell.

[0043] An "intact" antibody is one that comprises an antigen-binding site, as well as a constant domain (CL), and at least a heavy chain constant region, CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0044] As used herein, the term "immune response" relates to any one or more of a specific immune response, a non-specific immune response, both specific and non-specific responses, an innate response, a primary immune response, adaptive immunity, a secondary immune response, a memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0045] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral or parenteral route of administration. The term "enteral route" of administration refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal, or intragastric routes. A "parenteral route" of administration refers to an administration route other than the enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intrathecal, intraorbital, intracardiac, transtracheal, intraarticular, subthecal, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous, or topical administration. The therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. Suitable routes and methods of administration may vary depending on several factors, such as the particular therapeutic agent used, the desired absorption rate, the particular formulation or dosage form used, the type or severity of the disorder being treated, the particular site of action, and the condition of the patient, and can be readily selected by one of ordinary skill in the art.

[0046] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle-forming toxic plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogesterones, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in treatment methods include cytostatic and / or cytotoxic agents.

[0047] The term "variant," when used with reference to an antibody (e.g., an anti-PD-1 antibody) or an amino acid region within an antibody, can refer to a peptide or polypeptide containing one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) amino acid sequence substitutions, deletions, and / or additions compared to the native or unmodified sequence. For example, an anti-PD-1 antibody variant can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) changes to the amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants can be naturally occurring or artificially constructed. Polypeptide variants can be prepared from corresponding nucleic acid molecules encoding the variants. In certain embodiments, antibody variants (e.g., anti-PD-1 antibody variants) retain at least antibody functional activity. In some embodiments, the anti-PD-1 antibody variant binds to PD-1 and / or is antagonistic to PD-1 activity.

[0048] "Conservatively modified variants" or "conservative substitutions" refer to the substitution of an amino acid in a protein with another amino acid having similar properties (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), and thus changes can frequently be made without altering the biological activity of the protein or other desired properties, such as antigen affinity and / or specificity. Those skilled in the art will generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). Furthermore, substitution of structurally or functionally similar amino acids is unlikely to destroy biological activity. Exemplary conservative substitutions are shown in Table 2 below. [Table 2]

[0049] " Homology " refers to the similarity between two polypeptide sequences when they are optimally aligned. If a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, for example, if the position in the light chain CDR of two different Abs is occupied by alanine, the two Abs are homologous at that position. The percentage of homology is calculated by dividing the number of homologous positions shared by the two sequences by the total number of positions compared x 100. For example, if 8 out of 10 positions in two sequences match when the sequences are optimally aligned, the two sequences are 80% homologous. Generally, the comparison is performed when the two sequences are aligned to give the maximum percentage homology. For example, the comparison can be performed by the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence.

[0050] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST Algorithm: Altschul, S. F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T. L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S. F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J. C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J. Met. al., (1994) Comput.Appl.Biosci.10:67-70, ALIGNMENT SCORING SYSTEMS: Dayhoff, MO, et al., “A model of evolutionary change in proteins.” Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.MODayhoff(ed.),pp.345-352,Natl.Biomed.Res.Found.,Washington,DC,Schwartz,RM,et al.,“Matrices for detecting distant relationships.”Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.”MODayhoff(ed.),pp.353-358,Natl.Biomed.Res.Found.,Washington,DC,Altschul,SF,(1991)J.Mol.Biol.219:555-565,States,DJ,et al.,(1991)Methods 3:66-70, Henikoff,S.,et al.,(1992)Proc.Natl.Acad.Sci.USA 89:10915-10919,Altschul,SF,et al.,(1993)J.Mol.Evol.36:290-300, ALIGNMENT STATISTICS:Karlin,S.,et al.,(1990)Proc.Natl.Acad.Sci.USA 87:2264-2268,Karlin,S.,et al.,(1993)Proc.Natl.Acad.Sci.USA 90:5873-5877,Dembo,A.,et al., (1994) Ann.Prob.22:2022-2039, and Altschul, SF “Evaluating the statistical significance of multiple distinct local alignments.” Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, New York.

[0051] As used herein, "RECIST 1.1 response criteria" means the definitions set forth in Eisenhauer, E. A. et al., Eur. J. Cancer 45:228-247 (2009), for target lesions or non-target lesions, as appropriate, based on the context in which response is measured.

[0052] "Sustained response" refers to a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration at least equal to the duration of treatment or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0053] "Non-responder patient," when referring to a specific anti-tumor response to a treatment described herein, means that the patient did not exhibit an anti-tumor response.

[0054] When referring to a specific anti-tumor response to a treatment described herein, a "responder patient" means that the patient exhibited an anti-tumor response.

[0055] As used herein, "treating" or "treating" cancer means administering a described agent(s) (e.g., an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, a decoy-resistant (DR) IL-18 composition, combinations thereof, etc.) to a subject having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, a reduced number of cancer cells, a reduced tumor size, a reduced rate of cancer cell invasion into peripheral organs, or a reduced rate of tumor metastasis or tumor growth, including oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. Typically, the agent(s) of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing regression of such symptom(s) or inhibiting their progression to any clinically measurable extent. The amount of agent(s) in a treatment method that is effective in alleviating any particular disease symptom can vary depending on factors such as the subject's or patient's condition, age, and weight, as well as the ability of the therapeutic biologic to induce a desired response in the subject or patient. Alleviation of disease symptoms can be assessed by any clinical measurement typically used by a physician or other skilled healthcare provider to assess the severity or progression of the symptom. "Treatment" can include one or more of the following: inducing / increasing an anti-tumor immune response, reducing the number of one or more tumor markers, halting or slowing the growth of a tumor or blood cancer or the progression of a disease such as cancer, stabilizing the disease, inhibiting tumor cell growth or survival, eliminating or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers, alleviating or ameliorating clinical symptoms of the disease, reducing the severity or duration of clinical symptoms, extending the survival or lifespan of a patient compared to the expected survival of a similar untreated patient, and inducing complete or partial remission of a cancerous condition, where the disease is cancer.

[0056] The amount of a therapeutic biologic that is effective in alleviating any particular disease symptom can vary depending on factors such as the subject's or patient's condition, age, and weight, as well as the ability of the therapeutic biologic to elicit a desired response in the subject or patient. Alleviation of disease symptoms can be assessed by any clinical measurement typically used by a physician or other skilled health care provider to assess the severity or progression of the condition.

[0057] Positive therapeutic effects in cancer can be measured in several ways (see W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, for tumor growth inhibition, according to NCI criteria, T / C≦42% is the minimum level of anti-tumor activity. T / C<10% is considered a high level of anti-tumor activity, where T / C (%)=median treated tumor volume / median control tumor volume×100. In some embodiments, the treatment achieved by the disclosed therapy is any of partial response (PR), complete response (CR), objective response (OR), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). PFS, also referred to as "time to tumor progression," indicates the length of time during and after treatment during which the cancer does not grow, and includes the length of time the patient experiences CR or PR, as well as the amount of time the patient experiences stable disease (SD). DFS refers to the length of time a patient remains disease-free during and after treatment. OS refers to the extension of life expectancy compared to naive or untreated individuals or patients. In some embodiments, the response to both of the present disclosure is either PR, CR, PFS, DFS, or OR, as assessed using RECIST 1.1 response criteria. The treatment regimen for the disclosed therapies that is effective in treating cancer patients can vary according to factors such as the patient's disease state, age, and weight, as well as the ability of the therapy to induce an anti-cancer response in the subject. Any embodiment of the aspects of the present disclosure may not be effective in achieving a positive therapeutic effect in all subjects, but should be effective in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi-square test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkheel-Tapstra test, and Wilcoxon test.

[0058] "Cytokine release syndrome" or CRS, as used herein, refers to an acute systemic inflammatory syndrome that can be triggered by various factors, such as infection, and can occur after treatment with several types of immunotherapy, such as monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy, as well as some non-protein-based cancer drugs. CRS is characterized by a large and rapid increase in cytokines and inflammatory responses. Signs and symptoms of CRS include fever, fatigue, nausea, headache, rash, joint pain, muscle pain, tachycardia, hypotension, and dyspnea. CRS can progress to an uncontrolled systemic inflammatory response accompanied by circulatory shock requiring vasopressors, vascular leakage, disseminated intravascular coagulation, and multiple organ system failure. Patients may have a mild reaction, or the reaction may be severe or life-threatening. CRS grading can be performed according to the Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading system, as described, for example, in Lee et al., Biology of Blood and Marrow Transplantation. 25 (2019) 625-639, the disclosure of which is incorporated herein by reference in its entirety.

[0059] By "PD-1 antagonist" or "anti-PD-1 antibody" is meant any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 (for PD-1), PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H (for PD-L1), and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 (for PD-L2). In any of the therapeutic methods, medicaments, and uses of the present disclosure in which a human individual is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found at NCBI locus number NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers NP_054862 and NP_079515, respectively.

[0060] By "anti-PD-1 antibody composition" is meant a composition or formulation comprising a particular concentration of an anti-PD-1 antibody (e.g., pembrolizumab) that is administered to a human patient or subject.

[0061] "Pembrolizumab" (formerly known as MK-3475, SCH900475, and lambrolizumab), alternatively referred to herein as "pembro," is a humanized IgG4 mAb having the structure set forth in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013), and containing the heavy and light chain amino acid sequences and CDRs set forth in Table 3. Pembrolizumab is approved by the USFDA as set forth in the prescribing information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ USA, initial US approval in 2014 (updated January 2024)). The term pembrolizumab includes mAbs' having the structure as set forth above (ibid.) but without the C-terminal lysine in the heavy chain.

[0062] As used herein, "pembrolizumab variant" refers to a monoclonal antibody comprising heavy and light chain sequences identical to those of pembrolizumab, except that it has three, two, or one conservative amino acid substitution at positions located outside the light chain CDRs and six, five, four, three, two, or one conservative amino acid substitution at positions located outside the heavy chain CDRs, e.g., the variant positions are located in the FR or constant region, and optionally have a deletion of the C-terminal lysine residue of the heavy chain. In other words, pembrolizumab and pembrolizumab variants contain the same CDR sequences, but differ from each other by having conservative amino acid substitutions at three or less or six or less other positions in their full-length light and heavy chain sequences, respectively. Pembrolizumab variants are substantially identical to pembrolizumab with respect to their binding affinity to PD-1 and their ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0063] "Platinum-containing chemotherapy" (also known as platins) refers to the use of chemotherapeutic agents (or agents) used to treat cancer that are coordination complexes of platinum. Platinum-containing chemotherapeutic agents are alkylating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and, generally, apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.

[0064] PD-1 antagonists or anti-human PD-1 monoclonal antibodies useful in the methods of the disclosure Examples of mAbs that bind to human PD-1 and are useful in the therapeutic methods, compositions, and uses of the present disclosure are described in U.S. Patent Nos. 7,521,051, 8,008,449, and 8,354,509. Specific anti-human PD-1 mAbs useful as PD-1 antagonists in the therapeutic methods, compositions, and uses of the present disclosure include pembrolizumab (formerly known as MK-3475, SCH 900475, and lambrolizumab), a humanized IgG4 mAb having a structure comprising the heavy and light chain amino acid sequences described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and shown in Figure 7, and the humanized antibodies h409A11, h409A16, and h409A17 described in WO2008 / 156712.

[0065] Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks the binding of PD-L1 to PD-1, and preferably also blocks the binding of PD-L2 to PD-1.

[0066] In some embodiments, the anti-PD-1 antibody is pembrolizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab.

[0067] In some embodiments, an anti-human PD-1 antibody or antigen-binding fragment thereof for use in the methods and uses of the disclosure comprises the three light chain CDRs, CDRL1, CDRL2, and CDRL3, and / or the three heavy chain CDRs, CDRH1, CDRH2, and CDRH3.

[0068] In one embodiment, CDRL1 has the amino acid sequence set forth in SEQ ID NO: 1 or a variant of the amino acid sequence set forth in SEQ ID NO: 1, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 2 or a variant of the amino acid sequence set forth in SEQ ID NO: 2, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 3 or a variant of the amino acid sequence set forth in SEQ ID NO: 3.

[0069] In one embodiment, CDRH1 has the amino acid sequence set forth in SEQ ID NO: 6 or a variant of the amino acid sequence set forth in SEQ ID NO: 6, CDRH2 has the amino acid sequence set forth in SEQ ID NO: 7 or a variant of the amino acid sequence set forth in SEQ ID NO: 7, and CDRH3 has the amino acid sequence set forth in SEQ ID NO: 8 or a variant of the amino acid sequence set forth in SEQ ID NO: 8.

[0070] In one embodiment, the three light chain CDRs have the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the three heavy chain CDRs have the amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8.

[0071] In one embodiment, the three light chain CDRs have the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the three heavy chain CDRs have the amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8.

[0072] In a further embodiment, CDRL1 has the amino acid sequence set forth in SEQ ID NO: 21 or a variant of the amino acid sequence set forth in SEQ ID NO: 21, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 22 or a variant of the amino acid sequence set forth in SEQ ID NO: 22, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 23 or a variant of the amino acid sequence set forth in SEQ ID NO: 23.

[0073] In yet another embodiment, CDRH1 has the amino acid sequence set forth in SEQ ID NO:24 or a variant of the amino acid sequence set forth in SEQ ID NO:24, CDRH2 has the amino acid sequence set forth in SEQ ID NO:25 or a variant of the amino acid sequence set forth in SEQ ID NO:25, and CDRH3 has the amino acid sequence set forth in SEQ ID NO:26 or a variant of the amino acid sequence set forth in SEQ ID NO:26.

[0074] In another embodiment, the three light chain CDRs have the amino acid sequences set forth in SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, and the three heavy chain CDRs have the amino acid sequences set forth in SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26.

[0075] Some anti-human PD-1 antibodies and antigen-binding fragments comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:4 or a variant of the amino acid sequence set forth in SEQ ID NO:4, and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:9 or a variant of the amino acid sequence set forth in SEQ ID NO:9. In further embodiments, the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:27 or a variant of the amino acid sequence set forth in SEQ ID NO:27, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:28 or a variant of the amino acid sequence set forth in SEQ ID NO:28, the amino acid sequence set forth in SEQ ID NO:29 or a variant of the amino acid sequence set forth in SEQ ID NO:29, or the amino acid sequence set forth in SEQ ID NO:30 or a variant of the amino acid sequence set forth in SEQ ID NO:30. In such embodiments, the light chain variable region or heavy chain variable region sequence is identical to the reference sequence except for one, two, three, four, or five amino acid substitutions. In some embodiments, the substitutions are within the framework regions (i.e., outside the CDRs). In some embodiments, one, two, three, four, or five of the amino acid substitutions are conservative substitutions.

[0076] In one embodiment of the methods, kits, or uses of the disclosure, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:4, and a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:9. In one embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:28, and a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:27. In a further embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:29, and a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:27. In another embodiment, the antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:30, and a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:27.

[0077] In another embodiment, the method, kit, or use of the present disclosure comprises the steps of: L Domain or V H V having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the domains L Domain and / or V H In another embodiment, the anti-human PD-1 antibody or antigen binding protein of the present method comprises an anti-human PD-1 antibody or antigen binding protein having a V domain and exhibiting specific binding to PD-1. In another embodiment, the anti-human PD-1 antibody or antigen binding protein of the present method comprises an anti-human PD-1 antibody or antigen binding protein having up to one, two, three, four, five or more amino acid substitutions. L and V H domain and exhibits specific binding to PD-1.

[0078] In any of the above embodiments, the PD-1 antagonist may be a full-length anti-PD-1 antibody or antigen-binding fragment thereof that specifically binds to human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any IgG isotype can be used, including IgG1, IgG2, IgG3, and IgG4. Different constant domains can be used in the V-cells provided herein. L and V H A heavy chain constant domain other than IgG1 may be used if, for example, the particular intended use of the antibody (or fragment) requires altered effector functions. IgG1 antibodies offer long half-lives and effector functions such as complement activation and antibody-dependent cellular cytotoxicity, but such activities may not be desirable for all uses of the antibody. In such instances, for example, an IgG4 constant domain may be used.

[0079] In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:5 and a heavy chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:10. In further embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:32 and a heavy chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:31. In additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:33 and a heavy chain comprising, or consisting of the sequence of amino acid residues set forth in SEQ ID NO:31. In yet additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising, or consisting of, the sequence of amino acid residues set forth in SEQ ID NO:34 and a heavy chain comprising, or consisting of the sequence of amino acid residues set forth in SEQ ID NO:31. In some methods, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar.

[0080] Typically, amino acid sequence variants of anti-PD-1 antibodies and antigen-binding fragments are derived from a reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, V H , V L or a humanized sequence). Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical to the anti-PD-1 residues after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Neither N-terminal, C-terminal, nor internal extensions, deletions, nor insertions into the antibody sequence shall be construed as affecting sequence identity or homology.

[0081] Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using the BLAST algorithm, where the algorithm parameters are selected to maximize the match between each sequence over the entire length of each reference sequence. The following references are related to BLAST algorithms commonly used for sequence analysis: BLAST algorithm: Altschul, SF, et al., (1990) J.Mol.Biol.215:403-410, Gish, W., et al., (1993) Nature Genet.3:266-272, Madden, TL, et al., (1996) Meth.Enzymol.266:131-141, Altschul, SF, et al. al., (1997) Nucleic Acids Res.25:3389-3402, Zhang, J., et al., (1997) Genome Res.7:649-656, Wootton, JC, et al., (1993) Comput.Chem.17:149-163, Hancock, JMet al., (1994) Comput.Appl.Biosci.10:67-70, ALIGNMENT SCORING SYSTEMS: Dayhoff, MO, et al., “A model of evolutionary change in proteins.” Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.MODayhoff(ed.),pp.345-352,Natl.Biomed.Res.Found.,Washington,DC,Schwartz,RM,et al.,“Matrices for detecting distant relationships.”Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.”MODayhoff(ed.),pp.353-358,Natl.Biomed.Res.Found.,Washington,DC,Altschul,SF,(1991)J.Mol.Biol.219:555-565, States, DJ, et al., (1991) Methods 3:66-70, Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919, Altschul, SF, et al.,(1993)J.Mol.Evol.36:290-300,ALIGNMENT STATISTICS:Karlin,S.,et al.,(1990)Proc.Natl.Acad.Sci.USA 87:2264-2268,Karlin,S.,et al.,(1993)Proc.Natl.Acad.Sci.USA 90:5873-5877, Dembo, A., et al. al., (1994) Ann.Prob.22:2022-2039, and Altschul, SF “Evaluating the statistical significance of multiple distinct local alignments.” Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, New York.

[0082] Similarly, any class of light chain can be used in the compositions and methods herein. In particular, kappa, lambda, or variants thereof are useful in the present compositions and methods. [Table 3] [Table 4] JPEG2026504943000006.jpg124159

[0083] Anti-PD-1 antibody medication In some embodiments, the anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is administered subcutaneously or intravenously at about 10, about 20, about 50, about 80, about 100, about 200, about 300, about 400, about 500, about 1000, or about 2500 mg per subject weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, monthly, every two months, or quarterly.

[0084] In some specific methods, the dose of the anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 0.01 mg / kg to about 50 mg / kg, about 0.05 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.2 mg / kg to about 9 mg / kg, about 0.3 mg / kg to about 8 mg / kg, about 0.4 mg / kg to about 7 mg / kg, about 0. 5 mg / kg to about 6 mg / kg, about 0.6 mg / kg to about 5 mg / kg, about 0.7 mg / kg to about 4 mg / kg, about 0.8 mg / kg to about 3 mg / kg, about 0.9 mg / kg to about 2 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.0 mg / kg to about 2.0 mg / kg, about 1.0 mg / kg to about 3.0 mg / kg, or about 2.0 mg / kg to about 4.0 mg / kg.

[0085] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 250 mg, about 175 mg to about 250 mg, about 200 mg to about 250 mg, about 150 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg. In some embodiments, the dose of the anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

[0086] In another embodiment, the PD-1 antagonist in the therapy is pembrolizumab or a pembrolizumab variant and is administered in a liquid formulation at a dose selected from the group consisting of 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, or 10 mg / kg Q3W.

[0087] In other embodiments, the PD-1 antagonist in the therapy is pembrolizumab or a pembrolizumab variant administered in a liquid formulation in a flat dose such as 200 mg Q3W or 400 mg Q6W.

[0088] In other embodiments, the PD-1 antagonist in the therapy is pembrolizumab administered in a liquid formulation in a flat dose such as 200 mg Q3W or 400 mg Q6W.

[0089] In some embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab once every three or six weeks. In one embodiment, the human patient is administered about 200 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg / kg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0090] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 200 mg of pembrolizumab once every three weeks.

[0091] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0092] In some embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab once every six weeks.

[0093] In one embodiment, a human patient is administered about 200 mg of pembrolizumab once every three weeks. In one embodiment, a human patient is administered about 400 mg of pembrolizumab once every six weeks. In one embodiment, a human patient is administered 2 mg / kg of pembrolizumab once every three weeks.

[0094] In some embodiments, pembrolizumab is provided as a liquid formulation comprising 25 mg / ml pembrolizumab, 7% (w / v) sucrose, and 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer, pH 5.5. In other embodiments, pembrolizumab is provided as a liquid formulation comprising about 125 to about 200 mg / mL pembrolizumab or an antigen-binding fragment thereof, about 10 mM histidine buffer, about 10 mM L-methionine or a pharmaceutically acceptable salt thereof, about 7% (w / v) sucrose, and about 0.02% (w / v) polysorbate 80.

[0095] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody is pembrolizumab and the human patient is administered about 200 mg of pembrolizumab once every three weeks. In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody is pembrolizumab and the human patient is administered about 400 mg of pembrolizumab once every six weeks.

[0096] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a period of 25 to 40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0097] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In some embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 320 mg to 420 mg, 340 mg to 420 mg, 345 mg to 415 mg, 350 mg to 410 mg, 355 mg to 405 mg, 360 mg to 400 mg, 365 mg to 395 mg, 370 mg to 390 mg, 375 mg to 385 mg, or 379 mg to 381 mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 280 mg to about 450 mg. In a further embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet another embodiment, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0098] In some embodiments, pembrolizumab is administered subcutaneously to a patient, and the pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg / mL. In some embodiments, pembrolizumab is administered subcutaneously to a patient, and the pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg / mL. In some embodiments, pembrolizumab is administered subcutaneously to a patient in two injections. In some embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 380 mg in one prefilled syringe. In some embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 380 mg in two prefilled syringes. In some embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 395 mg in one prefilled syringe. In some embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 395 mg in two pre-filled syringes.

[0099] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose at least about 1.6-fold higher than the 200 mg or 2 mg / kg dose. In one embodiment, the subcutaneous dose is administered once every three weeks. In one embodiment, the subcutaneous dose is administered once every six weeks. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 63%. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 64%. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 66%.

[0100] Decoy-resistant (DR) interleukin-18 (IL-18) polypeptides and DR IL-18 compositions The polypeptides of the decoy-resistant (DR) IL-18 compositions of the present disclosure are "decoy-resistant" variants of IL-18 that are designed to be impermeable to the decoy receptor IL-18BP, which blocks IL-18 from interacting with its receptor, thereby blocking the cytokine's immunostimulatory activity. Decoy-resistant IL-18 polypeptides have been shown in preclinical studies to maintain potent immunostimulation in the tumor microenvironment and are currently in Phase 1a / 2 clinical development as monotherapy in solid tumors.

[0101] In some embodiments, decoy-resistant (DR) IL-18 polypeptides comprise mutations relative to wild-type (WT) IL-18, such as WT IL-18 SEQ ID NO: 35. In some embodiments, decoy-resistant IL-18 polypeptides comprise at least about two mutations, at least about three mutations, at least about four mutations, at least about five mutations, at least about six mutations, at least about seven mutations, at least about eight mutations, at least about nine mutations, or at least about ten mutations relative to the WT IL-18 set forth in SEQ ID NO: 35. In some embodiments, decoy-resistant IL-18 polypeptides comprise at least one mutation (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, or eight mutations) selected from the group consisting of M51K, K53S, Q56L, P57A, M60L, S105D, D110S, and N111R relative to the WT IL-18 set forth in SEQ ID NO: 35.

[0102] In some embodiments, the decoy-resistant IL-18 polypeptide comprises one or more mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, and N111R compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSLARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 36).

[0103] In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 90% or more identity to SEQ ID NO: 36. In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 90-99.5% identity to SEQ ID NO: 36.

[0104] In some embodiments, the decoy-resistant IL-18 polypeptide comprises a mutation at amino acid position C38 compared to the WT IL-18 set forth in SEQ ID NO: 35. In some embodiments, the decoy-resistant IL-18 polypeptide comprises a mutation at amino acid position C68 compared to the WT IL-18 set forth in SEQ ID NO: 35. In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions C38 and C68 compared to the WT IL-18 set forth in SEQ ID NO: 35.

[0105] In some embodiments, the mutation at amino acid position C38 is a substitution mutation, hi some embodiments, the mutation at amino acid position C38 is a C38S substitution relative to WT IL-18 set forth in SEQ ID NO:35.

[0106] In some embodiments, the mutation at amino acid position C68 is a substitution mutation, hi some embodiments, the mutation at amino acid position C68 is a C68S, C68G, C68A, C68V, C68D, C68E, or C68N substitution relative to WT IL-18 set forth in SEQ ID NO: 35.

[0107] In some embodiments, the decoy-resistant IL-18 polypeptide comprises (i) one or more mutations at amino acid positions M51, K53, Q56, P57, M60, S105, D110, and N111 compared to WT IL-18 set forth in SEQ ID NO: 35, and (ii) one or more mutations at amino acid positions C38 and C68 compared to WT IL-18 set forth in SEQ ID NO: 35.

[0108] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68S compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKSEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 37).

[0109] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68G compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKGEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 38).

[0110] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68A compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKAEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 39).

[0111] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68V compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKVEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 40).

[0112] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68D compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKDEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 41).

[0113] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68E compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKEEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 42).

[0114] In some embodiments, the decoy-resistant IL-18 polypeptide comprises mutations at amino acid positions M51K, K53S, Q56L, P57A, M60L, S105D, D110S, N111R, C38S, and C68N compared to WT IL-18 set forth in SEQ ID NO: 35. In one embodiment, the amino acid sequence of the DR IL-18 polypeptide is: YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKNEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 43).

[0115] In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 90% or more identity to any one of SEQ ID NOs: 36-43. In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 90-99.5% identity to any one of SEQ ID NOs: 36-43. In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 95-99.5% identity to any one of SEQ ID NOs: 36-43. In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 97-99.5% identity to any one of SEQ ID NOs: 36-43. In some embodiments, the amino acid sequence of the DR IL-18 polypeptide comprises 98-99.5% identity to any one of SEQ ID NOs: 36-43.

[0116] method Methods for treating a disease in a subject in need thereof are provided. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor, such as, but not limited to, melanoma, Merkel cell, renal cell carcinoma (RCC), urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), any microsatellite instability-high (MSI-H), any high tumor mutation burden (TMB-H) or mismatch repair-deficient, gastric, cervical, endometrial, squamous cell skin, small cell lung, esophageal, hepatocellular carcinoma (HCC), including immune checkpoint inhibitor (ICI)-resistant (e.g., PD-1 checkpoint inhibitor-resistant) forms thereof, or platinum-resistant ovarian cancer, or microsatellite-stable colorectal cancer / tumor. In some embodiments, the cancer is a hematological cancer, such as, but not limited to, myeloma, B-cell lymphoma, or acute myeloid leukemia. One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab, and administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide is a modified IL-18 polypeptide comprising the amino acid sequence set forth in any one of SEQ ID NOs: 36-43. Administering such combination therapy of pembrolizumab and a DR IL-18 polypeptide thereby causes one or more improvements in the subject's condition, e.g., stable disease, immunotherapy-induced regression, partial response, complete response, or any combination thereof, in the subject.

[0117] Combination therapy methods are provided, including treating a subject with cancer, comprising administering to the subject sequential doses of a pembrolizumab-containing composition and sequential doses of a DR IL-18-containing composition, wherein the combination therapy results in one or more improvements in the subject's condition, such as, but not limited to, an objective response, a partial response, a complete response, immunotherapy-induced regression of the cancer or tumor, disease stabilization (e.g., stable disease for at least 12 months), etc. Administering such a combination therapy of pembrolizumab and a DR IL-18 polypeptide thereby results in an improvement in the subject's condition that is not achieved by administration of the monotherapy alone and / or is greater than the improvement in the corresponding outcome achieved by administering pembrolizumab or a DR IL-18 polypeptide monotherapy.

[0118] The observed improvement in the condition of the subject treated according to the method described herein can include any result of treating disease or cancer, including any result of treating disease or cancer as described herein.For example, the subject can experience one or more symptom improvements in condition, for example, one or more clinical symptoms of the subject's cancer.In some examples, the subject can experience a reduction in the rate of tumor growth, a reduction in the number of tumors, a reduction in the size of one or more tumors in the subject, a reduction in the clinical stage of tumors, a combination thereof, etc.

[0119] In some instances, the subject may experience stabilization of disease, such as stabilization of the subject's cancer, for example, for a period of at least 6 months, at least 12 months, or longer.Stable disease refers to disease that does not progress, such as tumor that does not show substantial growth, when measured using suitable methods, such as computed tomography (CT) or magnetic resonance imaging (MRI) scans, over a period of time, or between two or more relevant time points, such as, for example, at the start of treatment and 6 or 12 months after the start of treatment.Stable disease also includes the improvement of the subject's disease that does not reach the level of partial response (PR) or criteria.

[0120] In some instances, a subject may achieve PR in accordance with the RECIST guidelines (version 1.1) for cancer or tumors, where PR criteria used herein are defined as at least a 30% reduction in the sum of the diameters of target lesions, relative to the baseline sum diameter. See, for example, Eisenhauer et al. (2009) European Journal of Cancer 45:228-247, the disclosure of which is incorporated herein by reference in its entirety.

[0121] In some instances, a subject may achieve a complete response (CR), where the criteria for CR used herein for cancer or tumor are defined as the disappearance of all target lesions, with any pathological lymph nodes (whether target or non-target) having a short axis reduction of less than 10 mm, consistent with the RECIST guidelines (version 1.1). In some instances, a subject may achieve an objective response (OR), where achieving an OR generally refers to achieving either a PR or a CR.

[0122] In some examples, a subject with a disease such as cancer or a tumor may experience immunotherapy-induced regression of the disease, i.e., immunotherapy-induced regression of the cancer or tumor. Disease regression generally refers to a reduction in the severity of the disease or symptoms of the disease, including cases where the disease does not completely disappear. In cancer, regression generally refers to a decrease in tumor size and / or a reduction in the extent of cancer in the subject's body. Disease regression in a subject with cancer or a tumor may manifest as a decrease in the number of tumors, a decrease in the size of one or more tumors, or a combination thereof. Thus, cancer or tumor progression and regression can be measured by various means, including, but not limited to, radiological imaging such as CT and MRI scans. Disease progression and regression can generally be measured by various means, including, but not limited to, radiological imaging, clinical biomarkers, biopsies (e.g., needle biopsies and liquid biopsies), combinations thereof, and the like. Immunotherapy-induced regression refers to disease regression resulting from administering one or more immunotherapies to a subject, such as, for example, a combination immunotherapy comprising an anti-PD-1 composition and a DR IL-18 composition described herein. Thus, with respect to a cancer or tumor, immunotherapy-induced regression refers to a reduction in the number of tumors, a reduction in the size of one or more tumors, or a combination thereof, that results from administering one or more immunotherapies to a subject, such as a combination immunotherapy comprising an anti-PD-1 composition and a DR IL-18 composition described herein.

[0123] The improvement of the subject's condition can be expressed as the improvement of an individual subject, or as the improvement of one or more cohorts of multiple subjects.For example, a single subject can achieve stable disease, PR, or CR, or all (i.e., 100%) of the subjects of a cohort, or a certain number or percentage (for example, at least 10%, 25%, 50%, 75%, etc.) of the subjects of the cohort achieve stable disease, PR, CR, or a combination thereof.In some examples, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or 90% of the cohort achieves stable disease that lasts for at least 12 months.In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of the cohort achieve OR.In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of the cohort achieve PR. In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in the cohort achieve a CR. In some examples, the cohort shows multiple improvements in different categories, including, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or 90% of the cohort achieving stable disease and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in the cohort achieving an OR.

[0124] In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 composition results in a reduction in tumor size in a subject. In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 composition results in a reduction in the number of tumors in a subject. In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 polypeptide results in a reduction in tumor size and a reduction in the number of tumors in a subject.

[0125] Decoy-resistant IL-18 polypeptides bind to and signal through the formation of an IL-18Rα (IL-18 receptor α) and IL-18Rβ (IL-18 receptor β) receptor complex. Decoy-resistant IL-18 polypeptides do not bind to IL-18 binding protein (IL-18BP) or exhibit substantially reduced binding to IL-18BP, such as substantially reduced binding to IL-18BP compared to wild-type (WT) IL-18 (SEQ ID NO: 36) (i.e., compared to the binding of IL-18BP to WT IL-18 (SEQ ID NO: 36)). In some embodiments, decoy-resistant IL-18 polypeptides bind to IL-18Rα and do not bind to IL-18BP. In some embodiments, decoy-resistant IL-18 polypeptides bind to IL-18Rα and have reduced binding to IL-18BP compared to WT IL-18. In some embodiments, decoy-resistant IL-18 polypeptides are monomers. In some embodiments, the monomers are not present in a protein complex. In some embodiments, the monomer functions as a single polypeptide. In some embodiments, the decoy-resistant IL-18 polypeptide is not glycosylated. In some embodiments, the decoy-resistant IL-18 polypeptide is glycosylated. In some embodiments, the decoy-resistant IL-18 polypeptide is partially glycosylated. In some embodiments, the decoy-resistant IL-18 polypeptide is at least about 50% glycosylated. In some embodiments, the decoy-resistant IL-18 polypeptide is at most about 50% glycosylated.

[0126] In some embodiments, the decoy-resistant IL-18 polypeptide accounts for 10% to about 50% of the IL-18 receptors. In some embodiments, the decoy-resistant IL-18 polypeptide accounts for 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%, or more of the IL-18 receptors. In some embodiments, the decoy-resistant IL-18 polypeptide accounts for up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, or less of the IL-18 receptors. In some embodiments, the decoy-resistant IL-18 polypeptide occupies about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the IL-18 receptor.

[0127] In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 composition results in a reduction in tumor size in tumors that are resistant to PD-1 checkpoint inhibitors or anti-PD-1 inhibitors. In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 composition results in a reduction in tumor number in the subject. In some embodiments, administering sequential doses of an anti-PD-1 antibody composition and a DR IL-18 composition results in a reduction in tumor size and a reduction in tumor number in the subject.

[0128] Pembrolizumab Composition The anti-PD-1 antibody composition and the DR IL-18 composition can be administered to the subject starting on the first day. In some embodiments, the first dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject at least about 60 minutes before the first dose of the sequential doses of the DR IL-18 composition is administered to the subject. In some embodiments, the first dose of the sequential doses of the anti-PD-1 antibody composition comprises 200 mg of pembrolizumab.

[0129] In some embodiments, each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject Q3W, hi some embodiments, each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject about every 21 days.

[0130] In some embodiments, each dose of the continuous-dose anti-PD-1 antibody composition comprises a fixed dose of 200 mg of pembrolizumab. In some embodiments, each dose of the continuous-dose anti-PD-1 antibody composition comprises about 2 mg / kg of pembrolizumab per kg of subject body weight (i.e., 2 mg of pembrolizumab per kg of subject body weight).

[0131] In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject Q3W as a fixed dose of 200 mg pembrolizumab. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject about every 21 days as about 200 mg pembrolizumab. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered Q3W as a dose of about 2 mg / kg pembrolizumab per kg of the subject's body weight. In some embodiments, each dose of the continuous dose anti-PD-1 antibody composition is administered to a subject about every 21 days at a dose of about 2 mg / kg pembrolizumab per kg of the subject's body weight.

[0132] DR IL-18 composition The anti-PD-1 antibody composition and the DR IL-18 composition can be administered to the subject starting on the first day. In some embodiments, the dose of the DR IL-18 composition is at least one of the initial dose, the first dose, or the lowest dose administered to the subject.

[0133] In some embodiments, the first dose of the sequential doses of the DR IL-18 composition is administered to the subject at least about 60 minutes after the first dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject. In some embodiments, the first dose of the sequential doses of the DR IL-18 composition comprises about 15 μg / kg of polypeptide per kg of subject body weight (i.e., 15 μg of polypeptide per kg of subject body weight). In some embodiments, the first dose of the sequential doses of the DR IL-18 composition comprises about 20 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the first dose of the sequential doses of the DR IL-18 composition comprises about 30 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the first dose of the sequential doses of the DR IL-18 composition comprises about 15 μg / kg to about 30 μg / kg of polypeptide per kg of subject body weight.

[0134] In some embodiments, each dose of the sequential doses of the DR IL-18 composition is administered to the subject weekly. In some embodiments, each dose of the sequential doses of the DR IL-18 composition is administered to the subject about every 7 days. In some embodiments, the next dose of the DR IL-18 composition is administered to the subject at least 6 days after the previous dose of the DR IL-18 composition. In some embodiments, the next dose of the DR IL-18 composition is administered to the subject up to 9 days after the previous dose of the DR IL-18 composition.

[0135] In some embodiments, the polypeptide is at a concentration of about 30 mg / mL.

[0136] In some embodiments, the dose of the DR IL-18 composition comprises about 15 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 20 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 30 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 90 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 180 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 360 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 600 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 900 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition comprises about 1200 μg / kg of polypeptide per kg of subject body weight.

[0137] In some embodiments, each dose of the DR IL-18 composition comprises about 15 μg / kg to about 1200 μg / kg of polypeptide per kg of subject body weight. In some embodiments, each dose of the DR IL-18 composition comprises about 15 μg / kg to about 30 μg / kg, about 30 μg / kg to about 90 μg / kg, about 90 μg / kg to about 180 μg / kg, about 180 μg / kg to about 360 μg / kg, about 360 μg / kg to about 600 μg / kg, about 600 μg / kg to about 900 μg / kg, or about 900 μg / kg to about 1200 μg / kg of polypeptide per kg of subject body weight. In some embodiments, the dose of the DR IL-18 composition is about 15 μg / kg, about 30 μg / kg, about 90 μg / kg, about 180 μg / kg, about 360 μg / kg, about 600 μg / kg, about 900 μg / kg, or about 1200 μg / kg of the subject's body weight.

[0138] DR IL-18 dose escalation A subject may develop tolerance to a single dose of a DR IL-18 composition comprising the polypeptide, and higher doses of the polypeptide may be administered in subsequent doses of successive doses of the DR IL-18 composition.

[0139] In some embodiments, the dose of DR IL-18 composition comprises a greater amount of polypeptide per kg of the subject's body weight than the amount of polypeptide previously administered to the subject, in some embodiments, the previous amount of polypeptide was tolerated by the subject.

[0140] In some embodiments, a subsequent dose of the DR IL-18 composition comprises a greater amount of polypeptide per kg of subject body weight than the amount of polypeptide in the previous dose of the DR IL-18 composition, hi some embodiments, the previous dose was tolerated by the subject.

[0141] In some embodiments, subsequent doses of the DR IL-18 composition contain the same or equivalent amount of polypeptide per kg of the subject's body weight as the amount previously administered to the subject. In some embodiments, the amount of polypeptide is related to the subject's recorded treatment-emergent adverse events.

[0142] In some embodiments, the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. In some embodiments, the recorded treatment-emergent adverse event is associated with the subject receiving no or minimal medical intervention, support, or therapy. In some embodiments, the amount is the maximum tolerated dose.

[0143] In some embodiments, a subsequent dose of a DR IL-18 composition comprises the same or equivalent amount of polypeptide per kg of subject body weight as the amount of polypeptide in a previous dose of the DR IL-18 composition. In some embodiments, the previous dose is associated with causing a recorded treatment-emergent adverse event in the subject. In some embodiments, the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. In some embodiments, the recorded treatment-emergent adverse event is associated with providing the subject with no or minimal medical intervention, support, or therapy. In some embodiments, the previous dose is the maximum tolerated dose.

[0144] In some embodiments, a subsequent dose of a DR IL-18 composition contains a lower amount of polypeptide per kg of the subject's body weight than the amount of polypeptide previously administered to the subject. In some embodiments, the subject did not tolerate the previously administered amount of polypeptide. In some embodiments, the previously administered amount of polypeptide is associated with dose-limiting toxicity (DLT). In some embodiments, the subsequent dose is a previously tolerated dose.

[0145] In some embodiments, a subsequent dose of the DR IL-18 composition comprises a lower amount of polypeptide per kg of subject body weight than the amount of polypeptide in a previous dose of the DR IL-18 composition. In some embodiments, the previous dose was not tolerated by the subject. In some embodiments, the previous dose is associated with dose-limiting toxicity (DLT). In some embodiments, the subsequent dose is a previously tolerated dose.

[0146] Cycles of pembrolizumab and DR IL-18 administration In some embodiments, the anti-PD-1 and DR IL-18 composition is administered to the subject in a series of cycles, each cycle comprising about 21 days.

[0147] In some embodiments, the anti-PD-1 antibody composition is administered once per cycle, hi some embodiments, the DR IL-18 composition is administered once, twice, or three times during each cycle.

[0148] In some embodiments, the series of cycles includes a current cycle and a next cycle, where the next cycle is performed consecutively to the current cycle. In some embodiments, the series of cycles includes a first cycle, where the first cycle includes the first day. In some embodiments, a dose of an anti-PD-1 antibody composition comprising 200 mg of pembrolizumab is administered to a subject on the first day of the first cycle. In some embodiments, a dose of a DR IL-18 composition comprising 15 μg / kg of polypeptide is administered to a subject on the first day of the first cycle. In some embodiments, a dose of a DR IL-18 composition comprising 20 μg / kg of polypeptide is administered to a subject on the first day of the first cycle. In some embodiments, a dose of a DR IL-18 composition comprising 30 μg / kg of polypeptide is administered to a subject on the first day of the first cycle. In some embodiments, a dose of a DR IL-18 composition comprising 15 μg / kg to 30 μg / kg of polypeptide is administered to a subject on the first day of the first cycle.

[0149] In some embodiments, the series of cycles includes at least 8 cycles. In some embodiments, the series of cycles includes 35 or fewer cycles. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and is treated for at least 8 cycles. In some embodiments, a complete response is measured by a combined assessment of the magnitude and extent of change in tumor dimensions, which conveniently classifies and describes treatment efficacy.

[0150] cancel In some embodiments, the anti-PD-1 and DR IL-18 composition is administered for at least 24 weeks. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject has received at least 8 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 24 weeks or has received at least 8 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 8 cycles. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has received at least 8 doses of the anti-PD-1 antibody composition. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has received at least about 24 doses of the anti-PD-1 antibody composition.

[0151] Drug suspension In some embodiments, the anti-PD-1 and DR IL-18 composition is administered until the subject develops intervention-related toxicity designated as grounds for permanent discontinuation. In some embodiments, the intervention-related toxicity is at least one of a Grade 4, Grade 3, or recurrent Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. In some embodiments, the treatment-emergent adverse event is associated with a significant or severe limitation in the subject's activity. In some embodiments, the treatment-emergent adverse event is life-threatening or requires significant medical intervention or hospitalization. In some embodiments, the anti-PD-1 and DR IL-18 composition is administered for up to about 2 years. In some embodiments, the subject is administered up to 35 doses of the anti-PD-1 antibody composition.

[0152] Order of administration The anti-PD-1 antibody composition and the DR IL-18 composition can be administered to a subject on the same day (e.g., the first day). In some embodiments, a dose of the anti-PD-1 antibody composition is administered to a subject at least about 60 minutes before a dose of the DR IL-18 composition is administered to the subject. In some embodiments, a dose of the DR IL-18 composition is administered to a subject at least about 60 minutes after the anti-PD-1 antibody composition is administered to the subject. In some embodiments, (a) and (b) are performed sequentially. In some embodiments, (a) is performed before (b). In some embodiments, (b) is performed before (a). In some embodiments, (a) and (b) are performed simultaneously. In some embodiments, (a) and (b) are performed concurrently.

[0153] Route of administration In some embodiments, each dose of the anti-PD-1 antibody composition is administered to the subject by intravenous infusion. In some embodiments, one dose of the anti-PD-1 antibody composition is administered to the subject by intravenous infusion. In some embodiments, one dose of the anti-PD-1 antibody composition is administered to the subject by subcutaneous injection. In some embodiments, each dose of the DR IL-18 composition is administered to the subject by subcutaneous injection. In some embodiments, one dose of the DR IL-18 composition is administered to the subject by subcutaneous injection.

[0154] Target indications One aspect of the present disclosure provides a method for treating a disease in a subject in need thereof. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor.

[0155] In some embodiments, the cancer is leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma and / or sarcoma. Non-limiting examples of cancer include lymphoma, sarcoma, bladder cancer, biliary tract cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer ( For example, hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma. Additional non-limiting examples of cancer include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic cancer, These include insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, and prostate cancer.

[0156] In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer.

[0157] In some embodiments, the cancer is leukemia. Leukemia can be a progressive malignant disease of the blood-forming organs, which may distort the proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia can generally be clinically classified based on (1) the duration and characteristics of the disease - acute or chronic, (2) the type of cells involved - myeloid (myeloid), lymphocytic (lymphatic), or monocytic, and (3) the increase or absence of an increase in the number of abnormal cells in the blood - leukemic or non-leukemic (subleukemic). Non-limiting examples of leukemias include, for example, acute myeloid leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid ... leukemia), lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0158] In some embodiments, the cancer is a sarcoma. Sarcomas can be tumors that can be composed of a substance like embryonic connective tissue and can consist of closely packed cells embedded in a fibrillar and / or homogeneous substance. Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloromatous sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, and sarcoma. sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0159] In some embodiments, the cancer is melanoma. The term "melanoma" can refer to tumors arising from the melanocytic system of the skin and other organs. Non-limiting examples of melanoma include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentiginous malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0160] In some embodiments, the cancer is a solid tumor. Non-limiting examples of solid tumor cancers include bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, oral cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

[0161] In some embodiments, the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, renal cell carcinoma, urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-high (MSI-H) tumors, high tumor mutation burden (TMB-H) tumors, mismatch repair deficient tumors, gastric, cervical, endometrial, squamous cell skin, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof.

[0162] In some embodiments, the solid tumor is melanoma, renal cell carcinoma, triple-negative breast cancer, NSCLC, SCCHN, or an MSI-H tumor. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is renal cell carcinoma. In some embodiments, the solid tumor is TNBC. In some embodiments, the solid tumor is NSCLC. In some embodiments, the solid tumor is SCCHN. In some embodiments, the solid tumor is an MSI-H tumor.

[0163] In some embodiments, the cancer or solid tumor is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancers (dMMR) cancers, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), or Related to colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.

[0164] In some embodiments, the cancer or solid tumor is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancers (dMMR) cancers, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), or In some embodiments, the cancer or solid tumor is associated with colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof. In some embodiments, the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor.

[0165] In some embodiments, the cancer or solid tumor is associated with melanoma, Merkel cell, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation / fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor.

[0166] In some embodiments, the cancer or solid tumor is associated with platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.

[0167] In some embodiments, the methods of the present disclosure are useful for treating tumors or cancers that are resistant to immune checkpoint inhibitors (ICIs). Examples of immune checkpoint inhibitors include, but are not limited to, anti-PD1 agents such as anti-PD1 antibodies (e.g., zimverelimab, nivolumab, cemiplimab, dostarimab), anti-PD-L1 agents such as anti-PD-L1 antibodies (e.g., avelumab, durvalumab, atezolizumab), anti-PD-L2 antibodies, anti-CTLA4 (e.g., ipilimumab, tremelimumab), anti-TIM3, anti-TIGIT, anti-LAG3 (e.g., leratrimumab), anti-B7H3 (e.g., enoblituumab), anti-B7H4, anti-VISTA, anti-BTLA, anti-CD47, anti-SIRPα, anti-CD48, anti-CD155, anti-CD160, anti-TREM2, anti-IDO1, anti-adenosine 2A receptor, anti-aryl hydrocarbon receptor, anti-KIR, and anti-LILRB2. Examples of targets of immune checkpoint inhibitors include, but are not limited to, PD-L1, PD1, CTLA4, TIM3, TIGIT, LAG3, B7H3, B7H4, VISTA, BTLA, CD47, SIRPα, CD48, CD155, CD160, TREM2, IDO1, adenosine 2A receptor, aryl hydrocarbon receptor, KIR, and LILRB2, or any combination thereof.

[0168] In some embodiments, the disease is cancer. Cancer can be a hyperproliferation of cells that can have unregulated growth, lack of differentiation, local tissue invasion, and / or metastasis. In some embodiments, the cancer is a solid tumor. A tumor can be an abnormal proliferation of cells or tissues (e.g., malignant or benign).

[0169] CRS prevention combination Cytokine release syndrome (CRS) may occur in a subject after administering a DR IL-18 composition. In some embodiments, the method further comprises administering an additional treatment to the subject. In some embodiments, the additional treatment is a CRS preventative agent. Consistent with the above definitions, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical objects of the article, and thus, herein, reference to the administration of a CRS preventative agent or dose refers to the administration of one or more CRS preventative agents (i.e., one or more CRS preventative agents), the administration of one or more doses (i.e., one or more doses), the administration of at least one CRS preventative agent, or the administration of at least one dose. The administration of one or more CRS preventative agents may be referred to herein as CRS prevention.

[0170] The CRS prevention or CRS prophylactic agent can be administered to the subject starting with the first dose of the DR IL-18 composition. In some embodiments, the CRS prophylactic agent can be administered as a premedication or postmedication to the dose of the DR IL-18 composition. In some embodiments, the method further comprises administering to the subject a dose of a CRS prophylactic agent with or before the successive doses of the DR IL-18 composition. In some embodiments, the method further comprises administering to the subject a dose of a CRS prophylactic agent with or before each dose of the successive doses of the DR IL-18 composition.

[0171] One aspect of the present disclosure provides a method for treating a disease in a subject in need thereof. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; (b) administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide comprises an amino acid sequence set forth in any one of SEQ ID NOs: 36 to 43; and (c) administering to the subject a single dose of a cytokine release syndrome (CRS) prophylactic agent. One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; (b) administering sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43; and (c) administering to the subject a single dose of a cytokine release syndrome (CRS) prophylactic agent, thereby causing immunotherapy-induced regression of the disease in the subject. In some embodiments, the dose of the CRS prophylactic agent is administered concomitantly with or prior to each of the sequential doses of the DR IL-18 composition. In some embodiments, the method further comprises administering to the subject a single dose of the CRS prophylactic agent concomitantly with or prior to each of the sequential doses of the DR IL-18 composition. In some embodiments, the dose of CRS preventative agent comprises at least one of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid administered to the subject. In some embodiments, the dose of CRS preventative agent is administered to the subject orally or intravenously.

[0172] In some embodiments, the CRS preventative agent is administered orally. In some embodiments, one or more CRS preventative agents of the CRS preventative are administered orally. In some embodiments, the CRS preventative agent is administered subcutaneously. In some embodiments, one or more CRS preventative agents of the CRS preventative are administered subcutaneously. In some embodiments, the CRS preventative agent is administered intramuscularly. In some embodiments, one or more CRS preventative agents of the CRS preventative are administered intramuscularly. In some embodiments, the CRS preventative agent is administered intravenously. In some embodiments, one or more CRS preventative agents of the CRS preventative are administered intravenously. In some embodiments, the CRS preventative agent is administered intrathecally. In some embodiments, the CRS preventative agent is administered rectally. In some embodiments, the CRS preventative agent is administered intravaginally. In some embodiments, the CRS preventative agent is administered intranasally. In some instances, multiple routes of administration are used, including, for example, when one or more CRS preventative agents of the CRS preventative regimen are administered orally and one or more CRS preventative agents of the CRS preventative regimen are administered intravenously.

[0173] In some embodiments, the CRS preventative agent is administered hourly. In some embodiments, the CRS preventative agent is administered about every few hours. In some embodiments, the CRS preventative agent is administered twice daily. In some embodiments, the CRS preventative agent is administered daily. In some embodiments, the CRS preventative agent is administered every 6 days. In some embodiments, the CRS preventative agent is administered twice weekly. In some embodiments, the CRS preventative agent is administered weekly. In some embodiments, the CRS preventative agent is administered every 2 weeks. In some embodiments, the CRS preventative agent is administered every 3 weeks. In some embodiments, the CRS preventative agent is administered monthly. In some embodiments, the CRS preventative agent is administered every 2 months. In some embodiments, the CRS preventative agent is administered every 3 months. In some embodiments, the CRS preventative agent is administered every 4 months. In some embodiments, the CRS preventative agent is administered every 6 months. In some embodiments, the CRS preventative agent is administered once a year.

[0174] In some embodiments, the CRS preventative agent reduces the display of symptoms of cytokine release syndrome (CRS). In some embodiments, administering the CRS preventative agent reduces the display of symptoms of CRS compared to a comparable subject who did not receive the CRS preventative agent. In some embodiments, administering the CRS preventative agent reduces the display of symptoms of CRS compared to a comparable subject who has received a comparable therapy but has not received the CRS preventative agent. In some embodiments, administering the CRS preventative agent to a subject results in a reduced display of symptoms of CRS in the subject compared to a comparable subject who receives about 30 mg / ml or more of a DR IL-18 composition. In some embodiments, administering the CRS preventative agent to a subject results in a reduced display of symptoms of CRS in the subject compared to a comparable subject who has received a comparable therapy comprising administration of about 30 mg / ml or more of a DR IL-18 composition. In some embodiments, administering the CRS preventative agent to a subject results in a reduced display of symptoms of CRS in the subject compared to a comparable subject who has received a comparable therapy comprising administration of about 30 mg / ml or more of a DR IL-18 composition. In some embodiments, administering the CRS preventative agent to a subject results in a reduced display of symptoms of CRS in the subject compared to a comparable subject who receives about 30 μg / kg or more of a DR IL-18 composition. In some embodiments, administering a CRS prophylactic agent to a subject results in a reduced display of CRS symptoms in the subject compared to a corresponding subject who has received an equivalent therapy comprising administration of about 30 μg / kg or more of a DR IL-18 composition.

[0175] In some embodiments, CRS prevention reduces the symptomatic display of CRS in a subject administered a combination therapy comprising a DR IL-18 composition, including when the symptomatic display is reduced compared to a subject administered the same therapy without CRS prevention. In some embodiments, CRS prevention reduces the symptomatic display of CRS in a subject administered a combination therapy comprising administration of a DR IL-18 composition comprising at least about 30 μg / kg or more of a DR-IL-18 polypeptide, including when the symptomatic display of CRS is reduced compared to a subject administered the same therapy without CRS prevention. In some embodiments, CRS prevention reduces the symptomatic display of CRS in a subject administered an anti-PD-1 antibody composition and a DR IL-18 composition combination therapy, including when the symptomatic display is reduced compared to a subject administered the same therapy without CRS prevention.

[0176] In some embodiments, administering CRS prophylaxis prevents the onset or progression of CRS in a subject receiving combination therapy, where the combination therapy includes administering a DR-IL-18 composition comprising a DR-IL-18 polypeptide (e.g., at least about 30 μg / kg or more of a DR-IL-18 polypeptide). For example, administering CRS prophylaxis prevents the onset or progression to Grade 5 CRS, Grade 4 CRS or higher, and / or Grade 3 CRS or higher, including, for example, when CRS grading is performed according to the Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS as described in Lee et al. Biology of Blood and Marrow Transplantation. 25 (2019) 625-639. In some instances, the lack of development or progression of CRS may be indicated by the absence of fever (temperature above 38 degrees Celsius), the absence of hypotension, hypotension requiring only a single dose of vasopressors or no vasopressors, the absence of hypoxia, hypoxia requiring only low-flow nasal cannulae or blow-by, hypoxia requiring high-flow nasal cannulae (or face mask, non-rebreather mask, or Venturi mask) but no positive pressure, or a combination thereof.

[0177] In some embodiments, preventing CRS in a subject receiving a combination therapy comprising administration of a DR-IL-18 composition comprising a DR-IL-18 polypeptide (e.g., comprising at least about 30 μg / kg or more of a DR-IL-18 polypeptide) negates the need to subsequently treat the subject for CRS. For example, in some instances, preventing CRS in such a scenario means that the administration of immunosuppressants, such as corticosteroids (e.g., glucocorticoids), anti-interleukin-6 (IL-6) agents (e.g., tocilizumab, siltoximab, clazakizumab), TNF-α signaling inhibitors (e.g., etanercept), T-cell depletion antibodies (e.g., alemtuzumab), IL-1R-based inhibitors (e.g., anakinra), cyclophosphamide, Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), or combinations thereof, is not required or administered. In some embodiments, subjects undergoing CRS prophylaxis and receiving combination therapy including administration of a DR-IL-18 composition comprising a DR-IL-18 polypeptide (e.g., comprising at least about 30 μg / kg or more of a DR-IL-18 polypeptide) do not require or are not administered immunosuppressive agents to treat CRS. For example, in some instances, such subjects do not receive any corticosteroids (e.g., glucocorticoids) and / or any anti-interleukin 6 (IL-6) agents during the cycle of combination therapy or the entire course of combination therapy.

[0178] In some embodiments, the CRS preventative agent is at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid.

[0179] NSAID In some embodiments, the CRS preventative agent is a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is administered to the subject about 1 to 2 hours before administering a dose of the DR IL-18 composition. In some embodiments, the NSAID is administered to the subject at least about 48 hours after administering the dose of the DR IL-18 composition. In some embodiments, the NSAID comprises indomethacin or ibuprofen. In some embodiments, the indomethacin is administered to the subject at 25 mg three times daily. In some embodiments, the ibuprofen is administered to the subject at 200 mg to 600 mg every 6 to 8 hours. In some embodiments, the NSAID is administered orally to the subject.

[0180] Non-limiting examples of NSAIDs include ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, celecoxib, mefenamic acid, etoricoxib, indomethacin, or aspirin. In some embodiments, the NSAID is from about 25 mg to about 600 mg. In some embodiments, the NSAID is about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 3 In some embodiments, the NSAID is about 200 mg to about 600 mg.

[0181] In some embodiments, the NSAID is at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, at least about 500 mg, at least about 525 mg, at least about 550 mg, at least about 575 mg, at least about 600 mg, or more.

[0182] In some embodiments, the NSAID is up to about 600 mg, up to about 575 mg, up to about 550 mg, up to about 525 mg, up to about 500 mg, up to about 475 mg, up to about 450 mg, up to about 425 mg, up to 400 mg, up to 375 mg, up to 350 mg, up to 325 mg, up to about 300 mg, up to about 275 mg, up to about 250 mg, up to about 225 mg, up to about 200 mg, up to about 175 mg, up to about 150 mg, up to about 125 mg, up to about 100 mg, up to about 75 mg, up to about 50 mg, up to about 25 mg, or less.

[0183] In some embodiments, the NSAID is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

[0184] Acetaminophen In some embodiments, the CRS preventative agent is acetaminophen. In some embodiments, the acetaminophen is administered to the subject at 650 mg every 4 to 6 hours. In some embodiments, the acetaminophen is administered at least 24 hours after administration of a single dose of a DR IL-18 composition. In some embodiments, the acetaminophen is administered to the subject at 650 mg every 4 to 6 hours, starting 1 hour before administration of a single dose of a DR IL-18 composition. In some embodiments, the acetaminophen is administered for at least 48 hours after administration of a single dose of a DR IL-18 composition. In some embodiments, the acetaminophen is administered to the subject orally or enterally.

[0185] In some embodiments, the acetaminophen is from about 200 mg to about 800 mg, hi some embodiments, the acetaminophen is from about 600 mg to about 800 mg.

[0186] In some embodiments, the acetaminophen is at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, or more. In some embodiments, the acetaminophen is at most about 800 mg, at most about 750 mg, at most about 700 mg, at most about 650 mg, at most about 600 mg, at most about 550 mg, at most about 500 mg, at most about 450 mg, at most about 400 mg, at most about 350 mg, at most about 300 mg, at most about 250 mg, at most about 200 mg, or less. In some embodiments, the acetaminophen is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, the acetaminophen is about 650 mg.

[0187] Histamine H1 antagonists In some embodiments, the CRS prophylactic agent is a histamine H1 antagonist. In some embodiments, the histamine H1 antagonist is administered at 50 mg about 30 to 60 minutes prior to administration of the DR IL-18 composition. In some embodiments, the H1 antagonist is administered intravenously. In some embodiments, the H1 antagonist is administered orally.

[0188] Non-limiting examples of histamine H1 antagonists include brompheniramine, clemastine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine, mepyramine, chlorpheniramine, promethazine, and cyproheptadine. In some embodiments, the histamine H1 antagonist is present in an amount of about 20 to about 100 mg. In some embodiments, the histamine H1 antagonist is present in an amount of at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg, or more. In some embodiments, the histamine H1 antagonist is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the histamine H1 antagonist is at most about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the histamine H1 antagonist is at most about 50 mg.

[0189] Diphenhydramine In some embodiments, the CRS prophylactic agent is diphenhydramine. In some embodiments, diphenhydramine is administered at 50 mg about 30 to 60 minutes prior to administration of a single dose of the DR IL-18 composition. In some embodiments, diphenhydramine is administered intravenously. In some embodiments, diphenhydramine is administered orally.

[0190] In some embodiments, the diphenhydramine is about 20 to about 100 mg. In some embodiments, the diphenhydramine is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, or more. In some embodiments, the diphenhydramine is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the diphenhydramine is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the diphenhydramine is about 50 mg.

[0191] H2 blockers In some embodiments, the CRS prophylactic agent is a histamine H2 antagonist (H2 blocker). In some embodiments, the H2 blocker is administered at 20 mg about 30 to 60 minutes before administration of the DR IL-18 composition. In some embodiments, the H2 blocker is administered intravenously. In some embodiments, the H2 blocker is administered at 20 mg to 40 mg about 30 to 60 minutes before administration of a single dose of the DR IL-18 composition. In some embodiments, the H2 blocker is administered orally.

[0192] In some embodiments, the H2 blocker is cimetidine, ranitidine, or nizatidine. In some embodiments, the H2 blocker is cimetidine. In some embodiments, the H2 blocker is ranitidine. In some embodiments, the H2 blocker is nizatidine. In some embodiments, the H2 blocker is 10 mg to about 60 mg. In some embodiments, the H2 blocker is about 20 mg to about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the H2 blocker is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the H2 blocker is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

[0193] Famotidine In some embodiments, the CRS prophylactic agent is famotidine. In some embodiments, famotidine is administered at 20 mg about 30 to 60 minutes before administration of the DR IL-18 composition. In some embodiments, famotidine is administered intravenously. In some embodiments, famotidine is administered at 20 mg to 40 mg about 30 to 60 minutes before administration of a single dose of the DR IL-18 composition. In some embodiments, famotidine is administered orally.

[0194] In some embodiments, the famotidine is 10 mg to about 60 mg. In some embodiments, the famotidine is about 20 mg to about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the famotidine is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the famotidine is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

[0195] fluid In some embodiments, the subject has or is at risk of having low blood pressure. In some embodiments, administering a dose of a CRS preventative agent comprises administering a fluid to the subject. In some embodiments, the fluid comprises up to 3 liters of fluid (e.g., water, juice, sports drink, or IV fluid) within 24 hours after administration of a single dose of the DR IL-18 composition. In some embodiments, the fluid is administered intravenously. In some embodiments, the fluid is administered orally.

[0196] In some embodiments, administration of a CRS prophylactic agent results in reduced display of symptoms of cytokine release syndrome (CRS). Non-limiting examples of CRS symptoms include fever, chills, fatigue, nausea, vomiting, diarrhea, headache, cough, low blood pressure, joint pain, muscle pain, skin rash, shortness of breath, confusion, dizziness, difficulty swallowing, increased heart rate, decreased heart function, irregular heartbeat, organ failure, and swelling. In some embodiments, administration results in reduced display of symptoms of cytokine release syndrome compared to a comparable subject administered about 30 mg / ml to about 100 mg / ml of a DR IL-18 composition. In some embodiments, administration results in reduced display of symptoms of cytokine release syndrome compared to a comparable subject administered an equivalent therapy comprising about 30 mg / ml to about 100 mg / ml of a DR IL-18 composition. In some embodiments, administration results in a reduced display of symptoms of CRS compared to a comparable subject administered about 30 mg / ml to about 40 mg / ml, about 40 mg / ml to about 50 mg / ml, about 50 mg / ml to about 60 mg / ml, about 60 mg / ml to about 70 mg / ml, about 70 mg / ml to about 80 mg / ml, about 80 mg / ml to about 90 mg / ml, or about 90 mg / ml to about 100 mg / ml of a DR IL-18 composition. In some embodiments, administration results in a reduced display of symptoms of CRS compared to a corresponding subject administered an equivalent therapy of about 30 mg / ml to about 40 mg / ml, about 40 mg / ml to about 50 mg / ml, about 50 mg / ml to about 60 mg / ml, about 60 mg / ml to about 70 mg / ml, about 70 mg / ml to about 80 mg / ml, about 80 mg / ml to about 90 mg / ml, or about 90 mg / ml to about 100 mg / ml of a DR IL-18 composition.

[0197] CRS prevention combination Any of the groups of CRS preventative agents and individual CRS preventative agents described herein, and any of the methods described herein using such groups and individual CRS preventative agents, may be combined into useful CRS preventative agent combinations.

[0198] For example, in some embodiments, CRS prophylaxis administered to a subject includes at least an NSAID and at least a histamine H1 antagonist, at least acetaminophen and at least a histamine H1 antagonist, at least an NSAID and at least acetaminophen, or at least an NSAID, at least a histamine H1 antagonist, and at least acetaminophen. Such NSAIDs, histamine H1 antagonists, and acetaminophen used in such combinations can be administered according to the administration and / or dosage of each drug described herein. In some embodiments, CRS prophylaxis administered to a subject includes at least indomethacin or ibuprofen and at least diphenhydramine, at least acetaminophen and at least diphenhydramine, at least indomethacin or ibuprofen and at least acetaminophen, or at least indomethacin or ibuprofen, at least diphenhydramine, and at least acetaminophen. Such indomethacin or ibuprofen, diphenhydramine, and acetaminophen used in such combinations can be administered according to the administration and / or dosage of each drug described herein. In some embodiments, such combinations further comprise an H2 blocker, including, for example, when the H2 blocker used is famotidine, and the famotidine is administered in accordance with the administration and / or dosing described herein.

[0199] In some embodiments, CRS prophylaxis includes at least an NSAID, a histamine H1 antagonist, and acetaminophen, including, for example, when (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day (e.g., including 75 mg per day) or oral ibuprofen administered at 600 mg to 2,400 mg per day (e.g., including 800 mg to 1,800 mg per day), (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg (e.g., including a 50 mg dose), and (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day (e.g., including 650 mg to 3,900 mg per day). In some embodiments, such combinations further comprise an H2 blocker, including, for example, when the H2 blocker used is famotidine and the famotidine is administered in accordance with the administration and / or dosing described herein.

[0200] In some embodiments, the CRS prophylaxis combinations described herein reduce the manifestation of one or more symptoms of CRS, including alleviating one or more symptoms, compared to a subject administered the same treatment protocol without CRS prophylaxis. In some embodiments, the CRS prophylaxis combinations described herein, such as those described above, prevent a subject with cancer treated with a combination therapy comprising administration of a DR IL-18 composition comprising a polypeptide that is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 36-43 (e.g., SEQ ID NO: 41) from experiencing one or more (including all) symptoms of Grade 3 or higher CRS or Grade 4 CRS. In some embodiments, CRS prophylactic combinations described herein, such as those described above, can prevent a subject having cancer treated with a combination therapy comprising administration of a DR IL-18 composition comprising a polypeptide that is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 36-43 (e.g., SEQ ID NO: 41) from requiring treatment for CRS, including treatment with one or more (or any) immunosuppressive agents, such as, for example, a corticosteroid, an anti-interleukin-6 (IL-6) agent (e.g., tocilizumab), or any combination thereof.

[0201] Examples of Non-Limiting Aspects of the Disclosure Aspects, including embodiments of the subject matter described above, may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing, certain non-limiting aspects of the present disclosure are provided below. As will be apparent to those skilled in the art upon reading this disclosure, each of the individually numbered aspects may be used and combined with any of the preceding or subsequent individually numbered aspects. This is intended to support all such combinations of aspects, and is not limited to the combinations of aspects explicitly provided below. 1. A method of treating a disease in a subject in need thereof, the method comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; and (b) administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, thereby causing immunotherapy-induced regression of the disease in the subject. 2. The method of embodiment 1, further comprising administering to the subject a dose of a cytokine release syndrome (CRS) prophylactic agent. 3. The method of embodiment 2, wherein the dose of the CRS preventative agent is administered concomitantly with or prior to the dose of the sequential doses of the DR IL-18 composition. 4. The method of embodiment 2 or 3, comprising administering to the subject a single dose of a CRS prophylactic agent with or before each dose of the sequential doses of the DR IL-18 composition. 5. The method of any one of aspects 2-4, wherein the dose of CRS preventative agent comprises at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, a histamine H1 antagonist, an H2 blocker, or a fluid administered to the subject. 6. The method of any one of aspects 2-5, wherein the dose of CRS preventative agent comprises an NSAID, and optionally, the NSAID is an oral NSAID. 7. The method of embodiment 6, wherein the dose of the CRS preventative agent is administered before, optionally at least 1 hour, and optionally 1 to 2 hours before, the dose of the DR IL-18 composition or each dose of the consecutive doses of the DR IL-18 composition. 8. The method of embodiment 6 or 7, wherein an NSAID is further administered for at least 24 hours, and optionally at least 48 hours, after the dose of the DR IL-18 composition or each dose of the consecutive doses of the DR IL-18 composition. 9. The method of any one of aspects 6-8, wherein the NSAID is indomethacin, optionally oral indomethacin. 10. The method of embodiment 9, wherein indomethacin is administered at 50 mg to 100 mg per day, optionally 75 mg per day. 11. The method of aspect 9 or 10, wherein indomethacin is administered at a dose of 25 mg, optionally three times a day. 12. The method of any one of aspects 6-8, wherein the NSAID is ibuprofen, optionally oral ibuprofen. 13. The method of embodiment 12, wherein ibuprofen is administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day. 14. The method of aspect 12 or 13, wherein ibuprofen is administered in a dose of 200 mg to 600 mg, optionally with 6 to 8 hours between ibuprofen doses. 15. The method of any one of aspects 2-5, wherein the dose of CRS prophylactic agent comprises a histamine H1 antagonist, optionally wherein the histamine H1 antagonist is an intravenous histamine H1 antagonist or an oral histamine H1 antagonist. 16. The method of embodiment 15, wherein the histamine H1 antagonist is administered prior to, optionally at least 30 minutes, and optionally 30 to 60 minutes before, the dose of the DR IL-18 composition or each dose of the consecutive doses of the DR IL-18 composition. 17. The method of aspect 15 or 16, wherein the histamine H1 antagonist is diphenhydramine, optionally intravenous diphenhydramine or oral diphenhydramine. 18. The method of embodiment 17, wherein between 25 mg and 100 mg of diphenhydramine is administered, optionally, 50 mg of diphenhydramine is administered. 19. The method of any one of aspects 2-5, wherein the dose of CRS preventative agent comprises acetaminophen, and optionally, the acetaminophen is oral acetaminophen. 20. The method of embodiment 19, wherein acetaminophen is administered prior to, optionally within 2 hours or 1 hour before, the dose of the DR IL-18 composition, or each dose of the DR IL-18 composition in successive doses. 21. The method of embodiment 20, wherein acetaminophen is further administered for at least two days after the dose of the DR IL-18 composition, or after each dose of the consecutive doses of the DR IL-18 composition. 22. The method of embodiment 19, wherein acetaminophen is administered within 24 hours of the dose of the DR IL-18 composition, or each dose of consecutive doses of the DR IL-18 composition. 23. The method of any one of aspects 19-22, wherein between 350 mg and 4,000 mg of acetaminophen is administered per day, and optionally between 650 mg and 3,900 mg of acetaminophen is administered per day. 24. The method of any one of aspects 19-23, wherein acetaminophen is administered in one or more 650 mg doses, optionally with 4-6 hours between doses. 25. The method of any one of aspects 2-5, wherein the dose of CRS prophylactic agent comprises an H2 blocker, optionally wherein the H2 blocker is an oral H2 blocker or an intravenous H2 blocker. 26. The method of embodiment 25, wherein the H2 blocker is administered only before each successive dose of the DR IL-18 composition, optionally at least 30 minutes before each successive dose of the DR IL-18 composition, optionally 30 to 60 minutes before each successive dose of the DR IL-18 composition. 27. The method of aspect 25 or 26, wherein the H2 blocker is famotidine, optionally oral famotidine or intravenous famotidine. 28. The method of embodiment 27, wherein 20 mg to 40 mg of oral famotidine is administered. 29. The method of embodiment 27, wherein 20 mg of intravenous famotidine is administered. 30. The method of any one of the preceding aspects, wherein the method comprises administering to the subject multiple doses of a CRS preventative comprising at least one dose of an NSAID and at least one dose of a histamine H1 antagonist, at least one dose of acetaminophen and at least one dose of a histamine H1 antagonist, at least one dose of an NSAID and at least one dose of acetaminophen, or at least one dose of an NSAID, at least one dose of a histamine H1 antagonist, and at least one dose of acetaminophen, optionally wherein the NSAID is selected from indomethacin and ibuprofen, and the histamine H1 antagonist is diphenhydramine. 31. The method of aspect 30, further comprising at least one dose of an H2 blocker, optionally wherein the H2 blocker is famotidine, and optionally wherein the famotidine is oral famotidine administered at a dose of 20 mg to 40 mg or intravenous famotidine administered at a dose of 20 mg. 32. (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day; (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg; (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day; or (iv) The method of any one of aspects 30 and 31, any combination thereof. 33. The method of any one of the preceding aspects, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS compared to a comparable subject who has not received the CRS prophylactic agent. 34. The method of any one of the preceding aspects, wherein administering the CRS preventative agent reduces the display of one or more symptoms of CRS compared to a subject who has not received the CRS preventative agent and who is receiving a comparable treatment comprising administration of about 30 μg / kg or more of a DR IL-18 composition. 35. The method of any one of the preceding aspects, wherein the subject does not experience CRS of grade 4 or higher, and optionally, the subject does not experience CRS of grade 3 or higher. 36. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject once every three weeks (Q3W). 37. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject about every 21 days. 38. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition comprises a fixed dose of 200 mg pembrolizumab. 39. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition comprises about 2 mg of pembrolizumab per kg of the subject's body weight. 40. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject as a fixed dose of 200 mg mbrolizumab Q3W. 41. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject as a fixed dose of 200 mg pembrolizumab about every 21 days. 42. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject Q3W at a dose of about 2 mg of pembrolizumab per kg of the subject's body weight. 43. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the anti-PD-1 antibody composition is administered to the subject about every 21 days at a dose of about 2 mg of pembrolizumab per kg of the subject's body weight. 44. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the DR IL-18 composition is administered to the subject weekly. 45. The method of any one of the preceding aspects, wherein each dose of the sequential doses of the DR IL-18 composition is administered to the subject about every 7 days. 46. ​​The method of any one of the preceding aspects, wherein the subsequent dose of the DR IL-18 composition is administered to the subject at least 6 days after the previous dose of the DR IL-18 composition. 47. The method of embodiment 46, wherein the subsequent dose of the DR IL-18 composition is administered to the subject a maximum of 9 days after the previous dose of the DR IL-18 composition. 48. The method of any one of the preceding aspects, wherein the polypeptide is a modified IL-18 polypeptide comprising the amino acid sequence set forth in SEQ ID NO:41. 49. The method of any one of the preceding aspects, wherein the polypeptide is a modified IL-18 polypeptide consisting of the amino acid sequence set forth in SEQ ID NO:41. 50. The method of any one of the preceding aspects, wherein the polypeptide is at a concentration of about 30 mg / mL. 51.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 15 μg of polypeptide per kg of subject body weight. 52. The method of any one of the preceding aspects, wherein the dose of DR IL-18 composition comprises at least about 20 μg of polypeptide per kg of subject body weight. 53.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 30 μg of polypeptide per kg of subject body weight. 54. The method of any one of the preceding aspects, wherein the dose of DR IL-18 composition comprises at least about 90 μg of polypeptide per kg of subject body weight. 55.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 180 μg of polypeptide per kg of subject body weight. 56.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 360 μg of polypeptide per kg of subject body weight. 57.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 600 μg of polypeptide per kg of subject body weight. 58.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 900 μg of polypeptide per kg of subject body weight. 59.DR The method of any one of the preceding aspects, wherein the dose of IL-18 composition comprises at least about 1200 μg of polypeptide per kg of subject body weight. 60. The method of any one of aspects 51-53, wherein the dose of the DR IL-18 composition is at least one of the initial dose, the first dose, or the lowest dose administered to the subject. 61. The method of any one of the preceding aspects, wherein each dose of the IL-18 composition comprises at least about 15 μg to about 1200 μg of polypeptide per kg of subject body weight. 62.DR The method of any one of the preceding aspects, wherein the dose of the IL-18 composition comprises from about 15 μg to about 30 μg, from about 30 μg to about 90 μg, from about 90 μg to about 180 μg, from about 180 μg to about 360 μg, from about 360 μg to about 600 μg, from about 600 μg to about 900 μg, or from about 900 μg to about 1200 μg of polypeptide per kg of body weight of the subject. 63.DR The method of any one of the preceding aspects, wherein the dose of the IL-18 composition comprises about 15 μg, about 30 μg, about 90 μg, about 180 μg, about 360 μg, about 600 μg, about 900 μg, or about 1200 μg of polypeptide per kg of body weight of the subject. 64. The method of any one of the preceding aspects, wherein subsequent doses of the IL-18 composition comprise a greater amount of polypeptide per kg of subject body weight than the amount of polypeptide previously administered to the subject. 65. The method of embodiment 64, wherein the amount of polypeptide previously administered to the subject was tolerated by the subject. 66. The method of any one of aspects 1-63, wherein the subsequent dose of the DR IL-18 composition comprises a greater amount of polypeptide per kg body weight of the subject than the amount of polypeptide in the previous dose of the DR IL-18 composition. 67. The method of embodiment 66, wherein the previous dose was tolerated by the subject. 68. The method of any one of aspects 1-63, wherein subsequent doses of the DR IL-18 composition comprise the same or equivalent amount of polypeptide per kg of body weight of the subject to the amount previously administered to the subject. 69. The method of embodiment 68, wherein the amount of the polypeptide is related to a recorded treatment-emergent adverse event in the subject. 70. The method of embodiment 69, wherein the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. 71. The method of embodiment 69 or 70, wherein the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. 72. The method of any one of aspects 69-71, wherein the recorded treatment-emergent adverse event is associated with no or minimal medical intervention, support, or therapy being provided to the subject. 73. The method of embodiment 68, wherein the amount is the maximum tolerated dose. 74. The method of any one of aspects 1-63, wherein the subsequent dose of the DR IL-18 composition comprises the same or equivalent amount of polypeptide per kg body weight of the subject to the amount of polypeptide in the previous dose of the DR IL-18 composition. 75. The method of embodiment 74, wherein the previous dose is associated with causing a recorded treatment-emergent adverse event in the subject. 76. The method of embodiment 75, wherein the recorded treatment-emergent adverse event is a Grade 1 or Grade 2 treatment-emergent adverse event according to NCI CTCAE version 5.0. 77. The method of embodiment 75 or 76, wherein the recorded treatment-emergent adverse event is associated with no to mild limitation in the subject's activity. 78. The method of any one of aspects 75 to 77, wherein the recorded treatment-emergent adverse event is associated with no or minimal medical intervention, support, or therapy being provided to the subject. 79. The method of embodiment 74, wherein the previous dose is the maximum tolerated dose. 80. The method of any one of aspects 1-63, wherein subsequent doses of the DR IL-18 composition comprise a lower amount of polypeptide per kg of subject body weight than the amount of polypeptide previously administered to the subject. 81. The method of embodiment 80, wherein the subject has not tolerated a previously administered amount of the polypeptide. 82. The method of embodiment 80 or 81, wherein the amount of previously administered polypeptide is associated with dose-limiting toxicity (DLT). 83. The method of embodiment 80, wherein the subsequent dose is the previously tolerated dose. 84. The method of any one of aspects 1-63, wherein the subsequent dose of the DR IL-18 composition comprises a lower amount of polypeptide per kg body weight of the subject than the amount of polypeptide in the previous dose of the DR IL-18 composition. 85. The method of embodiment 84, wherein the previous dose was not tolerated by the subject. 86. The method of embodiment 84, wherein the previous dose is associated with a dose-limiting toxicity (DLT). 87. The method of embodiment 84, wherein the subsequent dose is the previously tolerated dose. 88. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered to the subject in a series of cycles, each cycle comprising about 21 days. 89. The method of embodiment 88, wherein the anti-PD-1 antibody composition is administered once per cycle. 90. The method of embodiment 88 or 89, wherein the DR IL-18 composition is administered 1, 2, or 3 times during each cycle. 91. The method of any one of aspects 88-90, wherein the series of cycles includes a current cycle and a next cycle, and the next cycle is performed consecutively to the current cycle. 92. The method of any one of aspects 88-91, wherein the series of cycles comprises a first cycle, and the first cycle comprises the first day. 93. The method of embodiment 92, wherein a dose of the anti-PD-1 antibody composition comprising 200 mg of pembrolizumab is administered to the subject on the first day of the first cycle. 94. The method of embodiment 92 or 93, wherein a dose of the DR IL-18 composition comprising about 15 μg to about 30 μg of polypeptide per kg of subject body weight is administered to the subject on the first day of the first cycle. 95. The method of any one of aspects 88-94, wherein the series of cycles comprises at least 8 cycles. 96. The method of any one of aspects 88-95, wherein the series of cycles comprises 35 or fewer cycles. 97. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered for at least 24 weeks. 98. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject has received at least 8 doses of the anti-PD-1 antibody composition. 99. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 24 weeks or has received at least 8 doses of the anti-PD-1 antibody composition. 100. The method of any one of aspects 88-96, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has been treated for at least 8 cycles. 101. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject experiences a complete response (CR) and has received at least 8 doses of the anti-PD-1 antibody composition. 102. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject has received at least about 24 doses of the DR IL-18 composition. 103. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered until the subject exhibits intervention-related toxicity designated as grounds for permanent discontinuation. 104. The method of aspect 103, wherein the intervention-related toxicity is at least one of Grade 4, Grade 3, or recurrent Grade 2 treatment-emergent adverse events according to NCI CTCAE version 5.0. 105. The method of embodiment 104, wherein the treatment-emergent adverse event is associated with a significant or severe limitation in the subject's activity. 106. The method of embodiment 104 or 105, wherein the treatment-emergent adverse event is life-threatening or requires significant medical intervention or hospitalization. 107. The method of any one of the preceding aspects, wherein the anti-PD-1 and DR IL-18 composition is administered for up to about 2 years. 108. The method of any one of the preceding aspects, wherein the subject is administered up to 35 doses of the anti-PD-1 antibody. 109. The method of any one of the preceding aspects, wherein one dose of the PD-1 antibody composition is administered to the subject at least about 60 minutes before the one dose of the DR IL-18 composition is administered to the subject. 110. The method of any one of the preceding aspects, wherein one dose of the DR 1L-18 composition is administered to the subject at least 60 minutes after the one dose of the anti-PD-1 antibody composition is administered. 111. The method of any one of the preceding aspects, wherein (a) and (b) are performed sequentially. 112. The method of any one of the preceding aspects, wherein (a) is performed before (b). 113. The method of any one of embodiments 1-108, wherein (b) is performed before (a). 114. The method of any one of embodiments 1-108, wherein (a) and (b) are performed simultaneously. 115. The method of any one of the preceding aspects, wherein one dose of the anti-PD-1 antibody is administered to the subject by intravenous infusion. 116. The method of any one of the preceding aspects, wherein each dose of the anti-PD-1 antibody is administered to the subject by intravenous infusion. 117. The method of any one of the preceding aspects, wherein one dose of the DR IL-18 composition is administered to the subject by subcutaneous injection. 118. The method of any one of the preceding aspects, wherein each dose of the DR IL-18 composition is administered to the subject by subcutaneous injection. 119. The method of any one of the preceding aspects, wherein the disease comprises cancer or a solid tumor. 120. Your cancer is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancer (dMMR) cancer, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophagogastric cancer, or gastric cancer. 120. The method of embodiment 119, relating to esophageal junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof. 121. The method of aspect 120, wherein the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. 122. The method of aspect 119, wherein the cancer or solid tumor is associated with melanoma, Merkel cell, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation / fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. 123. The method of aspect 119, wherein the cancer or solid tumor is associated with platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. 124. The method of embodiment 119, wherein the cancer is a blood cancer. 125. The method of embodiment 124, wherein the hematological cancer is selected from the group consisting of leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative disorder, and myeloma. 126. The method of aspect 125, wherein the blood cancer is myeloma. 127. The method of aspect 125, wherein the hematological cancer is lymphoma, optionally B-cell lymphoma. 128. The method of aspect 125, wherein the blood cancer is leukemia, optionally acute myeloid leukemia. 129. A method of treating a subject comprising administering to the subject one or more doses of a CRS prophylactic agent with or before each dose of the sequential doses of a DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of an NSAID, a histamine H1 antagonist, acetaminophen, or an H2 blocker; (i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41; (ii) the dose of the DR IL-18 composition comprises at least about 30 μg of polypeptide per kg of subject body weight; (iii) the dose of the anti-PD-1 antibody composition comprises at least about 200 mg of pembrolizumab; (iv) The method of any one of the preceding aspects, wherein the disease comprises a PD-1 checkpoint inhibitor resistant solid tumor selected from the group consisting of melanoma, Merkel cell, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. 130. A method of treating a disease in a human patient, comprising administering to the patient an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a decoy-resistant (DR) IL-18 composition comprising a polypeptide to the subject, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, and the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) comprising the sequence of amino acids set forth in SEQ ID NOs: 1, 2, and 3, and a heavy chain CDR comprising the sequence of amino acids set forth in SEQ ID NOs: 6, 7, and 8. 131. The method of embodiment 130, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is an anti-PD-1 monoclonal antibody. 132. The method of embodiment 130 or 131, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient at a dose of about 200 mg once every three weeks. 133. The method of any one of aspects 130-132, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient at a dose of about 400 mg once every six weeks. 134. The method of any one of aspects 130-133, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient by IV infusion. 135. The method of aspect 134, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient by IV infusion over about 30 minutes on day 1 of each treatment cycle. 136. The method of any one of aspects 130-135, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. 137. The method of any one of aspects 130 to 135, wherein the anti-PD-1 monoclonal antibody is a pembrolizumab variant. 138. The method of any one of aspects 130-137, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition, and the composition comprises 130 mg / mL of the anti-PD-1 antibody or antigen-binding fragment thereof. 139. The method of any one of aspects 130-137, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition, and the composition comprises 165 mg / mL of the anti-PD-1 antibody or antigen-binding fragment thereof. 140. The method of any one of aspects 130-139, wherein the DR IL-18 composition is administered to the patient weekly. 141. The method of any one of aspects 130-140, wherein the DR IL-18 composition is administered to the subject every 7 days. 142. The method of any one of aspects 130-141, wherein doses of the DR IL-18 composition are administered to the patient at least 6 days apart. 143. A method according to embodiment 142, wherein doses of the DR IL-18 composition are administered to the patient at intervals of up to 9 days. 144. The method of any one of aspects 130-143, wherein the polypeptide is a modified IL-18 polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 41. 145. The method according to any one of aspects 130 to 144, wherein the polypeptide is a modified IL-18 polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 41. 146. The method of any one of aspects 130-145, wherein the polypeptide is at a concentration of about 30 mg / mL. 147. The method of any one of aspects 130-146, wherein the IL-18 composition comprises from about 15 μg to about 1200 μg of polypeptide per kg of patient body weight. 148.DR The method of any one of aspects 130-147, wherein the IL-18 composition is administered to the patient at a dose of from about 15 μg to about 30 μg, from about 30 μg to about 90 μg, from about 90 μg to about 180 μg, from about 180 μg to about 360 μg, from about 360 μg to about 600 μg, from about 600 μg to about 900 μg, or from about 900 μg to about 1200 μg of polypeptide per kg of patient body weight. 149. The method of any one of aspects 130-148, wherein the DR IL-18 composition is administered to the patient at a dose of at least about 30 μg of polypeptide per kg of patient body weight. 150. The method of any one of aspects 130-149, wherein the DR IL-18 composition is administered to the patient by subcutaneous injection. 151. The method of any one of aspects 130-150, wherein the disease comprises cancer or a solid tumor. 152. The method of embodiment 151, wherein the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. 153. The cancer or solid tumor is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancer (dMMR) cancer, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, or esophagogastric junction cancer. 153. The method of embodiment 151 or 152, wherein the cancer is or is associated with esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof. 154. The method of aspect 153, wherein the cancer or solid tumor is or is associated with melanoma, Merkel cell, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation / fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor. 155. The method of embodiment 151, wherein the cancer or solid tumor is or is associated with platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. 156. The method of embodiment 151, wherein the cancer is a blood cancer. 157. The method of embodiment 156, wherein the hematological cancer is selected from the group consisting of leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative disorder, and myeloma. 158. The method of aspect 157, wherein the blood cancer is myeloma. 159. The method of aspect 157, wherein the hematological cancer is lymphoma, optionally B-cell lymphoma. 160. The method of aspect 157, wherein the blood cancer is leukemia, optionally acute myeloid leukemia. 161. The method of any one of aspects 130-160, further comprising administering to the subject a cytokine release syndrome (CRS) prophylactic agent. 162. The method of embodiment 161, wherein the CRS prophylactic agent is administered together with or before the DR IL-18 composition. 163. The method of embodiment 161 or 162, wherein the CRS prophylactic agent comprises at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, a histamine H1 antagonist, or an H2 blocker. 164. The method of any one of aspects 161-163, wherein CRS prophylaxis comprises an NSAID, optionally wherein the NSAID is an oral NSAID. 165. The method of embodiment 164, wherein the CRS prophylactic agent is administered before the DR IL-18 composition, optionally at least 1 hour before, optionally 1 to 2 hours before. 166. The method of embodiment 164 or 165, wherein the NSAID is further administered after the DR IL-18 composition for at least 24 hours, optionally for at least 48 hours. 167. The method of any one of aspects 164-166, wherein the NSAID is indomethacin, optionally oral indomethacin. 168. The method of embodiment 167, wherein indomethacin is administered at 50 mg to 100 mg per day, optionally 75 mg per day. 169. The method of embodiment 167 or 168, wherein indomethacin is administered at a dose of 25 mg, optionally three times a day. 170. The method of any one of aspects 164-166, wherein the NSAID is ibuprofen, optionally oral ibuprofen. 171. The method of embodiment 170, wherein ibuprofen is administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day. 172. The method of embodiment 170 or 171, wherein ibuprofen is administered in a dose of 200 mg to 600 mg, optionally with 6 to 8 hours between ibuprofen doses. 173. The method of any one of aspects 161-163, wherein the CRS prophylactic agent comprises a histamine H1 antagonist, optionally wherein the histamine H1 antagonist is an intravenous histamine H1 antagonist or an oral histamine H1 antagonist. 174. The method of embodiment 173, wherein the histamine H1 antagonist is administered before the DR IL-18 composition, optionally at least 30 minutes, optionally 30-60 minutes before. 175. The method of aspect 173 or 174, wherein the histamine H1 antagonist is diphenhydramine, optionally intravenous diphenhydramine or oral diphenhydramine. 176. The method of embodiment 175, wherein 25 mg to 100 mg of diphenhydramine is administered, optionally, 50 mg of diphenhydramine is administered. 177. The method of any one of aspects 161-163, wherein the CRS prophylactic agent comprises acetaminophen, and optionally, the acetaminophen is oral acetaminophen. 178. The method of embodiment 177, wherein acetaminophen is administered before the DR IL-18 composition, optionally within 2 hours or 1 hour before. 179. The method of embodiment 178, wherein acetaminophen is further administered for at least 2 days after the DR IL-18 composition. 180. The method of embodiment 179, wherein the acetaminophen is administered within 24 hours of the DR IL-18 composition. 181. The method of any one of aspects 177-180, wherein between 350 mg and 4,000 mg of acetaminophen is administered per day, and optionally between 650 mg and 3,900 mg of acetaminophen is administered per day. 182. The method of any one of aspects 177-181, wherein acetaminophen is administered in one or more 650 mg doses, optionally with 4-6 hours between doses. 183. The method of any one of aspects 161-163, wherein the CRS prophylactic agent comprises an H2 blocker, optionally wherein the H2 blocker is an oral H2 blocker or an intravenous H2 blocker. 184. The method of embodiment 183, wherein the H2 blocker is administered only before the DR IL-18 composition, optionally at least 30 minutes before the DR IL-18 composition, optionally 30-60 minutes before the DR IL-18 composition. 185. The method of aspect 183 or 184, wherein the H2 blocker is famotidine, optionally oral famotidine or intravenous famotidine. 186. The method of embodiment 185, wherein 20 mg to 40 mg of oral famotidine is administered. 187. The method of embodiment 185, wherein 20 mg of intravenous famotidine is administered. 188. The method of any one of aspects 161-187, wherein the method comprises administering to the patient multiple doses of a CRS preventative comprising at least an NSAID and at least a histamine H1 antagonist, at least acetaminophen and at least a histamine H1 antagonist, at least an NSAID and at least acetaminophen, or at least an NSAID, at least a histamine H1 antagonist, and at least acetaminophen, optionally wherein the NSAID is selected from indomethacin and ibuprofen, and the histamine H1 antagonist is diphenhydramine. 189. The method of embodiment 188, further comprising at least an H2 blocker, optionally wherein the H2 blocker is famotidine, and optionally wherein the famotidine is oral famotidine administered in a dose of 20 mg to 40 mg or intravenous famotidine administered in a dose of 20 mg. 190. (i) The NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day; (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg; (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day; or (iv) The method of any one of embodiments 188 and 189, any combination thereof. 191. The method of any one of aspects 161-190, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS compared to a comparable subject not receiving the CRS prophylactic agent. 192. The method of any one of aspects 161-191, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS compared to a subject who has not received the CRS prophylactic agent and who is receiving a comparable treatment comprising administration of about 30 μg / kg or more of a DR IL-18 composition. 193. The method of any one of aspects 161-192, wherein the patient does not experience CRS of grade 4 or higher, and optionally, the subject does not experience CRS of grade 3 or higher. 194. Administering to a subject one or more CRS prophylactic agents together with or prior to the DR IL-18 composition, wherein the one or more CRS prophylactic agents comprise an NSAID, a histamine H1 antagonist, acetaminophen, an H2 blocker, or a combination thereof; (i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41; (ii) the dose of the DR IL-18 composition comprises at least about 30 μg of polypeptide per kg of patient body weight; (iii) the dose of the anti-PD-1 antibody composition comprises at least about 200 mg of pembrolizumab or a pembrolizumab variant; (iv) The method of any one of aspects 130 to 193, wherein the disease comprises a PD-1 checkpoint inhibitor-resistant solid tumor selected from the group consisting of melanoma, Merkel cell, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. 195. The method of any one of aspects 130-194, wherein the disease is cancer or tumor, and the method thereby causes one or more improvements in the cancer or tumor in the patient. 196. The method of embodiment 195, wherein the one or more improvements comprise stable disease for at least 12 weeks. 197. The method of embodiment 195 or 196, wherein the one or more improvements comprise immunotherapy-induced regression of cancer or tumor in the patient. 198. The method of any one of aspects 195-197, wherein the one or more improvements comprise a partial response as assessed by RECIST version 1.1. 199. The method of any one of aspects 195-198, wherein the one or more improvements comprise a complete response as assessed by RECIST version 1.1. 200. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in a method for treating cancer according to any one of aspects 130 to 199. 201. A method for treating cancer, comprising administering pembrolizumab and a decoy-resistant IL-18 polypeptide to a human patient in need thereof. 202. The method of embodiment 201, wherein the patient is administered about 200 mg of pembrolizumab once every three weeks. 203. The method of embodiment 201, wherein the patient is administered about 400 mg of pembrolizumab once every six weeks. [Example]

[0202] Example #1: Pembrolizumab Combination Therapy with DR IL-18 Polypeptides Phase Ia and Phase II studies evaluating the safety, preliminary efficacy, PK, and PD of DR IL-18 polypeptide and pembrolizumab are being conducted in a variety of conditions / diseases, including cancer, solid tumors, melanoma, renal cell carcinoma, triple-negative breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, and MSI-Hgh. The Phase I clinical trial arm is for the combination of pembrolizumab and DR IL-18 polypeptide. The Phase I dose escalation study in combination with pembrolizumab will begin with 30 μg / kg of DR IL-18 polypeptide and 200 mg of pembrolizumab every three weeks. Patients will be treated with DR IL-18 polypeptide weekly and pembrolizumab every three weeks. The maximum tolerated dose (MTD) will be determined based on a modified toxicity probability interval (mTIP) design.

[0203] In an exemplary embodiment, a subject is administered pembrolizumab by intravenous infusion (200 mg Q3W) and decoy-resistant IL-18 polypeptide by subcutaneous injection (30 μg / kg of subject's body weight QW) for up to about two years to treat tumors associated with non-small cell lung cancer. Tumors shrink over the course of treatment, resulting in a significant reduction in tumor size and tumor number, until the patient exhibits signs of complete disease remission after two years of combined treatment.

[0204] Example #2DR Prevention of CRS in patients treated with IL-18 polypeptide + pembrolizumab combination therapy A risk of CRS was observed when DR IL-18 polypeptides were administered subcutaneously as monotherapy. All patients now receive prophylactic medication before each injection.

[0205] The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS is as follows: [Table 5] Abbreviations: BiPAP = bilevel positive airway pressure, CPAP = continuous positive airway pressure. See also, e.g., Lee et al. Biology of Blood and Marrow Transplantation. 25 (2019) 625-639.

[0206] A cohort of three patients who had previously experienced an inadequate response to PD-1 checkpoint inhibitor therapy received combination therapy with weekly subcutaneous DR IL-18 polypeptide with pembrolizumab at 30 μg / kg + 200 mg administered intravenously every 3 weeks. DR IL-18 polypeptide is administered with each dose by CRS prophylaxis, which consists of (a) an oral nonsteroidal anti-inflammatory drug (NSAID) (using indomethacin at 25 mg three times daily or oral ibuprofen at 200 mg to 600 mg every 6 to 8 hours) 1 to 2 hours before and continuing for at least 48 hours after DR IL-18 polypeptide dosing, (b) 50 mg intravenous or oral diphenhydramine (or an equivalent dose of a next-generation histamine H1 antagonist) 30 to 60 minutes before DR IL-18 polypeptide dosing, (c) 650 mg oral acetaminophen every 4 to 6 hours as needed for the first 24 hours after dosing, and (d) subsequent DR IL-18 polypeptide dosing, if indicated after the initial DR IL-18 polypeptide dosing. This included administration of 20 mg of intravenous oral famotidine (or other H2 blocker) or 20-40 mg of oral famotidine (or other H2 blocker) 30-60 minutes before IL-18 polypeptide administration. Unless contraindicated by post-administration vital signs, any blood pressure medication was withheld at least 24 hours before and at least 48 hours after DR IL-18 polypeptide administration. For subjects with contraindications to NSAIDs, 650 mg of oral acetaminophen was used every 4-6 hours starting 1 hour before DR IL-18 polypeptide administration and continued for at least 48 hours after administration. For subjects with or at risk for hypotension, up to 3 liters of oral and / or intravenous fluids were administered within 24 hours after administration.

[0207] All patients in the cohort remained on study through the dose-limiting toxicity (DLT) period (i.e., through 21 days of 3 doses of DR IL-18 polypeptide). No patients in the cohort experienced grade 3 or higher CRS, and no patients in the cohort required steroids for CRS.

[0208] Example #3: Efficacy in patients treated with DR IL-18 polypeptide + pembrolizumab combination therapy As described below, cohorts of patients will receive weekly subcutaneous DR IL-18 polypeptide at 30 μg / kg, 60 μg / kg, or other recommended dose (such as the recommended Phase 2 dose from the DR IL-18 polypeptide dose-finding study) plus 200 mg of pembrolizumab intravenously every 3 weeks (with CRS prophylaxis for each dose as described in Example #3). On days when subjects receive both drugs, pembrolizumab will be administered first, and DR IL-18 polypeptide will be administered after the pembrolizumab infusion, with appropriate CRS prophylaxis.

[0209] The cohort includes histologically or cytologically confirmed advanced / metastatic melanoma, Merkel cell carcinoma, renal cell carcinoma (RCC), urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), any microsatellite instability-high (MSI-H), any high tumor mutation burden (TMB-H) or mismatch repair-deficient, gastric, cervical, endometrial, squamous cell cutaneous, small cell lung, esophageal, and hepatocellular carcinoma (HCC) cancer / tumor(s) that have experienced an inadequate response to checkpoint inhibitor programmed death receptor-1 (PD-1) therapy. TNBC is diagnosed in tumors that do not express estrogen or progesterone receptors and are not human epidermal growth factor receptor 2 (HER2) 3+ by immunohistochemistry (IHC) or negative by fluorescence in situ hybridization (FISH). MSI-high tumors have mutations in ≥30% of microsatellites by PCR or are negative for MSH1 / 2 / 6 or PMS-2 by IHC. TMB-H-high tumors have ≥10 mutations per megabase (mut / Mb) calculated from whole-genome or whole-exome sequencing. The following tumors are accepted in the expansion cohort: platinum-resistant ovarian cancer and microsatellite-stable colorectal cancer.

[0210] Disease assessments are performed using computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis (and other relevant areas if they contain target lesions). Determination of the magnitude and duration of tumor size change is based on well-established response and progression criteria as applied to radiological measurements (see Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, Eisenhauer et al. (2009) European Journal of Cancer 45:228-247). Disease assessments are performed every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Clinical laboratory, pharmacodynamic, pharmacogenomic, pharmacokinetic, and other assessments are also performed.

[0211] The cohort is expected to demonstrate evidence of pharmacodynamic activity and substantial evidence of tumor regression, including objective responses (CR and PR) as assessed by RECIST version 1.1. Stable disease for ≥12 weeks is considered clinically relevant in this patient population.

[0212] Example #4: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth in the CT26 mouse colorectal tumor model. The antitumor activity of decoy-resistant (DR) IL-18 polypeptides, alone and in combination with anti-PD-1 immune checkpoint inhibitors (ICIs), was evaluated in colorectal cancer using the CT26 mouse colorectal cancer model. CT26 is an N-nitroso-N-methylurethane (NNMU)-induced undifferentiated colon cancer cell line established from BALB / c mice bearing aggressive colon cancer. CT26 is considered a "warm" tumor model, generally meaning it lies between immunogenic "hot" tumors and non-immunogenic "cold" tumors.

[0213] To establish the model, CT26 cells were implanted as xenografts into host mice and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (0.32 milligrams per kilogram (mpk) administered by intraperitoneal injection (IP) every other week (BIW) for five doses, with the final dose on study day 15), anti-PD-1 antibody alone (10 mpk BIW for five doses), or the combination of DR IL-18 polypeptide and anti-PD-1 (dosed at the same dose as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle alone (i.e., without DR IL-18 polypeptide or any ICI). As an assay for cancer growth, tumor size (in cubic millimeters (mm3)) was measured in each animal over time during the course of the study.

[0214] As can be seen in Figure 1, tumors grew rapidly in untreated vehicle control mice and mice treated with anti-PD-1 monotherapy. Tumor growth was substantially reduced in mice treated with DR IL-18 polypeptide monotherapy compared to vehicle control mice and anti-PD-1 monotherapy-treated mice. However, tumor growth in mice treated with a combination of DR IL-18 polypeptide and anti-PD-1 was substantially reduced, if not stopped, compared to either of the monotherapy treatment conditions. Thus, this example demonstrates that combination therapy comprising a DR IL-18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-tumor activity, significantly reducing, if not stopping, the growth of colorectal tumors. The anti-tumor activity of the combination therapy was substantially greater than either DR IL-18 polypeptide monotherapy or anti-PD-1 ICI monotherapy.

[0215] Example #5: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth in the MC38 mouse colorectal tumor model. We evaluated the antitumor activity of DR IL-18 alone and in combination with anti-PD-1 ICI in the MC38 mouse colorectal cancer model. The MC38 tumorigenic epithelial cell line was isolated from a mouse with colon adenocarcinoma and expresses high levels of human carcinoembryonic antigen (CEA). MC38 contains a high mutational burden and is sensitive to immune checkpoint immunotherapy.

[0216] To establish the model, MC38 cells were implanted as xenografts into host mice and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (5 IP doses of 0.32 mpk BIW, with the final dose on study day 15), anti-PD-1 antibody alone (5 IP doses of 10 mpk BIW), or a combination of DR IL-18 polypeptide and anti-PD-1 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle alone (i.e., without DR IL-18 polypeptide or any ICI). Tumor size (mm3) was measured over time in each animal as an assay for cancer growth during the course of the study.

[0217] As can be seen in Figure 2, tumors grew, on average, to over 2000 mm3 in untreated vehicle control mice. Mice treated with anti-PD-1 monotherapy showed reduced MC38 tumor growth compared to vehicle controls. Tumor growth was reduced in mice treated with DR IL-18 polypeptide monotherapy compared to mice treated with anti-PD-1 monotherapy. However, mice treated with a combination of DR IL-18 polypeptide and anti-PD-1 showed a more substantial reduction in MC38 tumor growth compared to either monotherapy. Thus, this example demonstrates that combination therapy comprising a DR IL-18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-colorectal tumor activity superior to both DR IL-18 polypeptide monotherapy and anti-PD-1 ICI monotherapy.

[0218] Example #6: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth and improves treatment response in a mouse heme tumor model. The antitumor activity of DR IL-18 polypeptides, alone and in combination with anti-PD-1 ICIs, was evaluated in various hematopoietic tumor mouse models, including MPC-11 (myeloma), A-20 (B-cell lymphoma), and C1498 (acute myeloid leukemia). MPC-11 (Merwin Plasma Cell tumor-11) is a murine plasma cell myeloma with the H-2d haplotype, commercially available and commonly used for anti-cancer immunotherapy efficacy and other studies. A-20 is a cell line derived from spontaneous reticulum cell sarcoma, commercially available and commonly used for B-cell lymphoma studies, including anti-cancer immunotherapy efficacy and other studies. C1498 is an aggressive acute myeloid leukemia (AML) cell line derived from C57BL / 6 mice, commercially available and commonly used for AML studies, including anti-cancer immunotherapy efficacy and other studies.

[0219] To establish the model, MPC-11, A-20, or C1498 cells were implanted as xenografts into host mice and allowed to engraft and form tumors. Mice were treated with DR IL-18 polypeptide alone (5 IP doses of 0.32 mpk BIW, with the final dose on study day 15), anti-PD-1 antibody alone (5 IP doses of 10 mpk BIW), or the combination of DR IL-18 polypeptide and anti-PD-1 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle alone (i.e., without DR IL-18 polypeptide or any ICI).

[0220] Both DR IL-18 polypeptide monotherapy and DR IL-18 polypeptide + anti-PD-1 antibody ICI combination therapy demonstrated reduced tumor growth compared with vehicle control and anti-PD-1 antibody ICI monotherapy. In addition to tumor growth inhibition, mice were also evaluated for treatment response using a pseudoclinical scoring scale that correlates with the scoring used for partial response (PR) and complete response (CR) in human clinical trials. In the A-20 tumor model, improved responses were observed in mice treated with combination therapy (DR IL-18 polypeptide + anti-PD-1 antibody ICI) compared with DR IL-18 polypeptide monotherapy. Treatment with DR IL-18 polypeptide monotherapy resulted in 60% CR and 40% PR, while treatment with the combination therapy resulted in 87.5% CR and 12.5% ​​PR. In summary, this example demonstrates that combining a DR IL-18 polypeptide with anti-PD-1 ICI therapy has effective anti-heme (e.g., anti-myeloma, anti-B cell lymphoma, and anti-AML) tumor activity that is superior to monotherapy with an anti-PD-1 ICI, and results in an improved therapeutic response compared to DR IL-18 polypeptide monotherapy.

[0221] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0222] Amino acid sequence SEQ ID NO: 35 Wild type IL-18 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 35) SEQ ID NO: 36 Decoy-resistant IL-18 polypeptide #1 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSLARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 36) SEQ ID NO: 37 Decoy-resistant IL-18 polypeptide #2 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKSEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 37) SEQ ID NO: 38 Decoy-resistant IL-18 polypeptide #3 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKGEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 38) SEQ ID NO: 39 Decoy-resistant IL-18 polypeptide #4 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKAEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 39) SEQ ID NO: 40 Decoy-resistant IL-18 polypeptide #5 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKVEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 40) SEQ ID NO: 41 Decoy-resistant IL-18 polypeptide #6 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKDEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 41) SEQ ID NO: 42 Decoy-resistant IL-18 polypeptide #7 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKEEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 42) SEQ ID NO: 43 Decoy-resistant IL-18 polypeptide #8 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKNEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 43)

Claims

1. 1. A method of treating a disease in a subject in need thereof, the method comprising: (a) administering to the subject sequential doses of an anti-PD-1 antibody composition comprising pembrolizumab; and (b) administering to the subject sequential doses of a decoy-resistant (DR) IL-18 composition comprising a polypeptide, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, thereby causing immunotherapy-induced regression of the disease in the subject.

2. 10. The method of claim 1, further comprising administering to the subject a dose of a cytokine release syndrome (CRS) prophylactic agent.

3. The method comprises administering to the subject multiple doses of a CRS prophylactic agent comprising at least one dose of an NSAID and at least one dose of a histamine H1 antagonist, at least one dose of acetaminophen and at least one dose of a histamine H1 antagonist, at least one dose of an NSAID and at least one dose of acetaminophen, or at least one dose of an NSAID, at least one dose of a histamine H1 antagonist, and at least one dose of acetaminophen.

10. The method of any one of the preceding claims, comprising administering to a patient a dose of at least one NSAID selected from indomethacin and ibuprofen, wherein the histamine H1 antagonist is diphenhydramine, and optionally further comprising at least one dose of an H2 blocker, wherein optionally the H2 blocker is famotidine, and optionally the famotidine is oral famotidine administered at a dose of 20 mg to 40 mg or intravenous famotidine administered at a dose of 20 mg.

4. (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day; (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg; (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day; or (iv) any combination thereof.

5. 10. The method of any one of the preceding claims, wherein each dose of the successive doses of the anti-PD-1 antibody composition is administered to the subject about every three weeks, and the anti-PD-1 antibody composition comprises 200 mg of pembrolizumab.

6. 10. The method of any one of the preceding claims, wherein each dose of the DR IL-18 composition of the successive doses is administered to the subject weekly.

7. 10. The method of any one of the preceding claims, wherein said polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:

41.

8. 10. The method of any one of the preceding claims, wherein the dose of the DR IL-18 composition comprises at least about 30 μg of the polypeptide per kg of body weight of the subject.

9. 10. The method of any one of the preceding claims, wherein the disease comprises cancer or a solid tumor.

10. administering to the subject one or more doses of a CRS prophylactic agent with or before each dose of the sequential doses of the DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of an NSAID, a histamine H1 antagonist, acetaminophen, or an H2 blocker; (i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:41; (ii) said dose of said DR IL-18 composition comprises at least about 30 μg of said polypeptide per kg of body weight of said subject; (iii) the dose of the anti-PD-1 antibody composition comprises at least about 200 mg of pembrolizumab; (iv) The method of any one of the preceding claims, wherein the disease comprises a PD-1 checkpoint inhibitor-resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.

11. 1. A method of treating a disease in a human patient, comprising administering to the patient an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a decoy-resistant (DR) IL-18 composition comprising a polypeptide to the subject, wherein the polypeptide is a modified IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 36-43, and the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) comprising the sequence of amino acids set forth in SEQ ID NOs: 1, 2, and 3, and a heavy chain CDR comprising the sequence of amino acids set forth in SEQ ID NOs: 6, 7, and 8.

12. 12. The method of claim 11, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient at a dose of about 200 mg once every three weeks.

13. The method of claim 11 or 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab or a pembrolizumab variant.

14. 14. The method of any one of claims 11-13, wherein the DR IL-18 composition is administered to the patient weekly, optionally wherein the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:41, and optionally wherein the DR IL-18 composition is administered to the patient at a dose of at least about 30 μg of the polypeptide per kg of the patient's body weight.

15. The method of any one of claims 11 to 14, wherein the disease comprises cancer or a solid tumor.

16. 16. The method of claim 15, wherein the cancer or solid tumor is or is associated with melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation / fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor.

17. 16. The method of claim 15, wherein the cancer is a blood cancer, optionally a myeloma, lymphoma, or leukemia.

18. 18. The method of any one of claims 11-17, further comprising administering to the patient a cytokine release syndrome (CRS) prophylactic agent, optionally wherein the CRS prophylactic agent comprises at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, a histamine H1 antagonist, or an H2 blocker.

19. 19. The method of claim 18, wherein the method comprises administering to the patient multiple doses of a CRS prophylaxis agent comprising at least an NSAID and at least a histamine H1 antagonist, at least acetaminophen and at least a histamine H1 antagonist, at least an NSAID and at least acetaminophen, or at least an NSAID, at least a histamine H1 antagonist, and at least acetaminophen, optionally wherein the NSAID is selected from indomethacin and ibuprofen, and the histamine H1 antagonist is diphenhydramine, and optionally further comprising at least an H2 blocker, and optionally wherein the H2 blocker is famotidine.

20. (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day; (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg; (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day; or (iv) any combination thereof.

21. administering to the patient one or more CRS prophylactic agents together with or prior to the DR IL-18 composition, wherein the one or more CRS prophylactic agents comprise an NSAID, a histamine H1 antagonist, acetaminophen, an H2 blocker, or a combination thereof; (i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:41; (ii) said dose of said DR IL-18 composition comprises at least about 30 μg of said polypeptide per kg of said patient's body weight; (iii) the dose of the anti-PD-1 antibody composition comprises at least about 200 mg of pembrolizumab or a pembrolizumab variant; (iv) The method of any one of claims 11 to 20, wherein the disease comprises a PD-1 checkpoint inhibitor-resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelium, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.

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