Methods and compositions for combination therapy

Abstract

The present disclosure provides compositions and methods for treating a disease, such as cancer or a tumor, comprising administering a combination therapy comprising a decoy-resistant (DR) IL-18 polypeptide, or successive doses of a DR IL-18 polypeptide, and an immune checkpoint inhibitor (ICI), or successive doses of an ICI.

Description

METHODS AND COMPOSITIONS FOR COMBINATION THERAPYCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application Nos. 63 / 481,214 filed January 24, 2023 and 63 / 488,384 filed March 3, 3023, each of which applications are incorporated herein by reference in their entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 23, 2024, is named “ST-009-WOl_seqlist.xml” and is 159kb in size.BACKGROUND

[0003] Despite recent advances in cancer therapy, the current statistics on cancer prevalence and mortality in the USA and worldwide indicate that cancer remains a major health challenge. In 2023, it is estimated that over 600,000 people will die of cancer in the United States. Lung cancer is still the leading cause of cancer death globally. Breast cancer is the most common infiltrating cancer in females worldwide, accounting for 16% of cancers in females and 23% of invasive cancers. In the USA, one in every eight women develops breast cancer in her lifetime. Colorectal cancer is the 3rd most common cancer among men and the 2nd most common cancer among women worldwide. While CRC mortality rates have been declining in the USA and Canada, they are increasing in regions like Latin America and the Caribbean.

[0004] Interleukin- 18 (IL-18) is a pro-inflammatory cytokine that can stimulate 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 anti-tumor cells. However, the clinical efficacy of human recombinant IL- 18 has been limited.

[0005] Immune checkpoint inhibitors (ICIs) are binding proteins that bind to and target immune checkpoint proteins thereby enhancing a subject’s immune system to fight a subject’s cancer. ICIs have demonstrated some clinical success in treating at least subsets of a variety of different cancers, including, e.g., non-small cell lung cancer, advanced-stage melanoma, gastric cancer, renal cell carcinoma, glioma, breast cancer brain metastasis, colorectal cancer, bladder cancer, testicular germ cell tumors, cervical squamous cell carcinomas, and head and neck squamous cell carcinomas. However, many cancers develop resistance to ICI treatment and eventually progress, reducing the therapeutic impact of these agents. For example, a proportion of patientswith lung cancer experience long-term clinical benefit with ICIs, but most patients develop disease progression during treatment or after treatment discontinuation.

[0006] Thus, there is a need for compositions and methods that treat and prevent cancer and other diseases and disorders.SUMMARY

[0007] One aspect of the present disclosure provides a method of treating a disease, comprising: (a) administering a composition comprising a decoy -resistant (DR) IL-18 polypeptide or a nucleic acid encoding the DR IL-18 peptide to a subject; and (b) administering a composition comprising an immune checkpoint inhibitor (ICI) that is not pembrolizumab. Such methods may employ various ICIs, including but not necessarily limited to e.g., those selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, finotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing; or the group consisting of Zimberelimab, Nivolumab, Cemiplimab, Dostarlimab, Vopratelimab, Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, INCMGA00012 , Pidilizumab, MEDI0680, SSI-361, AMP-224, Cetrelimab, Prolgolimab, Retifanlimab, Atezolizumab, Avelumab, Durvalumab, Envafolimab, Cosibelimab, CA-170, BMS-986189, BMS-936559, Sugemalimab, Adebrelimab, CBT-502, BGB-A333, Pacmilimab, Ipilimumab, Tremelimumab, Relatlimab, Enoblituzumab, and a variant of any of the foregoing.

[0008] One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a decoy -resistant (DR) composition comprising a DR IL- 18 polypeptide or a nucleic acid encoding the DR IL- 18 polypeptide; (b) an effective amount of an immune checkpoint inhibitor (ICI) composition comprising an ICI, wherein the ICI is not pembrolizumab; and (c) an additional treatment thatincludes a prophylactic agent. Administering such a prophylactic agent may reduce the display of the symptoms of cytokine release syndrome (CRS) in the subject and thus the additional treatment may comprise CRS prophylaxis. CRS prophylaxis includes administering one or more agents, CRS prophylactic agents, to a subject before the onset of CRS in the subject to prevent or reduce the display of the symptoms of CRS in the subject. CRS prophylactic agents (and combinations of CRS prophylactic agents), described in more detail below, may be administered with or before administration of a DR IL-18 composition, including with or before administration of each dose of a DR IL-18 composition where successive DR IL-18 composition doses are employed. Non -limiting examples of useful CRS prophylactic agents include NSAIDs, acetaminophen, diphenhydramine, histamine Hl antagonists, famotidine, and H2 blockers.

[0009] In some embodiments, the prophylactic agent comprises a pain medication. In some embodiments, the pain medication is a non-steroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is selected from the group consisting of ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is diclofenac. In some embodiments, the NSAID is between about 25 mg to about 60 mg. In some embodiments, the NSAID is from about 200 mg to about 600 mg.

[0010] In some embodiments, the pain medication is an analgesic. In some embodiments, the analgesic is selected from the group consisting of acetaminophen, aspirin, caffeine, butalbital, isometheptene mucate, magnesium salicylate, codeine, dihydrocodeine, hydrocodone, oxycodone, tramadol, co-codamol, co-codaprin, co-dydramol, alfentanil, fentanyl, hydromorphone, methadone, morphine, meperidine, and oxymorphone. In some embodiments, the analgesic is acetaminophen. In some embodiments, the analgesic is at least about 500 mg. In some embodiments, the analgesic is at least about 600 mg.

[0011] In some embodiments, the prophylactic agent is an antihistamine. In some embodiments, the antihistamine is a H-l receptor antagonist or a H-2 receptor antagonist. In some embodiments, the antihistamine is a H-l receptor antagonist. In some embodiments, the H-l receptor antagonist is selected from the group consisting of brompheniramine, chlorpheniramine, clemastine, cypropheptadine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine. In some embodiments, the H-l receptor antagonist is diphenhydramine. In some embodiments, the antihistamine is a H-2 receptor antagonist.

[0012] In some embodiments, the H-2 receptor antagonist is selected from the group consisting of cimetidine, famotidine, nizatidine, and ranitidine. In some embodiments, the H-2 receptor antagonist is famotidine. In some embodiments, the antihistamine is at least about 20 mg. In some embodiments, the antihistamine is at least about 40 mg.

[0013] In some embodiments, the prophylactic agent is an anti-infection drug. In some embodiments, the anti-infection drug is a cytokine inhibitor. In some embodiments, the cytokine inhibitor targets the cytokine receptor. In some embodiments, the cytokine receptor is for TNFa, TNFP, IFNa, IFNP, IFNy, IL-6, or IL-12. In some embodiments, the cytokine receptor is IL-6 receptor. In some embodiments, the anti-infection drug is an antibody or a small molecule. In some embodiments, the anti-infection drug is at least about 500 mg.

[0014] In some embodiments, the prophylactic agent comprises a supplemental fluid. In some embodiments, the supplemental fluid is selected from the group consisting of normal saline solution, lactated ringer’s solution, dextrose in water solution, sodium chloride solution, and any combinations thereof. In some embodiments, the supplemental fluid is at most about 3 liters.

[0015] In some embodiments, the prophylactic agent is a steroid. In some embodiments, the steroid is selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone. In some embodiments, the steroid is prednisone. In some embodiments, the steroid is at most about 10 mg / day.

[0016] In some embodiments, the prophylactic agent is administered at least two hours prior to the DR IL-18 polypeptide and the effective amount of the ICI. In some embodiments, the prophylactic agent is administered at least one hour prior to the DR IL- 18 polypeptide and the effective amount of the ICI. In some embodiments, the prophylactic agent is administered intravenously, intramuscularly, subcutaneously, or orally.

[0017] In some aspects of the methods of treatment provided herein, the disease comprises cancer. In some embodiments, the cancer is a solid tumor or a liquid tumor. In some embodiments, the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, ovarian cancer, renal cell carcinoma, urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of head and neck (SCCHN), microsatellite instability high (MSI-H) tumors, high tumor mutation burden (TMB- H) tumors, mismatch repair deficient tumors, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, TNBC, NSCLC, SCCHN, or MSI-H tumors. 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 solidtumor is NSCLC. In some embodiments, the solid tumor is SCCHN. In some embodiments, solid tumor is MSI-H tumors. In some embodiments, the cancer is resistant to one or more ICIs, i.e., the cancer is ICI-resistant, including e.g., where the ICI-resistant caner is melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (with no 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, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof. In some embodiments, the cancer is a liquid tumor selected from the group consisting of: myeloma, B cell lymphoma, and acute myeloid leukemia.

[0018] In some embodiments, the DR IL- 18 polypeptide is administered intravenously or subcutaneously. In some embodiments, the DR IL- 18 polypeptide is administered weekly. In some embodiments, the method results in reduction in tumor size or tumor number in the subject. In some embodiments, the DR IL-18 polypeptide comprises a plurality of mutations relative to wild-type IL- 18, as set forth in SEQ ID NO: 13. In some embodiments, the plurality of mutations comprise a plurality of amino acid substitutions. In some embodiments, the DR IL- 18 polypeptide comprises an amino acid sequence selected from any one of SEQ ID NOs: 1-12 or an amino acid sequence having at least 90%, 95%, or 98% sequence identity to any one of SEQ ID NOs: 1-12.INCORPORATION BY REFERENCE

[0019] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The following detailed description of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0021] FIG. 1 depicts the sequences for the decoy-resistant (DR) IL- 18 polypeptides of SEQ ID NOs: 8-12. The position of each mutated position and corresponding residue in the mature form of wild-type human IL- 18 is indicated at the top of the table. Shaded residues represent the five most conserved mutations. The sequence for the top row (“WT IL-18”) is set forth as SEQ ID NO: 13.

[0022] FIG. 2 depicts substantially reduced CT26 (colorectal) tumor growth in mice treated with a combination of a 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.

[0023] FIG. 3 depicts substantially reduced CT26 (colorectal) tumor growth in mice treated with a combination of a DR-18 and an anti-LAG3 ICI antibody. The y-axis is tumor growth in mm3 and error bars represent standard deviation.

[0024] FIG. 4 depicts reduced MC38 (colorectal) tumor growth in mice treated with a combination of a DR IL- 18 polypeptide and an anti-PD-1 ICI antibody as 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 zoom-in of the area of tumor growth between zero and 1000 mm3.

[0025] FIG. 5 depicts reduced MC38 (colorectal) tumor growth in mice treated with a combination of a DR- 18 and an anti-LAG3 ICI antibody as compared to anti-LAG3 ICI monotherapy. The y-axis is tumor growth in mm3 and error bars represent standard deviation.DETAILED DESCRIPTION

[0026] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0027] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0028] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0029] Although various features of the present disclosure can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present disclosure can be described herein in the context of separate embodiments for clarity, the disclosure can also be implemented in a single embodiment.

[0030] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosure.

[0031] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as“have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure.

[0032] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure.

[0033] Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0034] The term “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -20% or less, + / - 10% or less, + / -5% or less, or + / -1% or less of and from the specified value, insofar such variations are appropriate to perform in the present disclosure. It is to be understood that the value to which the modifier “about” or “approximately” refers is itself also specifically disclosed.

[0035] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0036] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” comprises a biological entity containing expressed genetic materials. In some embodiments, the subject comprises an animal, mammal, or human. In some embodiments, the subject is diagnosed with cancer. In some embodiments, the subject has a solid tumor.

[0037] As used herein, the terms “treat,” “treated,” “treating,” “treatment,” and the like are used in reference to an intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to prevention or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with prevention or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding thatthe subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or a condition, delaying or eliminating the onset of symptoms of a disease or a condition, slowing, halting, or reversing the progression of a disease or a condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease or a condition, or to a subject reporting one or more of the physiological symptoms of a disease or a condition may undergo treatment.

[0038] The term “prevent”, “preventing”, “prevention” and their grammatical equivalents as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.

[0039] The term “therapeutic effect” refers to some extent of relief of one or more of the symptoms of a disorder (e.g., a neoplasia, tumor, or infection by an infectious agent or an autoimmune disease) or its associated pathology. “Therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the cell or subject, in prolonging the survivability of the patient with such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying, and the like beyond that expected in the absence of such treatment. “Therapeutically effective amount” is intended to qualify the amount required to achieve a therapeutic effect. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the “therapeutically effective amount” (e.g., ED50) of the pharmaceutical composition required.

[0040] 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 the regression of or inhibiting the progression of such symptom(s) by any clinically measurable degree. The amount of the agent(s) of the treatment method that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapeutic combination to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. “Treatment” may include one or more of the following: inducing / increasing an antitumor immune response, decreasing the number of one or more tumor markers, halting or delaying the growth of a tumor or blood cancer or progression of disease such as cancer, stabilization of disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, decreasing the level of one or more tumor markers, ameliorating or abrogating the clinical manifestations of disease, reducing the severity or duration of the clinical symptoms, prolonging the survival or patientrelative to the expected survival in a similar untreated patient, and inducing complete or partial remission of a cancerous condition, wherein the disease is cancer.

[0041] The amount of a therapeutic agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom.

[0042] Positive therapeutic effects in cancer can be measured in a number of ways See, W. A. Weber, J. NucL Med. 50: 1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T / C = 42% is the minimum level of anti-tumor activity. A T / C < 10% is considered a high anti -tumor activity level, with T / C (%) = Median tumor volume of the treated / Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a therapy of the disclosure 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 that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere- Terpstra-test and the Wilcoxon-test.

[0043] The terms “neoplasia” and “cancer” refers to any disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Merkel cell carcinoma is one non-limiting example of a cancer. The terms “cancer” or “tumor” or “hyperproliferative disorder” refer to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancercells are often in the form of a tumor, but such cells can exist alone within an animal, or can be a non-tumorigenic cancer cell, such as a leukemia cell.

[0044] The term “liquid tumor” refers to cancers occurring, or the presence of cancerous cells, in bodily fluids. Accordingly, liquid tumors are cancers that affect the blood, bone marrow, and / or lymphatic systems. Liquid tumors include hematological (or “heme” or blood) cancers, such as e.g., a leukemia, a lymphoma, a myelodysplastic syndrome, a myeloproliferative disorder, and myeloma. The most common types of hematological cancers include leukemia, lymphoma, and myeloma. By contrast, a “solid tumor” refers to a grouping of cancerous cells that forms a solid mass in a tissue of a subject, such as bone tissue, muscle tissue, epithelial tissue, organ tissue (e.g., liver, lung, stomach, colon, kidney, or brain tissue), and the like. Types of solid tumors include e.g., carcinomas, sarcomas, lymphomas, melanomas, neuroendocrine tumors, germ cell tumors, gliomas, and the like.

[0045] An “agent” can include any type of molecule and includes, but is not limited to, an antibody, a peptide, a protein, a polynucleotide (e.g., an oligonucleotide, RNA, or DNA), a small molecule, derivatives thereof and analogs thereof.

[0046] The terms “peptide”, “polypeptide” and “protein” are used herein interchangeably to describe a series of at least two amino acids covalently linked by peptide bonds or modified peptide bonds such as isosteres. No limitation is placed on the maximum number of amino acids which may comprise a peptide or protein. Furthermore, the term polypeptide extends to fragments, analogues and derivatives of a peptide, wherein said fragment, analogue or derivative retains the same biological functional activity as the peptide from which the fragment, derivative or analogue is derived. A polypeptide as used herein may be encoded by a recombinant nucleic acid.

[0047] A “fragment” is a portion of a protein or nucleic acid that is substantially identical to a reference protein or nucleic acid. In some embodiments, the portion retains at least 50%, 75%, or 80%, or 90%, 95%, or even 99% of the biological activity of the reference protein or nucleic acid described herein.

[0048] A "functional derivative" or “functional fragment” of a native sequence polypeptide (e.g., antibody) is a compound having a qualitative biological property in common with a native sequence polypeptide. Functional derivatives or fragments include, but are not limited to, fragments of a native sequence and derivatives of a native sequence polypeptide and its fragments, provided that they have a biological activity in common with a corresponding native sequence polypeptide. The terms "derivative" and “fragment” encompass both amino acid sequence variants of polypeptide and covalent modifications thereof.

[0049] As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, 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 pyroglutamate) that may occur when an antibody is recombinantly expressed in host cells (e.g., CHO cells), or during purification / storage. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an 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 comprising an antigen binding fragment thereof that competes with the intact antibody for specific.

[0050] In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody 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. Furthermore, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s 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 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0051] “Variable regions” or “V region” or “V chain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH ” The variable region of the light chain may be referred to as “VL ”

[0052] Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned bythe framework regions, enabling binding to a specific epitope. In general, from N-terminal to C- terminal, both light and heavy chains variable domains comprise 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 is, generally, in accordance with the definitions of 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.

[0053] A “CDR” refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH P-sheet framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved P -sheet framework, and thus are able to adapt to different conformations. Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al- Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea c / a / ., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth 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 skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art and shown below in Table 1. 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 yet 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 yet other embodiments, the CDRs are as defined by the Contact numbering system.Table 1. Correspondence between the CDR Numbering Systems

[0054] “ Chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain contains sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0055] “Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0056] “Humanized antibody” refers to forms of antibodies that contain sequences from nonhuman (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix “hum”, “hu” or “h” may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

[0057] “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 preparationstypically include a multitude 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 population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0058] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions and the ability to bind specifically to the antigen. An antibody that “specifically binds to” PD-1 is an antibody that exhibits preferential binding to PD-1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, will bind to the target protein with an affinity that is at least two-fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.

[0059] Antigen binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g., PD-1). An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy-chain constant regions that correspond to the different 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.

[0060] An "antigen" is a structure to which an antibody can selectively bind. A target antigen may 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, an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.

[0061] An "intact" antibody is one comprising an antigen-binding site as well as a constant domain (CL) and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0062] As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.

[0063] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal, subcutaneous, or topical administration. The therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. A suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.

[0064] The term “variant” when used in relation to an antibody or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, 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) amino acid sequence substitutions, deletions, and / or additions as compared to a native or unmodified sequence. For example, a variant of an antibody may result from oneor more (such as, for example, 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) changes to an amino acid sequence of a native or previously unmodified antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, an antibody variant at least retains the antibody functional activity.

[0065] “Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics e.g., charge, side-chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and / or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4thEd.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below.Table 2. Exemplary Conservative Amino Acid Substitutions

[0066] “RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

[0067] “Cytokine Release Syndrome” or CRS, as used herein, refers to an acute systemic inflammatory syndrome that can be triggered by a variety of factors such as infections and may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies, as well as some non-protein-based cancer drugs. CRS is characterized by a large, rapid increase in cytokines and inflammatory response. Signs and symptoms of CRS include fever, fatigue, nausea, headache, rash, arthralgia, myalgia, rapid heartbeat, hypotension, and trouble breathing. CRS can progress to an uncontrolled systemic inflammatory response with vasopressor-requiring circulatory shock, vascular leakage, disseminated intravascular coagulation, and multi-organ system failure. Patients may have a mild reaction, or reactions may be severe or life threatening. Grading of CRS can be performed according to the Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading system, such as e.g., that described in Lee et al. Biology of Blood andMarrow Transplantation. 25 (2019) 625 - 639; the disclosure of which is incorporated herein by reference in its entirety.

[0068] “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab) alternatively referred to herein as “pembro,” is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs as shown in, e.g., FIG. 6 of US Pat. Pub. No. 20240010727A1 and PCT Pub. No. WO2018183408A1, the disclosures of which are incorporated herein by reference in their entirety. Pembrolizumab has been approved by the U.S. FDA as described in the Prescribing Information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ USA; initial U.S. approval 2014, updated February 2023). The term pembrolizumab includes mAb’s having a structure as described above (Id but which do not include the C-terminal lysine in the heavy chain.Methods

[0069] One aspect of the present disclosure provides methods and compositions for treating a disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a liquid tumor. In some embodiments, the method of treating cancer comprises administering multiple compositions to a subject in the form of a combination therapy. In some embodiments, the compositions administered comprise a DR IL- 18 polypeptide and an ICI, wherein the ICI is not pembrolizumab.

[0070] One aspect of the present disclosure provides a method of treating a disease, comprising: (a) administering a composition comprising a DR IL-18 polypeptide to a subject; and (b) administering a composition comprising an ICI to the subject, wherein the ICI is not pembrolizumab. In some embodiments, the method comprises administering a single composition comprising the DR IL-18 polypeptide and the ICI. In some embodiments, the method comprises a combination therapy that includes administering separate compositions, such as a first compositions comprising the DR IL-18 polypeptide and a second composition comprising the ICI. In some embodiments, the compositions are administered simultaneously. In some embodiments, the compositions are administered sequentially. In some embodiments, the first composition (e.g., a DR IL-18 composition) is administered before the second composition (e.g., a ICI composition). In some embodiments, the first composition (e.g., a DR IL-18 composition) is administered after the second composition (e.g., a ICI composition).

[0071] In some embodiments, one composition of the combination therapy or two or more compositions of the combination therapy is / are administered weekly. In some embodiments, the composition(s) is / are administered every six days. In some embodiments, the composition(s) is / are administered twice a week. In some embodiments, the composition(s) is / are administered daily. In some embodiments, the composition(s) is / are administered every two weeks. In some embodiments, the composition(s) is / are administered every three weeks. In some embodiments, the composition(s) is / are administered monthly. In some embodiments, the composition(s) is / are administered every two months. In some embodiments, the composition(s) is / are administered every three months. In some embodiments, the composition(s) is / are administered every four months. In some embodiments, the composition(s) is / are administered every six months. In some embodiments, the composition(s) is / are administered once a year.

[0072] In some embodiments, the first and second compositions are administered on the same schedule (e.g., both are administered weekly). In some embodiments, the first and second compositions are administered on different schedules (e.g., the first composition is administered daily, and the second composition is administered weekly). For example, the DR IL-18 composition of a combination therapy may be administered weekly and the ICI composition of the combination therapy may be administered less frequently, such as e.g., once every two, three, or four weeks.

[0073] Compositions may be administered according to any appropriate and convenient route, including e.g., orally, subcutaneously, intramuscularly, intravenously, intrathecally, rectally, vaginally, nasally, and the like. In some embodiments, the composition is injected into the patient without dilution.

[0074] In some embodiments, the first and second compositions are administered by the same route (e.g., both are administered subcutaneously). In some embodiments, the first and second compositions are administered by different routes (e.g., the first composition is administered subcutaneously, and the second composition is administered intravenously).

[0075] In some embodiments, the administering the composition results in a reduction in tumor size in the subject. In some embodiments, the administering the composition results in a reduction in tumor number in the subject. In some embodiments, the administering the composition results in a reduction in tumor size and a reduction in tumor number in the subject.

[0076] One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a DR IL-18 polypeptide; and (b) an effective amount of an ICI, wherein the ICI is not pembrolizumab. In some embodiments, the DR IL-18 polypeptide and ICI are administered simultaneously. In some embodiments, the DR IL-18 polypeptide and ICI are administered sequentially. In some embodiments, the DR IL-18 polypeptide is administered before the ICI. In some embodiments, the DR IL-18 polypeptide is administered after the ICI.

[0077] In some embodiments, the DR IL- 18 polypeptide, the ICI, or any combination thereof is administered weekly. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered every six days. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered twice a week. In some embodiments, the composition is administered daily. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered every two weeks. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered every three weeks. In some embodiments, the DR IL- 18 polypeptide, the ICI, or any combination thereof is administered monthly. In some embodiments, the composition is administered every two months. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered every three months. In some embodiments, the DR IL- 18 polypeptide, the ICI, or any combination thereof is administered every four months. In some embodiments, the composition is administered every six months. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered once a year.

[0078] In some embodiments, the DR IL- 18 polypeptide and the ICI are administered on the same schedule (e.g., both are administered weekly). In some embodiments, the DR IL-18 polypeptide and the ICI are administered on different schedules (e.g., the first composition is administered daily, and the second composition is administered weekly).

[0079] In some embodiments, the DR IL- 18 polypeptide and the ICI are fused into one drug product.

[0080] The DR IL-18 polypeptide, the ICI, or any combination thereof may be administered by a variety of routes including e.g., orally, subcutaneously, intramuscularly, intravenously, intrathecally, rectally, vaginally, nasally, and the like. In some embodiments, the DR IL- 18 polypeptide, the ICI, or any combination thereof is administered subcutaneously. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered intramuscularly. In some embodiments, the DR IL- 18 polypeptide, the ICI, or any combination thereof is administered intravenously. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is injected into the patient without dilution.

[0081] In some embodiments, the DR IL- 18 polypeptide and the ICI are administered by the same route (e.g., both are administered subcutaneously). In some embodiments, the DR IL-18 polypeptide and the ICI are administered by different routes (e.g., the first composition is administered subcutaneously, and the second composition is administered intravenously).

[0082] In some embodiments, the administering to the subject the DR IL- 18 polypeptide and ICI results in a reduction in tumor size in the subject. In some embodiments, the administering to the subject the DR IL- 18 polypeptide and ICI results in a reduction in tumor number in the subject. In some embodiments, the administering to the subject the DR IL- 18 polypeptide results in a reduction in tumor size and a reduction in tumor number in the subject.

[0083] Administering such a combination therapy of an ICI and a DR IL- 18 polypeptide as described herein will thereby cause one or more improvements in the condition of the subject, such as e.g., stable disease, immunotherapy-induced regression of the disease, partial response, complete response, or any combination thereof, in the subject.

[0084] Provided is a method of combination therapy that includes treating a subject with cancer, the method comprising administering successive doses of a ICI-containing composition and successive doses of a DR IL-18-containing composition to the subject, wherein the combination therapy causes one or more improvements in the condition of the subject, such as but not limited to e.g., an objective response, a partial response, a complete response, immunotherapy-induced regression of the cancer or tumor, stabilization of disease (e.g., stable disease for at least 12 months), or the like. Administering such a combination therapy of ICI and DR IL-18 polypeptide will thereby cause an improvement in the condition of the subject that is not obtained through administration of either monotherapy alone and / or is greater than an improvement obtained in a corresponding outcome through administration of ICI or DR IL-18 polypeptide monotherapy.

[0085] Observed improvements in the condition of a subject treated according to the methods described herein will vary and may include any result of treating a disease or treating cancer, including any result of treating a disease or treating cancer described herein. For example, thesubject may experience an improvement in one or more symptoms of the condition, e.g., improvement in one or more clinical symptoms of the subject’s cancer. In some instances, a subject may 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 a tumor, combinations thereof, or the like.

[0086] In some instances, the subject may experience a stabilization of disease, such as e.g., a stabilization of the subject’s cancer for some period of time, such as e.g., at least 6 months, at least 12 months, or more. A stable disease is a disease that does not progress, such as e.g., a tumor that does not show substantial growth, as measured using appropriate methods such as computed tomography (CT) or magnetic resonance imaging (MRI) scans, over a predetermined period of time or between two or more relevant timepoints, such as e.g., the start of treatment and 6 months or 12 months after the start of treatment. Stable disease will also include improvements in a subject’s disease that to not reach the level or criteria for a partial response (PR).

[0087] In some instances, a subject may achieve a PR, where the criteria for a PR, as used herein with respect to a cancer or a tumor, is defined, consistent with RECIST guideline (version 1.1), as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. See e.g., Eisenhauer et al. (2009) European Journal of Cancer 45:228- 247, the disclosure of which is incorporated herein by reference in its entirety.

[0088] In some instances, a subject may achieve a complete response (CR), where the criteria for a CR, as used herein with respect to a cancer or a tumor, is defined, consistent with RECIST guideline (version 1.1), as disappearance of all target lesions, where any pathological lymph nodes (whether target or non-target) have a reduction in short axis to less than 10 mm. In some instances, a subject may achieve an objective response (OR), where achieving an OR will generally refer to achieving either a PR or a CR.

[0089] In some instances, a subject with a disease, such as a 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 decrease in severity of the disease or symptoms of the disease, including when the disease does not become completely absent. In cancer, regression generally refers to a decrease in the size of a tumor and / or the extent of cancer in the body of a subject. Disease regression in a subject with a cancer or tumor may manifest as a reduction in the number of tumors, a reduction in the size of one or more tumors, or a combination thereof. Accordingly, cancer or tumor progression and regression may be measured by a variety of means, including but not limited to radiologic imaging, such as e.g., CT and MRI scans. Disease progression and regression generally may be measured by a variety of means,including but not limited to, through radiologic imaging, clinical biomarkers, biopsy (e.g., needle and liquid biopsies), combinations thereof, and the like. Immunotherapy-induced regression represents disease regression that is due to the administration of one or more immunotherapies to the subject, such as e.g., the combination immunotherapy comprising an ICI composition and an DR IL-18 composition as described herein. With regard to a cancer or a tumor, immunotherapy-induced regression therefore refers to a reduction in the number of tumors, a reduction in the size of one or more tumors, or a combination thereof, that is due to the administration of one or more immunotherapies to the subject, such as e.g., the combination immunotherapy comprising an ICI composition and an DR IL- 18 composition as described herein.

[0090] Improvements in the condition of the subject may be expressed as improvements in individual subjects or as improvements over one or more cohorts of multiple subjects. For example, a single subject may achieve stable disease, PR, or CR; or all (i.e., 100%) or some number or percentage (e.g., at least 10%, 25%, 50%, 75%, etc.) of subjects of a cohort may achieve stable disease, PR, CR, or a combination thereof. In some instances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or 90% of a cohort will achieve stable disease lasting at least 12 months. In some instances, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of a cohort will achieve an OR. In some instances, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of a cohort will achieve a PR. In some instances, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of a cohort will achieve a CR. In some instances, a cohort will display multiple improvements in different categories, including e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or 90% of the cohort achieves stable disease and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients of the cohort achieve an OR.Administering decoy -resistant IL- 18 polypeptides

[0091] Methods of the present disclosure include therapies involving the administration of decoy -resistant (DR) IL- 18 polypeptides, including combination therapies that include, as part of a combination therapy, administering a decoy-resistant (DR) IL-18 composition that includes a DR IL-18 polypeptide to a subject. Polypeptides that are “decoy-resistant” variants of IL-18 are designed to be impervious to the decoy receptor IL- 18 binding protein (IL-18BP), which blocks IL-18 from interacting with its receptor, thereby blocking the cytokine’s immunostimulatory activity. The decoy resistant IL-18 polypeptides have been shown in preclinical studies to maintain strong immune stimulation in the tumor microenvironment, even in the presence of IL- 18BP, and are currently in Phase la / 2 clinical development as a monotherapy in solid tumors.

[0092] Decoy-resistant IL- 18 polypeptides bind to, and signal through formation of, the IL- 18Ra (IL-18 receptor a) and IL-18RP (IL-18 receptor P) receptor complex. Decoy -resistant IL- 18 polypeptides do not bind to IL-18BP, or display substantially reduced binding to IL-18BP, such as substantially reduced binding to IL-18BP relative to wild-type (WT) IL-18 (SEQ ID NO: 13) (i.e., as compared to the binding of IL-18BP to WT IL-18 (SEQ ID NO: 13)). In some embodiments, the DR IL- 18 polypeptide employed binds to IL-18Ra and does not bind to IL- 18BP. In some embodiments, the DR IL- 18 polypeptide employed binds to IL-18Ra and has reduced binding to IL-18BP relative to WT IL-18. In some embodiments, the DR IL- 18 polypeptide comprises a modified IL-18 polypeptide comprising: (i) an amino acid sequence having 85% or more (e.g., 90%, 95%, or 98%) sequence identity with the IL-18 variant amino sequence set forth in any one of SEQ ID NO: 10-12; and (ii) mutations at amino acid positions Cysteine-38 and Cysteine-68 relative to wild-type (WT) IL-18 as set forth in SEQ ID NO: 13, thereby promoting IL-18 signaling activity.

[0093] DR IL-18 polypeptides, and compositions comprising DR IL-18 polypeptides, useful in the herein described methods are described in more detail below. Any of the below described DR IL-18 polypeptides may find use in the methods of the present disclosure. In some instances, the methods will employ a DR IL- 18 polypeptide (or a DR IL- 18 composition comprising such a polypeptide) comprising an amino acid sequence having 85% or more (e.g., 90%, 95%, or 98%) sequence identity with the IL-18 variant amino sequence set forth in any one of SEQ ID NO: 1- 12. In some instances, the methods will employ a DR IL-18 polypeptide (or a DR IL-18 composition comprising such a polypeptide) comprising an amino acid sequence having 85% or more (e.g., 90%, 95%, or 98%) sequence identity with the IL-18 variant amino sequence set forth in SEQ ID NO: 5.

[0094] Methods of the present disclosure comprise administering a DR IL- 18 polypeptide to the subject, including where such DR IL-18 polypeptide is administered as part of a DR IL-18 composition. In some embodiments, the method comprises administering a dose (or a composition comprising) between about 10 micrograms of the DR IL- 18 per kilograms of body weight of a subject (pg / kg) to about 1500 pg / kg to the subject. In some embodiments, the method comprises administering a dose (or a composition comprising) between about 10 pg / kg to about 20 pg / kg, between about 20 pg / kg to about 30 pg / kg, between about 30 pg / kg to about 40 pg / kg, between about 40 pg / kg to about 50 pg / kg, between about 50 pg / kg to about 60 pg / kg, between about 60 kg / ug to about 70 pg / kg, between about 70 pg / kg to about 80 pg / kg, between about 80 kg / ug to about 90 pg / kg, between about 90 pg / kg to about 100 pg / kg, between about 100 pg / kg to about 150 pg / kg, between about 150 pg / kg to about 200 pg / kg, between about 200 pg / kg to about 250 pg / kg, between about 250 pg / kg to about 300 pg / kg, betweenabout 300 .g / kg to about 550 gg / kg, between about 350 gg / kg to about 400 gg / kg, between about 400 gg / kg to about 450 gg / kg, between about 450 gg / kg to about 500 gg / kg, between about 500 gg / kg to about 600 gg / kg, between about 600 gg / kg to about 700 gg / kg, between about 700 gg / kg to about 800 gg / kg, between about 800 gg / kg to about 900 gg / kg, between about 900 gg / kg to about 1000 gg / kg, between about 1000 gg / kg to about 1100 gg / kg, between about 1200 gg / kg to about 1300 gg / kg, between about 1300 gg / kg to about 1400 gg / kg, or between about 1400 gg / kg to about 1500 gg / kg of the DR IL-18 polypeptide.

[0095] In some embodiments, the method comprises administering to the subject a dose of (or a composition comprising) at least about 10 gg / kg, at least about 20 gg / kg, at least about 30 gg / kg, at least about 40 gg / kg, at least about 50 gg / kg, at least about 60 gg / kg, at least about 70 gg / kg, at least about 80 gg / kg, at least about 90 gg / kg, at least about 100 gg / kg, at least about 110 gg / kg, at least about 120 gg / kg, at least about 130 gg / kg, at least about 140 gg / kg, at least about 150 gg / kg, at least about 160 gg / kg, at least about 170 gg / kg, at least about 180 gg / kg, at least about 190 gg / kg, at least about 200 gg / kg, at least about 210 gg / kg, at least about 220 gg / kg, at least about 230 gg / kg, at least about 240 gg / kg, at least about 250 gg / kg, at least about 260 gg / kg, at least about 270 gg / kg, at least about 280 gg / kg, at least about 290 gg / kg, at least about 300 gg / kg, at least about 310 gg / kg, at least about 320 gg / kg, at least about 330 gg / kg, at least about 340 gg / kg, at least about 350 gg / kg, at least about 360 gg / kg, at least about 370 gg / kg, at least about 380 gg / kg, at least about 390 gg / kg, at least about 400 gg / kg, at least about 500 gg / kg, at least about 600 gg / kg, at least about 700 gg / kg, at least about 800 gg / kg, at least about 900 gg / kg, at least about 1000 gg / kg, at least about 1100 gg / kg, at least about 1200 gg / kg, at least about 1300 gg / kg, at least about 1400 gg / kg, at least about 1500 gg / kg, or more of the DR IL- 18 polypeptide.

[0096] In some embodiments, the method comprises administering to the subject a dose of (or a composition comprising) at most about 1500 gg / kg, at most about 1400 gg / kg, at most about 1300 gg / kg, at most about 1200 gg / kg, at most about 1100 gg / kg, at most about 1000 gg / kg, at most about 900 gg / kg, at most about 800 gg / kg, at most about 700 gg / kg, at most about 600 gg / kg, at most about 500 gg / kg, at most about 400 gg / kg, at most about 390 gg / kg, at most about 380 gg / kg, at most about 370 gg / kg, at most about 360 gg / kg, at most about 350 gg / kg, at most about 340 gg / kg, at most about 330 gg / kg, at most about 320 gg / kg, at most about 310 gg / kg, at most about 300 gg / kg, at most about 290 gg / kg, at most about 280 gg / kg, at most about 270 gg / kg, at most about 260 gg / kg, at most about 250 gg / kg, at most about 240 gg / kg, at most about 230 gg / kg, at most about 220 gg / kg, at most about 210 gg / kg, at most about 200 gg / kg, at most about 190 gg / kg, at most about 180 gg / kg, at most about 170 gg / kg, at most about 160 gg / kg, at most about 150 gg / kg, at most about 140 gg / kg, at most about 130 gg / kg, atmost about 120 pg / kg, at most about 110 gg / kg, at most about 100 gg / kg, at most about 90 gg / kg, at most about 80 gg / kg, at most about 70 gg / kg, at most about 60 gg / kg, at most about 50 gg / kg, at most about 40 pg / kg, at most about 30 pg / kg, at most about 20 gg / kg, at most about 10 gg / kg, or less of the DR IL-18 polypeptide.

[0097] In some embodiments, the method comprises administering to the subject a dose of (or a composition comprising) about 10 pg / kg, about 20 pg / kg, about 30 pg / kg, about 40 pg / kg, about 50 pg / kg, about 60 pg / kg, about 70 pg / kg, about 80 pg / kg, about 90 pg / kg, about 100 pg / kg, about 110 pg / kg, about 120 pg / kg, about 130 pg / kg, about 140 pg / kg, about 150 pg / kg, about 160 pg / kg, about 170 pg / kg, about 180 pg / kg, about 190 pg / kg, about 200 pg / kg, about 210 pg / kg, about 220 pg / kg, about 230 pg / kg, about 240 pg / kg, about 250 pg / kg, about 260 pg / kg, about 270 pg / kg, about 280 pg / kg, about 290 pg / kg, about 300 pg / kg, about 310 pg / kg, about 320 pg / kg, about 330 pg / kg, about 340 pg / kg, about 350 pg / kg, about 360 pg / kg, about 370 pg / kg, about 380 pg / kg, about 390 pg / kg, about 400 pg / kg, about 500 pg / kg, about 600 pg / kg, about 700 pg / kg, about 800 pg / kg, about 900 pg / kg, about 1000 pg / kg, about 1100 pg / kg, about 1200 pg / kg, about 1300 pg / kg, about 1400 pg / kg, or about 1500 pg / kg of the DR IL-18 polypeptide.

[0098] In some embodiments, the method of treating a disease comprises administering between about 5 mg / ml to about 29 mg / ml of the DR IL-18 polypeptide. In some embodiments, the method of treating a disease comprises administering between about 5 mg / ml to about 10 mg / ml, between about 10 mg / ml to about 15 mg / ml, between about 15 mg / ml to about 20 mg / ml, between about 20 mg / ml to about 25 mg / ml, or between 25 mg / ml to about 29 mg / ml of the DR IL- 18 polypeptide.

[0099] In some embodiments, the method of treating a disease comprises administering at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml, at least about 11 mg / ml, at least about 12 mg / ml, at least about 13 mg / ml, at least about 14 mg / ml, at least about 15 mg / ml, at least about 16 mg / ml, at least about 17 mg / ml, at least about 18 mg / ml, at least about 19 mg / ml, at least about 20 mg / ml, at least about 21 mg / ml, at least about 22 mg / ml, at least about 23 mg / ml, at least about 24 mg / ml, at least about 25 mg / ml, at least about 26 mg / ml, at least about 27 mg / ml, at least about 28 mg / ml, at least about 29 mg / ml, or more of the DR IL-18 polypeptide. In some embodiments, the method of treating a disease comprises administering at most about 29 mg / ml, at most about 28 mg / ml, at most about 27 mg / ml, at most about 26 mg / ml, at most about 25 mg / ml, at most about 24 mg / ml, at most about 23 mg / ml, at most about 22 mg / ml, at most about 21 mg / ml, at most about 20 mg / ml, at most about 19 mg / ml, at most about 18 mg / ml, at most about 17 mg / ml, at most about 16 mg / ml, at most about 15 mg / ml, at most about 14 mg / ml, at most about 13mg / ml, at most about 12 mg / ml, at most about 11 mg / ml, at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, or less of the DR IL- 18 polypeptide. In some embodiments, the method of treating a disease comprises administering about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 11 mg / ml, about 12 mg / ml, about 13 mg / ml, about 14 mg / ml, about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, or about 29 mg / ml of the DR IL-18 polypeptide.

[0100] In some embodiments, the subject is administered between about 10 mg / ml to about 50 mg / ml of the DR IL- 18 polypeptide. In some embodiments, the subject is administered at least about 10 mg / ml, at least about 15 mg / ml, at least about 20 mg / ml, at least about 25 mg / ml, at least about 30 mg / ml, at least about 35 mg / ml, at least about 40 mg / ml, at least about 45 mg / ml, at least about 50 mg / ml, or more of the DR IL-18 polypeptide. In some embodiments, the subject is administered at most about 50 mg / ml, at most about 45 mg / ml, at most about 40 mg / ml, at most about 35 mg / ml, at most about 30 mg / ml, at most about 25 mg / ml, at most about 20 mg / ml, at most about 15 mg / ml, at most about 10 mg / ml, or less of the DR IL-18 polypeptide. In some embodiments, the subject is administered about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml of the DR IL- 18 polypeptide.

[0101] In some embodiments, the composition comprises about 20 mg / ml of the DR IL-18 polypeptide. In some embodiments, the subject is administered about 20 mg / ml of the DR IL-18 polypeptide.

[0102] In some embodiments, the DR IL- 18 polypeptide is a monomer. In some embodiments, the monomer is not in a protein complex. In some embodiments, the monomer is functional as a single polypeptide. In some embodiments, the DR IL- 18 polypeptide is not glycosylated. In some embodiments, the DR IL- 18 polypeptide is glycosylated. In some embodiments, the DR IL-18 polypeptide is partially glycosylated. In some embodiments, the DR IL-18 polypeptide is at least about 50% glycosylated. In some embodiments, the DR IL-18 polypeptide is at most about 50% glycosylated.

[0103] In some embodiments, the DR IL- 18 polypeptide occupies between 10% to about 50% of the IL- 18 receptor. In some embodiments, the DR IL- 18 polypeptide occupies 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 receptor. In some embodiments, the DR IL- 18 polypeptide occupies at most about 50%, at mostabout 45%, at most about 40%, at most about 35%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, or less of the IL- 18 receptor. In some embodiments, the DR 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.

[0104] In some embodiments, the composition comprising the DR IL- 18 polypeptide is administered weekly, every six days, twice a week, daily, every two weeks, every three weeks, monthly, every two months, every three months, every four months, or every six months. In some embodiments, the composition comprising the DR IL- 18 polypeptide is administered once a year.

[0105] In some embodiments, a dose of the DR IL- 18 polypeptide is between about 10 pg / kg to about 50 pg / kg. In some embodiments, a dose of the DR IL- 18 polypeptide is at least about 10 pg / kg, at least about 15 pg / kg, at least about 20 pg / kg, at least about 25 pg / kg, at least about 30 pg / kg, at least about 35 pg / kg, at least about 40 pg / kg, at least about 45 pg / kg, at least about 50 pg / kg, or more. In some embodiments, a dose of the DR IL- 18 polypeptide is at most about 50 pg / kg, at most about 45 pg / kg, at most about 40 pg / kg, at most about 35 pg / kg, at most about 30 pg / kg, at most about 25 pg / kg, at most about 20 pg / kg, at most about 15 pg / kg, at most about 10 pg / kg, or less. In some embodiments, a dose of the DR IL- 18 polypeptide is about 10 pg / kg, about 15 pg / kg, about 20 pg / kg, about 25 pg / kg, about 30 pg / kg, about 35 pg / kg, about 40 pg / kg, about 45 pg / kg, or about 50 pg / kg. In some embodiments, a dose of the DR polypeptide is about 20 pg / kg.

[0106] In some embodiments, the DR IL- 18 polypeptide is administered weekly, every six days, twice a week, daily, every two weeks, every three weeks, monthly, every two months, every three months, every four months, or every six months. In some embodiments, the DR IL-18 polypeptide is administered once a year.

[0107] In some embodiments, the DR IL- 18 polypeptide is administered to the subject about twice weekly, about once per week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, about once every 6 months, about once every 9 months, or about once every 12 months.

[0108] In some embodiments, the DR IL- 18 polypeptide is administered to the subject for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

[0109] In some embodiments, the DR IL- 18 polypeptide is administered until disease progression. In some embodiments, the DR IL- 18 polypeptide is administered until unacceptable toxicity. In some embodiments, the DR IL- 18 polypeptide is administered until disease recurrence.

[0110] In some embodiments, the DR IL- 18 polypeptide is administered up to about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, or about 24 months.[OHl] In some embodiments, administering the composition comprising the DR IL- 18 polypeptide results in a reduction in tumor size in the subject. In some embodiments, the administering the composition comprising the DR IL-18 polypeptide results in a reduction in tumor number in the subject. In some embodiments, the administering the composition comprising the DR IL-18 polypeptide results in a reduction in tumor size and a reduction in tumor number in the subject.

[0112] In some embodiments, the administering the DR IL-18 polypeptide results in a reduction in tumor size in the subject. In some embodiments, the administering the DR IL-18 polypeptide results in a reduction in tumor number in the subject. In some embodiments, the administering the DR IL-18 polypeptide results in a reduction in tumor size and a reduction in tumor number in the subject.

[0113] A DR IL-18 polypeptide as described herein will thereby cause one or more improvements in the condition of the subject, such as e.g., stable disease, immunotherapy- induced regression of the disease, partial response, complete response, or any combination thereof, in the subj ect.

[0114] Such improvements include, but are not limited to e.g., an objective response, a partial response, a complete response, immunotherapy -induced regression of the cancer or tumor, stabilization of disease (e.g., stable disease for at least 12 months), or the like.

[0115] Observed improvements in the condition of a subject treated according to the methods described herein will vary and may include any result of treating a disease or treating cancer, including any result of treating a disease or treating cancer described herein. For example, the subject may experience an improvement in one or more symptoms of the condition, e.g., improvement in one or more clinical symptoms of the subject’s cancer. In some instances, a subject may 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 a tumor, combinations thereof, or the like.

[0116] In some instances, the subject may experience a stabilization of disease, such as e.g., a stabilization of the subject’s cancer for some period of time, such as e.g., at least 6 months, at least 12 months, or more. A stable disease is a disease that does not progress, such as e.g., a tumor that does not show substantial growth, as measured using appropriate methods such as CT or MRI scans, over a predetermined period of time or between two or more relevant timepoints, such as e.g., the start of treatment and 6 months or 12 months after the start of treatment.

[0117] In some instances, a subject may achieve a PR, where the criteria for a PR, as used herein with respect to a cancer or a tumor, is defined, consistent with RECIST guideline (version 1.1. In some instances, a subject may achieve a CR, where the criteria for a CR, as used herein with respect to a cancer or a tumor, is defined, consistent with RECIST guideline (version 1.1). In some instances, a subject may achieve an OR. In some instances, a subject with a disease, such as a cancer or a tumor, may experience immunotherapy -induced regression of the disease, i.e., immunotherapy-induced regression of the cancer or tumor.Administering immune checkpoint inhibitors

[0118] Methods of the present disclosure include combination therapies that include, as part of a combination therapy, administering an immune checkpoint inhibitor (ICI) composition that includes an ICI to a subject, wherein the ICI is not pembrolizumab. ICIs are binding proteins that bind to immune checkpoint proteins thereby enhancing a subject’s immune system to fight a subject’s cancer. Examples of immune checkpoint proteins, including stimulatory and inhibitory molecules, and including receptors and ligands, include, but are not limited to, e.g., LAG-3, MHC-LL, PD-1, PD-L2, PD-L1, TCR, MHC, TIM-3, Galectin-9, GITR, GRTRL, 0X40, OX40L, 4-1BB, 4-1BBL, CD40, CD40L, CD27, CD70, CD28, CD80, CD86, CTLA-4, ICOS, ICOSL, CD155, TIGIT, A2AR, A2BR, B7-H3 (CD276), B7-H4 (VTCN1), BTLA, KIR, N0X2, VISTA, SIGLEC7, and SIGLEC9. ICIs may be binding antagonists, where e.g., binding of the ICI to its target prevents signaling through the immune checkpoint thereby improving the subject’s immune system’s ability to fight the subject’s cancer. Various binding antagonists find use as ICIs in cancer therapy, including e.g., small molecule inhibitors, immunoadhesins, antagonistic antibodies, antibody fragments, antibody fusions, and the like.

[0119] Useful ICIs include therapeutic antibodies and antibody-derived therapeutics, including monospecific and multi-specific (e.g., bi-specific, tri-specific) antibody and antibody-derived therapeutics. Useful monospecific ICI antibody and antibody-derived therapeutics target an immune checkpoint protein. Useful multi-specific ICI antibody and antibody-derived therapeutics target at least one immune checkpoint protein. For example, a bi-specific antibody or antibody-derived therapeutic may be employed that targets at least one immune checkpointprotein. In some instances, a bi-specific antibody or antibody-derived therapeutic may be employed that targets two immune checkpoint proteins. Non-limiting examples of therapeutic antibodies and antibody-derived therapeutics, and there corresponding heavy and light chain amino acid sequences, that are useful as ICIs, including in the herein described methods and compositions are provided below in Table 3.

[0120] Useful ICIs include those targeting the PD-1 / PD-L2 / PD-L1 immune checkpoint s), such as e.g., AMP -224 (a recombinant fusion protein comprised of the extracellular domain of the PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG), Atezolizumab (a monoclonal antibody used to treat advanced or metastatic urothelial carcinoma with disease progression during or up to 12 months after platinum-containing chemotherapy), AUNP-12 (a peptide antagonist of the PD-1 signaling pathway), Avelumab (an anti-PD-Ll monoclonal antibody used to treat metastatic Merkel cell carcinoma, metastatic urothelial carcinoma, or renal cell carcinoma), CA-170 (a selective, small molecule inhibitor of PD-L1), Camrelizumab (a PD-1 inhibitor that works by blocking the interaction between PD-1 and PD- Ll), Cemiplimab (a programmed death receptor- 1 blocking antibody used to treat cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer), Cosibelimab (a high-affinity programmed cell death-ligand 1 (PD-Ll)-blocking antibody), Dostarlimab (an anti- PD-1 monoclonal antibody used in the treatment of mismatch repair deficient endometrial cancers and solid tumours with no alternative treatment options), Durvalumab (an antineoplastic monoclonal antibody used to treat urothelial carcinoma and locally advanced, unresectable non- small cell lung cancer), Envafolimab (a single-domain PD-L1 antibody that is administered by subcutaneous injection), MEDI0680 (a humanized IgG4 mAb specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2)), Nivolumab (a PD- 1 blocking antibody used to treat melanoma, non small-cell lung cancer, renal cell cancer, head and neck cancer, and Hodgkin lymphoma), Retifanlimab (a PD-l-blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma), Sintilimab (an IgG4 anti -PD-1 monoclonal antibody), Spartalizumab (an investigational monoclonal antibody directed against the human programmed death-1 (PD-1) receptor), Tislelizumab (an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable, locally advanced or metastatic esophageal squamous cell carcinoma), Toripalimab (a PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinomas), Cetrelimab (an IgG4, anti-programmed cell death protein-1 (PD-1) antibody), SSI-361 (an anti-PD-1 humanized monoclonal antibody), Pidilizumab (a humanized IgG-1 kappa recombinant mAb directed against human inhibitory receptor programmed cell death 1 (PD-1)), INCMGA00012 (a humanized, hinge-stabilized,immunoglobulin G4K monoclonal antibody that binds to PD-1), Zimberelimab (a fully human IgG4 anti-PD-1 monoclonal antibody that binds human PD-1), Prolgolimab (an IgGl anti-PD-1 monoclonal antibody containing the Fc-silencing ‘LALA’ mutation), BMS-986189 (a macrocyclic peptide PDL1 inhibitor), BMS-936559 (a high-affinity, fully human, PD-L1- specific, IgG4 monoclonal antibody), Sugemalimab (a fully human, full length, anti-PD-Ll IgG4 monoclonal antibody), Adebrelimab (a high-affinity, humanized monoclonal antibody against PD-L1), CBT-502 (a humanized IgGl antibody against PD-L1), BGB-A333 (a humanized monoclonal antibody against PD-L1), and Pacmilimab (a Probody therapeutic directed against PD-L1). In some embodiments, methods and compositions of the present disclosure may include an ICI targeting the PD-1 / PD-L2 / PD-L1 immune checkpoint that is not pembrolizumab, such as e.g., one of the foregoing anti-PD-l / PD-L2 / PD-Ll ICIs.

[0121] Useful ICIs include those targeting the CTLA-4 immune checkpoint, such as e.g., Ipilimumab (a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody used to treat metastatic or unresectable melanoma), and Tremelimumab (an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab). In some embodiments, methods and compositions of the present disclosure may include an ICI targeting the CTLA-4 immune checkpoint, such as e.g., one of the foregoing anti-CTLA-4 ICIs.

[0122] Useful ICIs include those targeting the LAG-3 immune checkpoint, such as e.g., relatlimab (a monoclonal antibody targeted against LAG-3 which is used in combination with nivolumab for the treatment of unresectable or metastatic melanoma) encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, and tuparstobart. In some embodiments, methods and compositions of the present disclosure may include an ICI targeting the LAG-3 immune checkpoint, such as e.g., encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, or tuparstobart.

[0123] Useful ICIs include those targeting the B7-H3 immune checkpoint, such as e.g., Omburtamab (a humanized murine anti-CD276 (B7-H3) antibody) and Enoblituzumab (a monoclonal antibody that targets B7-H3 and has been enhanced using MacroGenics’ Fc Optimization platform). In some embodiments, methods and compositions of the present disclosure may include an ICI targeting the B7-H3 immune checkpoint, such as e.g., Omburtamab and Enoblituzumab.

[0124] One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a DR IL-18 polypeptide; and (b) an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3, wherein the ICI is not pembrolizumab.

[0125] In some embodiments, the ICI is a binding antagonist. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the ICI is an antibody or antigen binding fragment thereof. In some embodiments, the ICI is a monoclonal antibody or antigen binding fragment thereof.

[0126] In some embodiments, the ICI is a PD-1 checkpoint inhibitor. In some embodiments, the PD-1 checkpoint inhibitor is an antibody or antigen binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-1 checkpoint inhibitor is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is an antibody or antigen binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-1 antagonist is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, and AMP-224. In some embodiments, the PD-1 checkpoint inhibitor is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antibody or antigen binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-L1 antagonist is selected from the group consisting of adebrelimab, atezolizumab, avelumab, benm el Stobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.

[0127] In some embodiments, the PD-1 checkpoint inhibitor is CA-170.

[0128] One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a DR IL-18 polypeptide; and (b) an effective amount of an ICI, wherein the ICI is a PD-L1 or PD-L2 antagonist. In some embodiments, the PD-L1 antagonist comprises adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, or any combination thereof. In some embodiments, the ICI is an anti-PD-1 or anti-PD-Ll antibody or antigen binding fragment thereof. In some embodiments, the ICI is an anti-PD-L2 antibody or antigen binding fragment thereof.

[0129] In some embodiments, the ICI is an anti-CTLA-4 antibody or antigen binding fragment thereof. In some embodiments, the ICI is botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, or zalifrelimab.

[0130] In some embodiments, the ICI is an anti-LAG-3 antibody or antigen binding fragment thereof. In some embodiments, the ICI is encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, or tuparstobart.

[0131] In some embodiments, the ICI is an anti-B7-H3 antibody or antigen binding fragment thereof. In some embodiments, the ICI is enoblituzumab, ifinatamab, mirzotamab, omburtamab, or vobramitamab.

[0132] One aspect of the present disclosure provides a method of treating a disease, comprising: (a) administering a composition comprising a DR IL-18 polypeptide to a subject; and (b) administering a composition comprising an ICI selected from the group consisting of Zimberelimab, Nivolumab, Cemiplimab, Dostarlimab, Vopratelimab, Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, INCMGA00012 , Pidilizumab, MED 10680, SSI-361, AMP -224, Cetrelimab, Prolgolimab, Retifanlimab, Atezolizumab, Avelumab, Durvalumab, Envafolimab, Cosibelimab, CA-170, BMS-986189, BMS-936559, Sugemalimab, Adebrelimab, CBT-502, BGB-A333, Pacmilimab, Ipilimumab, Tremelimumab, Relatlimab, Enoblituzumab, and a variant of any of the foregoing.

[0133] One aspect of the present disclosure provides a method of treating a disease, comprising: (a) administering a composition comprising a DR IL-18 polypeptide to a subject; and (b) administering a composition comprising an ICI selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart,enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing.

[0134] In some embodiments, the ICI is administered as an about 1-250 mg / mL, about 1-10 mg / mL, about 10-20 mg / mL, about 20-30 mg / mL, about 30-40 mg / mL, about 40-50 mg / mL, about 50-75 mg / mL, about 75-100 mg / mL, about 100-150 mg / mL, or about 150-250 mg / mL solution.

[0135] In some embodiments, the ICI is administered as an at least about 1-250 mg / mL, at least about 1-10 mg / mL, at least about 10-20 mg / mL, at least about 20-30 mg / mL, at least about 30- 40 mg / mL, at least about 40-50 mg / mL, at least about 50-75 mg / mL, at least about 75-100 mg / mL, at least about 100-150 mg / mL, or at least about 150-250 mg / mL solution.

[0136] In some embodiments, the ICI is administered as an at most about 1-250 mg / mL, at most about 1-10 mg / mL, at most about 10-20 mg / mL, at most about 20-30 mg / mL, at most about 30- 40 mg / mL, at most about 40-50 mg / mL, at most about 50-75 mg / mL, at most about 75-100 mg / mL, at most about 100-150 mg / mL, or at most about 150-250 mg / mL solution.

[0137] In some embodiments, the ICI is administered as an at least about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 200 mg / mL, or about 250 mg / mL solution. In some embodiments, the ICI is administered as a 100 mg / 4 mL (25 mg / mL) solution.

[0138] In some embodiments, the ICI is administered until disease progression. In some embodiments, the ICI is administered until unacceptable toxicity. In some embodiments, the ICI is administered until disease recurrence.

[0139] In some embodiments, the ICI is administered up to about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, or about 24 months.

[0140] In some embodiments, the ratio of an ICI dose and a DR IL-18 polypeptide dose is about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, about 1 : 15, about 1 :20, about 1 :30, about 1 :40, about 1 :50, about 1 :60, about 1 :70, about 1 :80, about 1 :90, about 1 : 100, about 1 : 120, about 1 : 140, about 1 : 160, about 1 : 180, about 1 :200, about 200: 1, about 180: 1, about 160: 1, about 140: 1, about 120: 1, about 100: 1, about 90: 1, about80: 1, about 70: 1, about 60: 1, about 50: 1, about 40: 1, about 30: 1, about 20: 1, about 15: 1, about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, or about 2: 1 mg.

[0141] In some embodiments, the ICI is administered to the subject as a dose of about 0.1 mg / kg to about 20.0 mg / kg body weight of the subject.

[0142] In some embodiments, the ICI is administered to the subject as a dose of about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg body weight of the subject.

[0143] In some embodiments, the ICI is administered to the subject as a dose of at least about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg body weight of the subject.

[0144] In some embodiments, the ICI is administered to the subject as a dose of at most about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg body weight of the subject.

[0145] In some embodiments, the ICI is between about 10 mg / kg to about 50 mg / kg. In some embodiments, the ICI is at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, or more. In some embodiments, the ICI is at most about 50 mg / kg, at most about 45 mg / kg, at most about 40 mg / kg, at most about 35 mg / kg, at most about 30 mg / kg, at most about 25 mg / kg, at most about 20 mg / kg, at most about 15 mg / kg, at most about 10 mg / kg, or less. In some embodiments, the ICI is about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, or about 50 mg / kg. In some embodiments, the ICI is about 20 mg / kg.

[0146] In some embodiments, the ICI is administered to the subject as a dose of at least about 5- 1600 mg, at least about 5-10 mg, at least about 10-20 mg, at least about 20-40 mg, at least about 40-60 mg, at least about 60-80 mg, at least about 80-100 mg, at least about 100-200 mg, at least about 200-300 mg, at least about 300-400 mg, at least about 400-500 mg, at least about 500-600 mg, at least about 700-800 mg, at least about 800-900 mg, at least about 900-1000 mg, at least about 1000-1200 mg, at least about 1200-1400 mg, or at least about 1400-1600 mg.

[0147] In embodiments, the ICI is administered to the subject as a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580mg, about 600 mg, about 640 mg, about 680 mg, about 720 mg, about 760 mg, about 800 mg, about 840 mg, about 880 mg, about 920 mg, about 960 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1120 mg, about 1160 mg, about 1200 mg, about 1280 mg, about 1360 mg, about 1440 mg, about 1520 mg, or about 1600 mg.

[0148] In some embodiments, the ICI is administered to the subject as a dose of at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 560 mg, at least about 580mg, at least about 600 mg, at least about 640 mg, at least about 680 mg, at least about 720 mg, at least about 760 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 920 mg, at least about 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1080 mg, at least about 1120 mg, at least about 1160 mg, at least about 1200 mg, at least about 1280 mg, at least about 1360 mg, at least about 1440 mg, at least about 1520 mg, or at least about 1600 mg.

[0149] In some embodiments, the ICI is administered to the subject as a dose of at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 80 mg, at most about 100mg, at most about 120 mg, at most about 140 mg, at most about 160 mg, at most about 180 mg, at most about 200 mg, at most about 220 mg, at most about 240 mg, at most about 260 mg, at most about 280 mg, at most about 300 mg, at most about 320 mg, at most about 360 mg, at most about 380 mg, at most about 400 mg, at most about 420 mg, at most about 440 mg, at most about 460mg, at most about 480 mg, at most about 500 mg, at most about 520 mg, at most about 540 mg, at most about 560 mg, at most about 580mg, at most about 600 mg, at most about 640 mg, at most about 680 mg, at most about 720 mg, at most about 760 mg, at most about 800 mg, at most about 840 mg, at most about 880 mg, at most about 920 mg, at most about 960 mg, at most about 1000 mg, at most about 1040 mg, at most about 1080 mg, at most about 1120 mg, at most about 1160 mg, at most about 1200 mg, at most about 1280 mg, at most about 1360 mg, at most about 1440 mg, at most about 1520 mg, or at most about 1600 mg.

[0150] In some embodiments, the ICI is administered to the subject about twice weekly, about once per week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, about once every 6 months, about once every 9 months, or about once every 12 months.

[0151] In some embodiments, the ICI is administered as an additional recommended dosage.

[0152] In some embodiments, the ICI is administered to the subject for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

[0153] In some embodiments, the ICI is administered X mg Q8W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q7W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q6W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q5W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q4W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q3W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q2W, wherein X is 10-1600. In some embodiments, the ICI is administered X mg Q1W, wherein X is 10-1600. In some embodiments, X is about 240. In some embodiments, X is about 480. In some embodiments, X is about 200, about 400, about 600, or about 800.

[0154] In some embodiments, the ICI is administered X mg / kg Q8W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q7W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q6W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q5W, wherein X is 0.1-20. In someembodiments, the ICI is administered X mg / kg Q4W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q3W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q2W, wherein X is 0.1-20. In some embodiments, the ICI is administered X mg / kg Q1W, wherein X is 0.1-20. In some embodiments, X is about 2. In some embodiments, X is about 3. In some embodiments, X is about 10. In some embodiments, X is about 3, about 5, or about 10. In some embodiments, X is about 15.

[0155] In some embodiments, the amount of ICI administered is capped at 200 mg. In some embodiments, the subject is a pediatric patient.

[0156] In some embodiments, the ICI is administered for n weeks, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0157] In some embodiments, the ICI is administered to the subject in treatment intervals of about 2-weeks, about 3-weeks, about 4-weeks, about 5-weeks, about 6-weeks, about 7-weeks, about 8-weeks, about 9-weeks, about 10-weeks, about 11 -weeks, about 12-weeks, about 3- months, about 4 months, about 5-months, about 6-months, about 9-months, about 12-months, about 18-months, or about 24-months.

[0158] In some embodiments, the method comprises administering the ICI to the subject according to a dosing regimen of X mg / kg Q1W for n weeks followed by Y mg / kg Q2W, wherein X is 5-20, Y is 10-20, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0159] In some embodiments, the method comprises administering the ICI to the subject according to a dosing regimen of 400-1600 mg Q1W for n weeks followed by 800-1600 mg Q2W, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0160] In some embodiments, the composition comprising the ICI is administered orally. In some embodiments, the composition comprising the ICI is administered subcutaneously. In some embodiments, the composition comprising the ICI is administered intramuscularly. In some embodiments, the composition comprising the ICI is administered intravenously. In some embodiments, the composition comprising the ICI is administered intrathecally. In some embodiments, the composition comprising the ICI is administered rectally. In some embodiments, the composition comprising the ICI is administered vaginally. In some embodiments, the composition comprising the ICI is administered nasally. In some embodiments, the composition comprising the ICI is injected into the patient without dilution.

[0161] In some embodiments, the ICI is administered orally. In some embodiments, the ICI is administered subcutaneously. In some embodiments, the ICI is administered intramuscularly. Insome embodiments, the ICI is administered intravenously. In some embodiments, the ICI is administered intrathecally. In some embodiments, the ICI is administered rectally. In some embodiments, the ICI is administered vaginally. In some embodiments, the ICI is administered nasally. In some embodiments, the ICI is injected into the patient without dilution.

[0162] In some embodiments, the administering the composition comprising the ICI results in a reduction in tumor size in the subject. In some embodiments, the administering the composition comprising the ICI results in a reduction in tumor number in the subject. In some embodiments, the administering the composition comprising the ICI results in a reduction in tumor size and a reduction in tumor number in the subject.

[0163] In some embodiments, the administering the ICI results in a reduction in tumor size in the subject. In some embodiments, the administering the ICI results in a reduction in tumor number in the subject. In some embodiments, the administering the ICI results in a reduction in tumor size and a reduction in tumor number in the subject.Administering additional treatments

[0164] Methods of the present disclosure include combination therapies that include administering a DR IL-18 composition that includes a DR IL-18 polypeptide and an ICI composition that includes an ICI to a subject, wherein the ICI is not pembrolizumab. In addition to administration of the DR IL-18 composition and the ICI composition, the methods, in some embodiments, further include administering one or more additional treatments to the subject. Useful additional treatments include prophylactic treatments that prevent and / or reduce the display of the symptoms of cytokine release syndrome (CRS) in a subject administered the DR IL- 18 composition and ICI composition.

[0165] One aspect of the present disclosure provides methods and compositions for treating a disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a liquid tumor. In some embodiments, the method further comprises administering to the subject an additional treatment. In some embodiments, the additional treatment is a prophylactic agent or agents that prevent and / or reduce the display of the symptoms of CRS in a subject, such as a subject having a solid tumor or liquid tumor and receiving a combination therapy that includes administration of a DR IL-18 composition and an ICI composition.

[0166] CRS may occur in a subject following dosing with a DR IL- 18 composition. In some embodiments, the additional treatment reduces the display of the symptoms of CRS. In some embodiments, the administering the additional treatment reduces the display of the symptoms of CRS as compared to an equivalent subject who did not receive the additional treatment. In someembodiments, administering to the subject the additional treatment results in a reduced display of symptoms of CRS in the subject as compared to an equivalent subject administered about 30 mg / ml or more of the DR IL-18 polypeptide.

[0167] One aspect of the present disclosure provides a method of treating a disease, comprising:(a) administering a composition comprising a DR IL-18 polypeptide to a subject; (b) administering a composition comprising an ICI to the subject, wherein the ICI is not pembrolizumab; and (c) administering a composition comprising an additional treatment. In some embodiments, the additional treatment is a prophylactic agent. In some embodiments, the prophylactic agent is a CRS prophylactic agent that reduces the display of the symptoms of CRS in the subject.

[0168] One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a DR IL-18 polypeptide;(b) an effective amount of an ICI, wherein the ICI is not pembrolizumab, and (c) an additional treatment. In some embodiments, the additional treatment is a prophylactic agent. In some embodiments, the prophylactic agent is a CRS prophylactic agent that reduces the display of the symptoms of CRS in the subject.

[0169] Consistent with the definitions provided above, 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 and thus, reference herein to administration of an additional treatment agent or a CRS prophylactic agent or a dose will refer to administration of one or to more than one agents (i.e., one or more agents), CRS prophylactic agents (i.e., one or more CRS prophylactic agents), to administration of one or to more than one dose (i.e., one or more doses), to administration of at least one agent, to administration of at least one CRS prophylactic agent, or to administration of at least one dose. Administration of one or more CRS prophylactic agents may be referred to herein as CRS prophylaxis.

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

[0171] One aspect of the present disclosure provides methods for treating a disease in a subject in need thereof. In some embodiments, the disease is cancer, such as a solid tumor or liquidtumor. One aspect of the present disclosure provides methods of treating the cancer in the subject comprising (a) administering successive doses of an ICI composition, wherein the ICI is not Pembrolizumab to the subject; (b) administering successive doses of a DR IL- 18 composition comprising a DR IL- 18 polypeptide to the subject, wherein the DR IL- 18 polypeptide comprises an amino acid sequence set forth in any one of SEQ ID Nos: 1-12; and (c) administering CRS prophylaxis to the subject. In some embodiments, the CRS prophylaxis comprises administering a CRS prophylactic agent with or before the DR IL- 18 composition, including with or before a dose or each dose of successive doses of the DR IL-18 composition. In some embodiments, the method comprises administering a dose of a CRS prophylactic agent to the subject with or before each dose of the successive doses of the DR IL- 18 composition. In some embodiments, the dose of the CRS prophylactic agent comprises at least one of a NSAID, acetaminophen, diphenhydramine, histamine Hl antagonist, famotidine, H2 blocker, or fluid administered to the subject. In some embodiments, the dose of the CRS prophylactic agent is administered to the subject orally or intravenously.

[0172] In some embodiments, the CRS prophylactic agent is administered orally. In some embodiments, one or more CRS prophylactic agents of CRS prophylaxis are administered orally. In some embodiments, the CRS prophylactic agent is administered subcutaneously. In some embodiments, one or more CRS prophylactic agents of CRS prophylaxis are administered subcutaneously. In some embodiments, the CRS prophylactic agent is administered intramuscularly. In some embodiments, one or more CRS prophylactic agents of CRS prophylaxis are administered intramuscularly. In some embodiments, the CRS prophylactic agent is administered intravenously. In some embodiments, one or more CRS prophylactic agents of CRS prophylaxis are administered intravenously. In some embodiments, the CRS prophylactic agent is administered intrathecally. In some embodiments, the CRS prophylactic agent is administered rectally. In some embodiments, the CRS prophylactic agent is administered vaginally. In some embodiments, the CRS prophylactic agent is administered nasally. In some instances, multiple routes of administration are employed, including e.g., where one or more CRS prophylactic agents of a CRS prophylaxis regimen are administered orally and one or more CRS prophylactic agents of the CRS prophylaxis regimen are administered intravenously.

[0173] In some embodiments, the CRS prophylactic agent is administered hourly. In some embodiments, the CRS prophylactic agent is administered about every several hours. In some embodiments, the CRS prophylactic agent is administered twice daily. In some embodiments, the CRS prophylactic agent is administered daily. In some embodiments, the CRS prophylactic agent is administered every six days. In some embodiments, the CRS prophylactic agent isadministered twice a week. In some embodiments, the CRS prophylactic agent is administered weekly. In some embodiments, the CRS prophylactic agent is administered every two weeks. In some embodiments, the CRS prophylactic agent is administered every three weeks. In some embodiments, the CRS prophylactic agent is administered monthly. In some embodiments, the CRS prophylactic agent is administered every two months. In some embodiments, the CRS prophylactic agent is administered every three months. In some embodiments, the CRS prophylactic agent is administered every four months. In some embodiments, the CRS prophylactic agent is administered every six months. In some embodiments, the CRS prophylactic agent is administered once a year.

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

[0175] In some embodiments, CRS prophylaxis reduces the display of the symptoms of CRS in a subject administered a combination therapy comprising a DR IL-18 composition, including where the display of symptoms are reduced relative to a subject administered the same therapy without CRS prophylaxis. In some embodiments, CRS prophylaxis reduces the display of the symptoms of CRS in a subject administered a combination therapy comprising administration of a DR IL-18 composition comprising at least about 30 pg / kg or more of a DR-IL-18 polypeptide, including where the display of symptoms are reduced relative to a subject administered the sametherapy without CRS prophylaxis. In some embodiments, CRS prophylaxis reduces the display of the symptoms of CRS in a subject administered an ICI composition and DR IL-18 composition combination therapy, including where the display of symptoms are reduced relative to a subject administered the same therapy without CRS prophylaxis.

[0176] In some embodiments, administration of CRS prophylaxis will prevent the onset or progression of CRS in a subject administered a combination therapy that comprises administration of a DR IL-18 composition comprising a DR-IL-18 polypeptide, including e.g., at least about 30 pg / kg or more of a DR- IL-18 polypeptide. For example, administration of CRS prophylaxis will prevent the onset of or progression to grade 5 CRS, grade 4 CRS or higher, and / or grade 3 CRS or higher, including e.g., where CRS grading is performed according to 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, a lack of onset or progression of CRS may be indicated by a lack of fever (temp, greater than or equal to 38 deg. C), a lack of hypotension, hypotension that does not require vasopressors, hypotension requiring only one vasopressor with or without vasopressin, a lack of hypoxia, hypoxia requiring only low-flow nasal canula or blow-by, hypoxia requiring high-flow nasal-canula (or facemask, nonrebreather mask, or venturi mask) but not requiring positive pressure, or a combination thereof.

[0177] In some embodiments, CRS prophylaxis in a subject administered a combination therapy that comprises administration of a DR IL-18 composition comprising a DR-IL-18 polypeptide, including e.g., at least about 30 pg / kg or more of a DR-IL-18 polypeptide, will negate the need for later treating the subject for CRS. For example, in some instances, CRS prophylaxis in such scenarios will mean that administration of immunosuppressants, such as, e.g., corticosteroids (e.g., glucocorticoids), anti-interleukin 6 (IL-6) agents (e.g., tocilizumab, siltuximab, clazakizumab), TNF-a signaling inhibitors (e.g., etanercept), T cell-depleting antibodies (e.g., alemtuzumab), IL-lR-based inhibitors (e.g., anakinra), cyclophosphamide, Bruton’s tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), combinations thereof, and the like will not be necessary and will not be administered. In some embodiments, a subject receiving CRS prophylaxis and administered a combination therapy that comprises administration of a DR IL- 18 composition comprising a DR-IL-18 polypeptide, including e.g., at least about 30 pg / kg or more of a DR-IL- 18 polypeptide, will not require and will not be administered an immunosuppressant to treat CRS. For example, in some instances, such a subject will not be administered any corticosteroids (e.g., glucocorticoids) and / or any anti-interleukin 6 (IL-6) agents during a cycle of the combination therapy or during the entire course of the combination therapy.

[0178] In some embodiments, the CRS prophylactic agent is at least one of a non-steroidal antiinflammatory drug (NS AID), acetaminophen, diphenhydramine, histamine Hl antagonist, famotidine, H2 blocker, or fluids.

[0179] In some embodiments, the additional treatment is an agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NS AID), acetaminophen, diphenhydramine, a histamine Hl antagonist, famotidine, an H2 blocker, tocilizumab, and any combination thereof.

[0180] In some embodiments, a single composition comprises the additional treatment, the DR IL-18 polypeptide, and the ICI. In some embodiments, two or more compositions comprise the additional treatment, the DR IL-18 polypeptide, and the ICI. In some embodiments, the method comprises administering a first composition comprising the DR IL- 18 polypeptide and the ICI and a second composition comprising the additional treatment. In some embodiments, the method comprises administering a first composition comprising the DR IL-18 polypeptide and the additional treatment and a second composition comprising the ICI. In some embodiments, the method comprises administering a first composition comprising the DR IL- 18 polypeptide and a second composition comprising the ICI and the additional treatment.

[0181] In some embodiments, the additional treatment, such as CRS prophylaxis, is administered prior to the administering of the DR IL-18 polypeptide. In some embodiments, the additional treatment is administered simultaneously to the administering of the DR IL- 18 polypeptide. In some embodiments, the additional treatment is administered after the administering of the DR IL-18 polypeptide.

[0182] In some embodiments, the additional treatment, such as CRS prophylaxis, is administered prior to the administering of the ICI. In some embodiments, the prophylactic agent is administered simultaneously to the administering of the ICI. In some embodiments, the prophylactic agent is administered after the administering of the ICI.

[0183] In some embodiments, the additional treatment is administered orally. In some embodiments, the additional treatment is administered subcutaneously. In some embodiments, the additional treatment is administered intramuscularly. In some embodiments, the additional treatment is administered intravenously. In some embodiments, the additional treatment is administered intrathecally. In some embodiments, the additional treatment is administered rectally. In some embodiments, the additional treatment is administered vaginally. In some embodiments, the additional treatment is administered nasally.

[0184] In some embodiments, the additional treatment is administered hourly. In some embodiments, the additional treatment is administered about every several hours. In some embodiments, the additional treatment is administered twice daily. In some embodiments, theadditional treatment is administered daily. In some embodiments, the additional treatment is administered every six days. In some embodiments, the additional treatment is administered twice a week. In some embodiments, the additional treatment is administered weekly. In some embodiments, the additional treatment is administered every two weeks. In some embodiments, the additional treatment is administered every three weeks. In some embodiments, the additional treatment is administered monthly. In some embodiments, the additional treatment is administered every two months. In some embodiments, the additional treatment is administered every three months. In some embodiments, the additional treatment is administered every four months. In some embodiments, the additional treatment is administered every six months. In some embodiments, the additional treatment is administered once a year.NSAID

[0185] In some embodiments, the additional treatment, such as CRS prophylaxis, includes a non-steroidal anti-inflammatory drug (NSAID), and thus a CRS prophylactic agent employed in the combination therapy is a NSAID. In some embodiments, the NSAID is administered to the subject between about 1 hour to 2 hours prior to administering a dose of the DR IL- 18 composition. In some embodiments, the NSAID is administered to the subject for 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 between 200 mg to 600 mg every 6 to 8 hours. In some embodiments, the NSAID is administered to the subject orally. In some embodiments, the NSAID is administered to the subject intravenously.

[0186] 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, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is indomethacin. In some embodiments, the NSAID is naproxen. In some embodiments, the NSAID is aspirin. In some embodiments, the NSAID is between about 25 mg to about 600 mg. In some embodiments, the NSAID is between about 25 mg to about 50 mg, between about 50 mg to about 75 mg, between about 75 mg to about 100 mg, between about 100 mg to about 125 mg, between about 125 mg to about 150 mg, between about 150 mg to about 175 mg, between about 175 mg to about 200 mg, between about 200 mg to about 225 mg, between about 225 mg to about 250 mg, between about 250 mg to about 275 mg, between about 275 mg to about 300 mg, between about 300 mg to about 325 mg, between about 325 mg to about 350 mg, between about 350 mg to about 375 mg, between about375 mg to about 400 mg, between about 400 mg to about 425 mg, between about 425 mg to about 450 mg, between about 450 mg to about 475 mg, between about 475 mg to about 500 mg, between about 500 mg to about 525 mg, between about 525 mg to about 550 mg, between about 550 mg to about 575 mg, or between 575 mg to about 600 mg. In some embodiments, the NSAID is between about 200 mg to about 600 mg.

[0187] 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.

[0188] In some embodiments, the NSAID is at most about 600 mg, at most about 575 mg, at most about 550 mg, at most about 525 mg, at most about 500 mg, at most about 475 mg, at most about 450 mg, at most about 425 mg, at most about 400 mg, at most about 375 mg, at most about 350 mg, at most about 325 mg, at most about 300 mg, at most about 275 mg, at most about 250 mg, at most about 225 mg, at most about 200 mg, at most about 175 mg, at most about 150 mg, at most about 125 mg, at most about 100 mg, at most about 75 mg, at most about50 mg, at most about 25 mg, or less.

[0189] 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.Acetaminophen

[0190] In some embodiments, the additional treatment, such as CRS prophylaxis, includes acetaminophen, and thus a CRS prophylactic agent employed in the combination therapy 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 for at least 24 hours after administering a dose of the DR IL-18 composition. In some embodiments, the acetaminophen is administered to the subject at 650 mg every 4 to 6 hours beginning 1 hour prior to administering a dose of the DR IL-18 composition. In some embodiments, the acetaminophen is administered for at least 48 hours after administering a dose of the DR IL- 18 composition. In some embodiments, the acetaminophen is administered to the subject orally. In some embodiments, the acetaminophen is administered to the subject intravenously.

[0191] In some embodiments, the acetaminophen is between about 200 mg to about 800 mg. In some embodiments, the acetaminophen is between about 600 mg to about 800 mg.

[0192] 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.Histamine Hl antagonists

[0193] In some embodiments, the additional treatment, such as CRS prophylaxis, includes a histamine Hl antagonist, and thus a CRS prophylactic agent employed in the combination therapy is a histamine Hl antagonist. In some embodiments the histamine Hl antagonist is administered at 50 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL-18 composition. In some embodiments, the histamine Hl antagonist is administered intravenously. In some embodiments, the histamine Hl antagonist is administered orally.

[0194] Non-limiting examples of histamine Hl antagonists include brompheniramine, clemastine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine, mepyramine, chlorpheniramine, promethazine, cyproheptadine. In some embodiments, the histamine Hl antagonist is between about 20 to about 100 mg. In some embodiments, the histamine Hl antagonist 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 histamine Hl 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 Hl antagonist 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 histamine Hl antagonist is about 50 mg.Diphenhydramine

[0195] In some embodiments, the additional treatment, such as CRS prophylaxis, includes diphenhydramine, and thus a CRS prophylactic agent employed in the combination therapy is diphenhydramine. In some embodiments the diphenhydramine is administered at 50 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL-18 composition. In some embodiments, the diphenhydramine is administered intravenously. In some embodiments, the diphenhydramine is administered orally.

[0196] In some embodiments, the diphenhydramine is between 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.H2 blocker

[0197] In some embodiments, the additional treatment, such as CRS prophylaxis, includes a histamine H2 antagonist (H2 blocker), and thus a CRS prophylactic agent employed in the combination therapy is a H2 blocker. In some embodiments, the H2 blocker is administered at 20 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL-18 composition. In some embodiments, the H2 blocker is administered intravenously. In some embodiments, the H2 blocker is administered at between 20 mg to 40 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL- 18 composition. In some embodiments, the H2 blocker is administered orally.

[0198] In some embodiments, the H2 blocker is famotidine, cimetidine, ranitidine, or nizatidine. In some embodiments, the H2 blocker is famotidine. 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 between 10 mg to about 60 mg. In some embodiments, the H2 blocker is between 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.Famotidine

[0199] In some embodiments, the additional treatment, such as CRS prophylaxis, includes famotidine, and thus a CRS prophylactic agent employed in the combination therapy is famotidine. In some embodiments, the famotidine is administered at 20 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL-18 composition. In some embodiments, the famotidine is administered intravenously. In some embodiments, the famotidine is administered at between 20 mg to 40 mg about 30 minutes to 60 minutes prior to administering a dose of the DR IL-18 composition. In some embodiments, the famotidine is administered orally.

[0200] In some embodiments, the famotidine is between 10 mg to about 60 mg. In some embodiments, the famotidine is between 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.Fluids

[0201] In some embodiments, a subject has hypotension or is at risk of having hypotension. In some embodiments, administering the dose of the CRS prophylactic agent comprises administering a fluid to the subject. In some embodiments, the fluid comprises at most 3 liters of fluid (e.g., water, juice, sports drink, or IV fluids) within 24 hours after administering a dose of the DR IL-18 composition. In some embodiments, the fluid is administered intravenously. In some embodiments, the fluid is administered orally.

[0202] In some embodiments, the additional treatment is tocilizumab. In some embodiments, the tocilizumab is between about 400 mg to about 1000 mg. In some embodiments, the tocilizumab is between about 500 mg to about 900 mg. In some embodiments, the tocilizumab is 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, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, or more. In some embodiment, the tocilizumab is at most about 1000 mg, at most about 950 mg, at most about 900 mg, at most about 850 mg, 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 least about 400 mg, or less. In some embodiments, the tocilizumab is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.

[0203] In some embodiments, administering the additional treatment results in a reduced display of symptoms of cytokine release syndrome (CRS). Non-limiting examples of symptoms of CRS include fever, chills, tiredness, nausea, vomiting, diarrhea, headache, cough, low blood pressure, joint pain, muscle pain, skin rash, shortness of breath, confusion, dizziness, difficulty swallowing, increased heart rate, reduced heart function, irregular heartbeat, organ failure, and swelling. In some embodiments, the administering results in a reduced display of symptoms of cytokine release syndrome as compared to an equivalent subject administered between about 30 mg / ml to about 100 mg / ml of the DR IL- 18 polypeptide. In some embodiments, the administering results in a reduced display of symptoms of cytokine release syndrome as compared to a corresponding subject having been administered an equivalent therapy comprising between about 30 mg / ml to about 100 mg / ml of the DR IL-18 composition. In some embodiments, the administering results in a reduced display of symptoms of CRS as compared to an equivalent subject administered between about 30 mg / ml to about 40 mg / ml, between about 40 mg / ml to about 50 mg / ml, between about 50 mg / ml to about 60 mg / ml, between about 60 mg / ml to about 70 mg / ml, between about 70 mg / ml to about 80 mg / ml, between about 80 mg / ml to about 90 mg / ml, or between about 90 mg / ml to about 100 mg / ml of the DR IL- 18 polypeptide. In some embodiments, the administering results in a reduced display of symptoms of CRS as compared to a corresponding subject having been administered an equivalent therapy between about 30 mg / ml to about 40 mg / ml, between about 40 mg / ml to about 50 mg / ml, between about 50 mg / ml to about 60 mg / ml, between about 60 mg / ml to about 70 mg / ml, between about 70 mg / ml to about 80 mg / ml, between about 80 mg / ml to about 90 mg / ml, or between about 90 mg / ml to about 100 mg / ml of the DR IL- 18 composition.

[0204] In some embodiments, the administering results in a reduced display of symptoms of CRS as compared to an equivalent subject (or compared to a corresponding subject having been administered an equivalent therapy) administered at least about 30 mg / ml, at least about 35 mg / ml, at least about 40 mg / ml, at least about 45 mg / ml, at least about 50 mg / ml, at least about 55 mg / ml, at least about 60 mg / ml, at least about 65 mg / ml, at least about 70 mg / ml, at least about 75 mg / ml, at least about 80 mg / ml, at least about 85 mg / ml, at least about 90 mg / ml, at least about 95 mg / ml, at least about 100 mg / ml, or more of the DR IL- 18 polypeptide. In some embodiments, the administering results in a reduced display of symptoms of CRS as compared to an equivalent subject (or compared to a corresponding subject having been administered an equivalent therapy) administered at most about 100 mg / ml, at most about 95 mg / ml, at most about 90 mg / ml, at most about 85 mg / ml, at most about 80 mg / ml, at most about 75 mg / ml, at most about 70 mg / ml, at most about 65 mg / ml, at most about 60 mg / ml, at most about 55 mg / ml, at most about 50 mg / ml, at most about 45 mg / ml, at most about 40 mg / ml, at most about 35mg / ml, at most about 30 mg / ml, or less of the DR IL- 18 polypeptide. In some embodiments, the administering results in a reduced display of symptoms of CRS as compared to an equivalent subject (or compared to a corresponding subject having been administered an equivalent therapy) administered about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, or about 100 mg / ml of the DR IL- 18 polypeptide.CRS prophylaxis combinations

[0205] Any of the herein described groups of CRS prophylactic agents and individual CRS prophylactic agents and any of the herein described method of using such groups and individual CRS prophylactic agents may be combined into a useful CRS prophylaxis combination.

[0206] For example, in some embodiments, CRS prophylaxis administered to a subject will include at least a NSAID and at least a histamine Hl antagonist; at least acetaminophen and at least a histamine Hl antagonist; at least a NSAID and at least acetaminophen; or at least a NSAID, at least a histamine Hl antagonist, and at least acetaminophen. Such NSAID, histamine Hl antagonist, and acetaminophen used in such combinations may be administered according to the administration and / or dosing of each agent as described herein. In some embodiments, CRS prophylaxis administered to a subject will include 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 may be administered according to the administration and / or dosing of each agent as described herein. In some embodiments, such combinations will further include an H2 blocker, including e.g., where the H2 blocker used is famotidine and the famotidine is administered according to the administration and / or dosing described herein.

[0207] In some embodiments, CRS prophylaxis will include at least an NSAID, a histamine Hl antagonist, and acetaminophen, including e.g., where (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day (inc., e.g., at 75 mg per day), or oral ibuprofen administered at 600 mg to 2,400 mg per day (inc. e.g., at 800 mg to 1,800 mg per day); (ii) the histamine Hl antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg (inc. e.g., a dose of 50 mg); and (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day (inc. e.g., at 650 mg to 3,900 mg per day). In some embodiments, such a combination will further include an H2 blocker, including e.g., where theH2 blocker used is famotidine and the famotidine is administered according to the administration and / or dosing described herein.

[0208] In some embodiments, a CRS prophylaxis combination described herein will reduce the display of one or more symptoms of CRS, including reducing the one or more symptoms as compared to a subject administered the same treatment protocol without the CRS prophylaxis. In some embodiments, a CRS prophylaxis combination described herein, such as the combination described above, will prevent a subject with cancer, treated with a combination therapy that includes administration of DR IL-18 composition comprising a DR IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1-12 (such as, e.g., SEQ ID NO: 5), from experiencing one or more (including all) symptoms of grade 3 or higher CRS or grade 4 CRS. In some embodiments, a CRS prophylaxis combination described herein, such as the combination described above, will prevent a subject with cancer, treated with a combination therapy that includes administration of 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: 1-12 (such as, e.g., SEQ ID NO:5), from requiring treatment for CRS, including treatment with one or more (or any) immunosuppressants, such as e.g., a corticosteroid, an anti-interleukin 6 (IL-6) agents (such as e.g., tocilizumab), or any combination thereof.Indications of the subject

[0209] One aspect of the present disclosure provides methods 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.

[0210] In some embodiments, the compositions and methods of the disclosure are useful for treating a tumor or cancer that is resistant to ICIs. Examples of ICIs include, but are not limited to: anti-PDl agents such as an anti-PDl antibody (e.g., acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, and AMP-224), anti-PD-Ll agents such as an anti-PD-Ll antibody (e.g., adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, andBGB-A333), anti-PD-L2 agents such as an anti-PD-L2 antibody, anti-CTLA4 (e.g., botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, and zalifrelimab), anti-TIM3 (e.g., cobolimab, sabatolimab, surzebiclimab, and verzi stobart), anti- TIGIT (e.g., belrestotug, dargistotug, domvanalimab, etigilimab, lancastotug, ociperlimab, ralzapastotug, renvistobart, tamgiblimab, tiragolumab, and vibostolimab), anti-LAG3 (e.g., encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, and tuparstobart), anti-B7H3 (e.g., enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab), anti-B7H4 (e.g., alsevalimab, puxitatug), anti-VISTA (onvatilimab), anti- BTLA, anti-CD47 (e.g., lemzoparlimab, letaplimab, ligufalimab, magrolimab, urabrelimab), anti-SIRP alpha (e.g., anzurstobart, epacmarstobart), anti-CD48, anti-CD155, anti-CD160, anti- TREM2 (e.g., iluzanebart), anti-IDOl, anti- Adenosine 2 A receptor, anti- Aryl hydrocarbon receptor, anti -KIR, and anti-LILRB2. Examples of targets of ICIs include but are not limited to: PD-L1, PD1, CTLA4, TIM3, TIGIT, LAG3, B7H3, B7H4, VISTA, BTLA, CD47, SIRP alpha, CD48, CD155, CD160, TREM2, IDO1, Adenosine 2A receptor, Aryl hydrocarbon receptor, KIR, and LILRB2, or any combination thereof.

[0211] In some embodiments, the disease is cancer. Cancer can be a hyperproliferation of cells which 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 growth of cells or tissues, (e.g., of malignant type or benign type).

[0212] In some embodiments, the cancer is leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma and / or sarcoma. Non-limiting examples of cancers include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, 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 e.g., hepatocellular carcinoma) , lung cancer e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, 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., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma. Additional non-limiting examples of cancer include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small celllung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, 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 Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, and prostate cancer.

[0213] 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.

[0214] In some embodiments, the cancer is leukemia. Leukemia can be progressive, malignant diseases of the blood-forming organs and can have distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia can be clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Non-limiting examples of leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairycell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0215] In some embodiments, the cancer is sarcoma. Sarcoma can be a tumor which can be made up of a substance like the embryonic connective tissue and can be composed of closely packed cells embedded in a fibrillar and / or homogeneous substance. Non-limiting examples of sarcomasinclude a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewings sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin’s sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0216] In some embodiments, the cancer is melanoma. Melanoma can be a tumor arising from the melanocytic system of the skin and other organs. Non-limiting examples of melanomas include acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanomajuvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0217] 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, lip cancer, oral cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), nonmelanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

[0218] 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 head and neck (SCCHN), microsatellite instability high (MSI-H) tumors, high tumor mutation burden (TMB- H) tumors, mismatch repair deficient tumors, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof.

[0219] In some embodiments, the solid tumor is melanoma, renal cell carcinoma, triple-negative breast cancer, NSCLC, SCCHN, or MSI-H tumors. 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 MSI-H tumors.

[0220] In some embodiments, cancer or solid tumor is associated with melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer (HNSCC), classical Hodgkin Lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSLH) or mismatch repair deficient cancer (dMMR) cancer, microsatellite instability -high or mismatch repair deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophageal or gastroesophageal junction cancer, esophageal or gastroesophageal junction adenocarcinoma, locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinoma, malignant pleural mesothelioma, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial carcinoma, liver cancer, tumor mutational burden-high (TMB-H) cancer, cutaneous squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.

[0221] In some embodiments, the cancer or solid tumor is resistant to ICI checkpoint inhibitors and is associated with melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer (HNSCC), classical Hodgkin Lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability- high (MSI-H) or mismatch repair deficient cancer (dMMR) cancer, microsatellite instability- high or mismatch repair deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophageal or gastroesophageal junction cancer, esophageal or gastroesophageal junction adenocarcinoma, locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinoma, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial carcinoma, liver cancer, tumor mutational burden-high (TMB-H) cancer, cutaneous squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.

[0222] In some embodiments, the cancer or solid tumor is associated with melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (with no 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, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof, and wherein the cancer or solid tumor is resistant to PD-1 checkpoint inhibitors.

[0223] In some embodiments, the cancer or solid tumor is associated with platinum-resistant ovarian cancer or microsatellite stable colorectal cancer.Compositions

[0224] One aspect of the present disclosure provides therapeutic compositions for treating a disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the therapeutic composition comprises a DR IL- 18 polypeptide. In some embodiments, the therapeutic composition comprises an ICI, wherein the ICI is not pembrolizumab.

[0225] One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) an ICI, wherein the ICI is not pembrolizumab. In some embodiments, a single therapeutic composition comprises the DR IL- 18 polypeptide and the ICI. In some embodiments, a first therapeutic composition comprises the DR IL- 18 polypeptide and a second therapeutic composition comprises the ICI.

[0226] In some embodiments, the DR IL- 18 polypeptide and the ICI are fused into one drug product.Compositions comprising a DR IL-18 polypeptide

[0227] Provided herein, including for use in the methods described herein, are compositions that comprise a DR IL-18 polypeptide, i.e., DR IL-18 compositions. Useful DR IL-18 polypeptides, including DR IL-18 polypeptides useful in such DR IL-18 compositions may vary.

[0228] In some embodiments, the DR IL- 18 polypeptide has between 60-100% sequence identity to any one of SEQ ID nOs: 1-12. In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 1. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 1. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 1.

[0229] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 2. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 2. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 2.

[0230] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 3. In some embodiments, the DR IL- 18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 3. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 3.

[0231] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 4. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 4. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 4.

[0232] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 5. In some embodiments, the DR IL- 18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 5. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 5.

[0233] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 6. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 6. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 6.

[0234] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 7. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 7. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 7.

[0235] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 8. In some embodiments, the DR IL- 18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 8. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 8.

[0236] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 9. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 9. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 9.

[0237] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 10. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 10. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 10.

[0238] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 11. In some embodiments, the DR IL- 18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 11. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 11.

[0239] In some embodiments, the DR IL- 18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% sequence identity to SEQ ID NO: 12. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 12. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 12.

[0240] In some embodiments, the DR IL- 18 polypeptide has mutations relative to wild-type (WT) IL-18. In some embodiments, WT IL-18 is SEQ ID NO: 13. In some embodiments, theIL-18 DR polypeptide has 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 WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the IL- 18 DR polypeptide has about two mutations, about three mutations, about four mutations, about five mutations, about six mutations, about seven mutations, about eight mutations, about nine mutations, or about ten mutations, relative to WT IL- 18 as set forth in SEQ ID NO: 13.

[0241] In some embodiments, the IL- 18 DR polypeptide has a mutation at amino acid position C38, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the IL- 18 DR polypeptide has a mutation at amino acid position C68, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the IL- 18 DR polypeptide has mutations at amino acid positions C38 and C68, relative to WT IL-18 as set forth in SEQ ID NO: 13.

[0242] In some embodiments, the mutation at amino acid position C38 is a substitution mutation. In some embodiments, the mutation at amino acid position C38 is a C38S substitution, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a substitution mutation. In some embodiments, the mutation at amino acid position C68 is a C68S substitution, a C68G substitution, a C68A substitution, a C68V substitution, a C68D substitution, a C68E substitution, or a C68N substitution, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68S substitution, relative to WT IL-18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68G substitution, as relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68A substitution, relative to WT IL-18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68V substitution, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68D substitution, relative to WT IL-18 as set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68D substitution, relative to WT IL-18 as set forth is SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68E substitution, relative to WT IL-18 as set forth in SEQ ID NO: 13 In some embodiments, the mutation at amino acid position C68 is a C68N substitution, relative to WT IL-18 as set forth in SEQ ID NO: 13.

[0243] In some embodiments, the DR IL- 18 polypeptide has at least one mutation (e.g., at least 2, at least 3, at least 4, at least 5, or at least 6 mutations) at an amino acid position selected from the group consisting of Yl, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, DI 10, N111, Ml 13, V153, and N155, relative to WT IL- 18 as set forth in SEQ ID NO: 13. Insome embodiments, the DR IL- 18 polypeptide has at least 4 mutations at amino acid positions selected from the group consisting of Yl, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, DI 10, Nl l l, Ml 13, V153, and N155, relative to WT IL-18 as set forth in SEQ ID NO: 13. In some embodiments, the DR IL- 18 polypeptide has at least 6 mutations at amino acid positions selected from the group consisting of Yl, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, DUO, Nl l l, Ml 13, V153, and N155, relative to WT IL-18 as set forth in SEQ ID NO: 13. In some embodiments, the DR IL- 18 polypeptide has at least one mutation (e.g., at least 2, at least 3, at least 4, at least 5, or at least 6 mutations) at an amino acid position selected from the group consisting of Yl, L5, K8, S55, Q56, P57, G59, E77, Q103, S105, DUO, Nl l l, Ml 13, V153, and N155, relative to WT IL- 18 as set forth in SEQ ID NO: 13. In some embodiments, the DR IL-18 polypeptide has at least one mutation (e.g., at least 2, at least 3, at least 4, at least 5, or at least 6 mutations) at an amino acid position selected from the group consisting of Y1H, Y1R, LSH, L51, LSY, K8Q, K8R, M51T, M51K, M51D, M51N, M51E, M51R, K53R, K53G, K53S, K53T, S55K, S55R, Q56E, Q56A, Q56R, Q56V, Q56G, Q56K, Q56L, P57L, P57G, P57A, P57K, G59T, G59A, M60K, M60Q, M60R, M60L, E77D, Q103E, Q103K, Q103P, Q103A, Q103R, S105R, S105D, S105K, S105N, S105A, D110H, D110K, DI ION, DI 10Q, DI 10E, DI 10S, DI 10G, N111H, N111 Y, N11 ID, N111R, N11 IS, N111G, Ml 13 V, M113R, M113T, M113K, V1531, V153T, V153A, N155K, and N155H, relative to WT IL- 18 as set forth in SEQ ID NO: 13. Examples of mutations in DR IL- 18 polypeptides relative to WT IL-18 (SEQ ID NO: 13) are shown in FIG. 1.

[0244] Decoy-resistant IL- 18 polypeptides bind to, and signal through formation of, the IL- 18Ra (IL-18 receptor a) and IL-18RP (IL-18 receptor P) receptor complex. Decoy -resistant IL- 18 polypeptides do not bind to IL-18BP, or display substantially reduced binding to IL-18BP, such as substantially reduced binding to IL-18BP relative to wild-type (WT) IL-18 (SEQ ID NO: 13) (i.e., as compared to the binding of IL-18BP to WT IL-18 (SEQ ID NO: 13)). In some embodiments, the DR IL- 18 polypeptide does not bind to IL- 18 binding protein (IL-18BP). In some embodiments, the DR IL- 18 polypeptide has reduced binding to IL-18BP relative to WT IL-18. In some embodiments, the DR IL- 18 polypeptide binds to IL-18Ra and does not bind to IL-18BP. In some embodiments, the DR IL-18 polypeptide binds to IL-18Ra and has reduced binding to IL-18BP relative to WT IL-18. In some embodiments, the DR IL-18 polypeptide is a monomer. In some embodiments, the monomer is not in a protein complex. In some embodiments, the monomer is functional as a single polypeptide. In some embodiments, the DR IL-18 polypeptide is not glycosylated. In some embodiments, the DR IL-18 polypeptide is glycosylated. In some embodiments, the DR IL-18 polypeptide is partially glycosylated. In someembodiments, the DR IL-18 polypeptide is at least about 50% glycosylated. In some embodiments, the DR IL-18 polypeptide is at most about 50% glycosylated.

[0245] In some embodiments, the DR IL- 18 polypeptide occupies between 10% to about 50% of the IL- 18 receptor. In some embodiments, the DR IL- 18 polypeptide occupies 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 receptor. In some embodiments, the DR IL- 18 polypeptide occupies at most about 50%, at most about 45%, at most about 40%, at most about 35%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, or less of the IL- 18 receptor. In some embodiments, the DR 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.

[0246] In some embodiments, the composition comprises between about 10 micrograms of the DR IL-18 per kilograms of body weight of a subject (pg / kg) to about 1500 pg / kg. In some embodiments, the composition comprises between about 10 pg / kg to about 20 pg / kg, between about 20 pg / kg to about 30 pg / kg, between about 30 pg / kg to about 40 pg / kg, between about 40 pg / kg to about 50 pg / kg, between about 50 pg / kg to about 60 pg / kg, between about 60 kg / ug to about 70 pg / kg, between about 70 pg / kg to about 80 pg / kg, between about 80 kg / ug to about 90 pg / kg, between about 90 pg / kg to about 100 pg / kg, between about 100 pg / kg to about 150 pg / kg, between about 150 pg / kg to about 200 pg / kg, between about 200 pg / kg to about 250 pg / kg, between about 250 pg / kg to about 300 pg / kg, between about 300 pg / kg to about 550 pg / kg, between about 350 pg / kg to about 400 pg / kg, between about 400 pg / kg to about 450 pg / kg, between about 450 pg / kg to about 500 pg / kg, between about 500 pg / kg to about 600 pg / kg, between about 600 pg / kg to about 700 pg / kg, between about 700 pg / kg to about 800 pg / kg, between about 800 pg / kg to about 900 pg / kg, between about 900 pg / kg to about 1000 pg / kg, between about 1000 pg / kg to about 1100 pg / kg, between about 1200 pg / kg to about 1300 pg / kg, between about 1300 pg / kg to about 1400 pg / kg, or between about 1400 pg / kg to about 1500 pg / kg of the DR IL- 18 polypeptide.

[0247] In some embodiments, the composition comprises at least about 10 pg / kg, at least about 20 pg / kg, at least about 30 pg / kg, at least about 40 pg / kg, at least about 50 pg / kg, at least about 60 pg / kg, at least about 70 pg / kg, at least about 80 pg / kg, at least about 90 pg / kg, at least about 100 pg / kg, at least about 110 pg / kg, at least about 120 pg / kg, at least about 130 pg / kg, at least about 140 pg / kg, at least about 150 pg / kg, at least about 160 pg / kg, at least about 170 pg / kg, at least about 180 pg / kg, at least about 190 pg / kg, at least about 200 pg / kg, at least about 210 pg / kg, at least about 220 pg / kg, at least about 230 pg / kg, at least about 240 pg / kg, at least about 250 pg / kg, at least about 260 pg / kg, at least about 270 pg / kg, at least about 280 pg / kg, at leastabout 290 pg / kg, at least about 300 gg / kg, at least about 310 gg / kg, at least about 320 gg / kg, at least about 330 pg / kg, at least about 340 pg / kg, at least about 350 pg / kg, at least about 360 pg / kg, at least about 370 gg / kg, at least about 380 gg / kg, at least about 390 gg / kg, at least about 400 gg / kg, at least about 500 gg / kg, at least about 600 gg / kg, at least about 700 gg / kg, at least about 800 gg / kg, at least about 900 gg / kg, at least about 1000 gg / kg, at least about 1100 gg / kg, at least about 1200 gg / kg, at least about 1300 gg / kg, at least about 1400 gg / kg, at least about 1500 gg / kg, or more of the DR IL-18 polypeptide.

[0248] In some embodiments, the composition comprises at most about 1500 pg / kg, at most about 1400 pg / kg, at most about 1300 pg / kg, at most about 1200 pg / kg, at most about 1100 pg / kg, at most about 1000 pg / kg, at most about 900 pg / kg, at most about 800 pg / kg, at most about 700 pg / kg, at most about 600 pg / kg, at most about 500 pg / kg, at most about 400 pg / kg, at most about 390 pg / kg, at most about 380 pg / kg, at most about 370 pg / kg, at most about 360 pg / kg, at most about 350 pg / kg, at most about 340 pg / kg, at most about 330 pg / kg, at most about 320 pg / kg, at most about 310 pg / kg, at most about 300 pg / kg, at most about 290 pg / kg, at most about 280 pg / kg, at most about 270 pg / kg, at most about 260 pg / kg, at most about 250 pg / kg, at most about 240 pg / kg, at most about 230 pg / kg, at most about 220 pg / kg, at most about 210 pg / kg, at most about 200 pg / kg, at most about 190 pg / kg, at most about 180 pg / kg, at most about 170 pg / kg, at most about 160 pg / kg, at most about 150 pg / kg, at most about 140 pg / kg, at most about 130 pg / kg, at most about 120 pg / kg, at most about 110 pg / kg, at most about 100 pg / kg, at most about 90 pg / kg, at most about 80 pg / kg, at most about 70 pg / kg, at most about 60 pg / kg, at most about 50 pg / kg, at most about 40 pg / kg, at most about 30 pg / kg, at most about 20 pg / kg, at most about 10 pg / kg, or less of the DR IL- 18 polypeptide.

[0249] In some embodiments, the composition comprises about 10 pg / kg, about 20 pg / kg, about 30 pg / kg, about 40 pg / kg, about 50 pg / kg, about 60 pg / kg, about 70 pg / kg, about 80 pg / kg, about 90 pg / kg, about 100 pg / kg, about 110 pg / kg, about 120 pg / kg, about 130 pg / kg, about 140 pg / kg, about 150 pg / kg, about 160 pg / kg, about 170 pg / kg, about 180 pg / kg, about 190 pg / kg, about 200 pg / kg, about 210 pg / kg, about 220 pg / kg, about 230 pg / kg, about 240 pg / kg, about 250 pg / kg, about 260 pg / kg, about 270 pg / kg, about 280 pg / kg, about 290 pg / kg, about 300 pg / kg, about 310 pg / kg, about 320 pg / kg, about 330 pg / kg, about 340 pg / kg, about 350 pg / kg, about 360 pg / kg, about 370 pg / kg, about 380 pg / kg, about 390 pg / kg, about 400 pg / kg, about 500 pg / kg, about 600 pg / kg, about 700 pg / kg, about 800 pg / kg, about 900 pg / kg, about 1000 pg / kg, about 1100 pg / kg, about 1200 pg / kg, about 1300 pg / kg, about 1400 pg / kg, or about 1500 pg / kg of the DR IL- 18 polypeptide.

[0250] In some embodiments, the composition comprises about 20 pg / kg of the DR IL-18 polypeptide. In some embodiments, the composition comprises about 30 pg / kg of the DR IL-18polypeptide. In some embodiments, the composition comprises about 90 pg / kg of the DR IL- 18 polypeptide. In some embodiments, the composition comprises about 180 pg / kg of the DR IL- 18 polypeptide. In some embodiments, the composition comprises about 360 pg / kg of the DR IL-18 polypeptide. In some embodiments, the composition comprises about 600 pg / kg of the DR IL-18 polypeptide. In some embodiments, the composition comprises about 900 pg / kg of the DR IL-18 polypeptide. In some embodiments, the composition comprises about 1200 pg / kg of the DR IL- 18 polypeptide per body weight of the subject.

[0251] In some embodiments, the composition comprises between about 5 milligrams per milliliter (mg / ml) to about 50 mg / ml of the DR IL-18 polypeptide. In some embodiments, the composition comprises between about 5 mg / ml to about 10 mg / ml, between about 10 mg / ml to about 29 mg / ml, between 30 mg / ml to about 50 mg / ml of the DR IL-18 polypeptide.

[0252] In some embodiments, the composition comprises at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml, at least about 11 mg / ml, at least about 12 mg / ml, at least about 13 mg / ml, at least about 14 mg / ml, at least about 15 mg / ml, at least about 16 mg / ml, at least about 17 mg / ml, at least about 18 mg / ml, at least about 19 mg / ml, at least about 20 mg / ml, at least about 21 mg / ml, at least about 22 mg / ml, at least about 23 mg / ml, at least about 24 mg / ml, at least about 25 mg / ml, at least about 26 mg / ml, at least about 27 mg / ml, at least about 28 mg / ml, at least about 29 mg / ml, at least about 30 mg / ml, at least about 31 mg / ml, at least about 32 mg / ml, at least about 33 mg / ml, at least about 34 mg / ml, at least about 35 mg / ml, at least about 36 mg / ml, at least about 37 mg / ml, at least about 38 mg / ml, at least about 39 mg / ml, at least about 40 mg / ml, at least about 41 mg / ml, at least about 42 mg / ml, at least about 43 mg / ml, at least about 44 mg / ml, at least about 45 mg / ml, at least about 46 mg / ml, at least about 47 mg / ml, at least about 48 mg / ml, at least about 49 mg / ml, at least about 50 mg / ml, or more of the DR IL-18 polypeptide.

[0253] In some embodiments, the composition comprises at most about 50 mg / ml, at most about 49 mg / ml, at most about 49 mg / ml, at most about 48 mg / ml, at most about 47 mg / ml, at most about 46 mg / ml, at most about 45 mg / ml, at most about 44 mg / ml, at most about 43 mg / ml, at most about 43 mg / ml, at most about 42 mg / ml, at most about 41 mg / ml, at most about 40 mg / ml, at most about 39 mg / ml, at most about 38 mg / ml, at most about 37 mg / ml, at most about 36 mg / ml, at most about 35 mg / ml, at most about 34 mg / ml, at most about 33 mg / ml, at most about 32 mg / ml, at most about 31 mg / ml, at most about 30 mg / ml, at most about 29 mg / ml, at most about 28 mg / ml, at most about 27 mg / ml, at most about 26 mg / ml, at most about 25 mg / ml, at most about 24 mg / ml, at most about 23 mg / ml, at most about 22 mg / ml, at most about 21 mg / ml, at most about 20 mg / ml, at most about 19 mg / ml, at most about 18 mg / ml, at most about 17 mg / ml, at most about 16 mg / ml, at most about 15 mg / ml, at most about 14 mg / ml, at most about13 mg / ml, at most about 12 mg / ml, at most about 11 mg / ml, at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, or less of the DR IL-18 polypeptide.

[0254] In some embodiments, the composition comprises about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 11 mg / ml, about 12 mg / ml, about 13 mg / ml, about 14 mg / ml, about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, about 29 mg / ml, about 30 mg / ml, about 31 mg / ml, about 32 mg / ml, about 33 mg / ml, about 34 mg / ml, about 35 mg / ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml, about 44 mg / ml, about 45 mg / ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml, about 50 mg / ml, or more of the DR IL- 18 polypeptide.Formulation

[0255] Compositions of the present disclosure, useful in the methods of the present disclosure, may be formulated with a DR IL-18 polypeptide as described herein, one or more ICIs, or both a DR IL-18 polypeptide and one or more ICIs. Compositions of the present disclosure may include one or more formulation agents, including e.g., a buffering agent, a stabilizer, surfactant, an anti-oxidation agent, solvent, or any combination thereof.

[0256] In some embodiments, in addition to an amount of the DR IL-18 polypeptide, an amount of one or more ICIs, or amounts of both, the composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from the group consisting of: L-Histidine, L- Histidine Hydrochloride, Phosphate, Tris, Citrate, Glycine, Diethanolamine (DEA), and any combination thereof. In some embodiments, the buffering agent is L-Histidine. In some embodiments, the embodiments, the buffering agent is L-Histidine Hydrochloride. In some embodiments, the buffering agent is L-Histidine and L-Histidine Hydrochloride.

[0257] In some embodiments, the composition comprises between about 1 mg / ml to about 2 mg / ml, between about 1 mg / ml to about 5 mg / ml, between about 5 mg / ml to about 10 mg / ml, between about 10 mg / ml to about 20 mg / ml, between about 20 mg / ml to about 30 mg / ml, between about 30 mg / ml to about 40 mg / ml, or between about 40 mg / ml to about 50 mg / ml of the buffering agent. In some embodiments, the composition comprises at least about 1 mg / ml, at least about 2 mg / ml, at least about 3 mg / ml, at least about 4 mg / ml, at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml, at least about 15 mg / ml, at least about 20 mg / ml, at least about 25 mg / ml,at least about 30 mg / ml, at least about 35 mg / ml, at least about 40 mg / ml, at least about 45 mg / ml, at least about 50 mg / ml, or more of the buffering agent.

[0258] In some embodiments, the composition comprises at most about 50 mg / ml, at most about 45 mg / ml, at most about 40 mg / ml, at most about 35 mg / ml, at most about 30 mg / ml, at most about 35 mg / ml, at most about 30 mg / ml, at most about 25 mg / ml, at most about 20 mg / ml, at most about 15 mg / ml, at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, at most about 4 mg / ml, at most about 3 mg / ml, at most about 2 mg / ml, at most about 1 mg / ml, or less of the buffering agent. In some embodiments, the composition comprises about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml of the buffering agent.

[0259] In some embodiments, in addition to an amount of the DR IL-18 polypeptide, an amount of one or more ICIs, or amounts of both, the composition further comprises a stabilizer. In some embodiments, the stabilizer is selected from the group consisting of: glycerol, sucrose, glucose, therhalose, ethylene glycol, glycerol, erythritol, threitol, arabitol, ethylenediaminetetraacetic acid (EDTA), disodium salt of EDTA, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetritol, polyglycitol, and any combination thereof. In some embodiments, the stabilizer is sucrose. In some embodiments, the stabilizer is EDTA. In some embodiments, the stabilizer is a disodium salt of EDTA. In some embodiment, the stabilizer comprises sucrose and EDTA. In some embodiments, the stabilizer comprises sucrose and the disodium salt of EDTA. In some embodiments, the stabilizer comprises EDTA and the disodium salt of EDTA. In some embodiments, the stabilizer comprises sucrose, EDTA, and disodium salt of EDTA.

[0260] In some embodiments, the composition comprises between about 20 mg / ml to about 200 mg / ml of the stabilizer. In some embodiments, the composition comprises between about 20 mg / ml to about 30 mg / ml, between about 30 mg / ml to about 40 mg / ml, between about 40 mg / ml to about 50 mg / ml, between about 50 mg / ml to about 60 mg / ml, between about 60 mg / ml to about 99 mg / ml, between about 60 mg / ml to about 70 mg / ml, between about 70mg / ml to about 99 mg / ml, between about 70 mg / ml to about 80 mg / ml, between about 90 mg / ml to about 100 mg / ml, between about 100 mg / ml to about 110 mg / ml, between about 110 mg / ml to about 120 mg / ml, between about 120 mg / ml to about 130 mg / ml, between about 130 mg / ml to about 140 mg / ml, between about 140 mg / ml to about 150 mg / ml, between about 150 mg / ml to about 160 mg / ml, between about 160 mg / ml to about 170 mg / ml, between about 170 mg / ml to about 180mg / ml, between about 180 mg / ml to about 190 mg / ml, between about 190 mg / ml to about 200 mg / ml of the stabilizer.

[0261] In some embodiments, the composition comprises at least about 20 mg / ml, at least about 25 mg / ml, at least about 30 mg / ml, at least about 35 mg / ml, at least about 40 mg / ml, at least about 45 mg / ml, at least about 50 mg / ml, at least about 55 mg / ml, at least about 60 mg / ml, at least about 65 mg / ml, at least about 70 mg / ml, at least about 71 mg / ml, at least about 72 mg / ml, at least about 73 mg / ml, at least about 73 mg / ml, at least about 74 mg / ml, at least about 75 mg / ml, at least about 76 mg / ml, at least about 77 mg / ml, at least about 78 mg / ml, at least about 79 mg / ml, at least about 80 mg / ml, at least about 81 mg / ml, at least about 82 mg / ml, at least about 83 mg / ml, at least about 84 mg / ml, at least about 85 mg / ml, at least about 86 mg / ml, at least about 87 mg / ml, at least about 88 mg / ml, at least about 89 mg / ml, at least about 90 mg / ml, at least about 91 mg / ml, at least about 92 mg / ml, at least about 93 mg / ml, at least about 94 mg / ml, at least about 95 mg / ml, at least about 96 mg / ml, at least about 97 mg / ml, at least about 98 mg / ml, at least about 99 mg / ml, at least about 100 mg / ml, at least about 110 mg / ml, at least about 120 mg / ml, at least about 130 mg / ml, at least about 140 mg / ml, at least about 150 mg / ml, at least about 160 mg / ml, at least about 170 mg / ml, at least about 180 mg / ml, at least about 190 mg / ml, at least about 200 mg / ml, or more of the stabilizer.

[0262] In some embodiments, the composition comprises at most about 200 mg / ml, at most about 190 mg / ml, at most about 180 mg / ml, at most about 170 mg / ml, at most about 160 mg / ml, at most about 150 mg / ml, at most about 140 mg / ml, at most about 130 mg / ml, at most about 120 mg / ml, at most about 110 mg / ml, at most about 100 mg / ml, at most about 99 mg / ml, at most about 98 mg / ml, at most about 97 mg / ml, at most about 96 mg / ml, at most about 95 mg / ml, at most about 94 mg / ml, at most about 93 mg / ml, at most about 92 mg / ml, at most about 91 mg / ml, at most about 90 mg / ml, at most about 89 mg / ml, at most about 88 mg / ml, at most about 87 mg / ml, at most about 86 mg / ml, at most about 85 mg / ml, at most about 84 mg / ml, at most about 83 mg / ml, at most about 82 mg / ml, at most about 81 mg / ml, at most about 80 mg / ml, at most about 79 mg / ml, at most about 78 mg / ml, at most about 77 mg / ml, at most about 76 mg / ml, at most about 75 mg / ml, at most about 74 mg / ml, at most about 73 mg / ml, at most about 72 mg / ml, at most about 71 mg / ml, at most about 70 mg / ml, at most about 65 mg / ml, at most about 60 mg / ml, at most about 55 mg / ml, at most about 50 mg / ml, at most about 45 mg / ml, at most about 40 mg / ml, at most about 35 mg / ml, at most about 30 mg / ml, at most about 25 mg / ml, at most about 20 mg / ml, or less of the stabilizer.

[0263] In some embodiments, the composition comprises about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70, about 71 mg / ml, about 72 mg / ml, about 73mg / ml, about 74 mg / ml, about 75 mg / ml, about 76 mg / ml, about 77 mg / ml, about 78 mg / ml, about 79 mg / ml, about 80 mg / ml, about 81 mg / ml, about 82 mg / ml, about 83 mg / ml, about 84 mg / ml, about 85 mg / ml, about 86 mg / ml, about 87 mg / ml, about 88 mg / ml, about 89 mg / ml, about 90 mg / ml, about 91 mg / ml, about 92 mg / ml, about 93 mg / ml, about 94 mg / ml, about 95 mg / ml, about 96 mg / ml, about 97 mg / ml, about 98 mg / ml, about 99 mg / ml, about 100 mg / ml, about 110 mg / ml, about 120 mg / ml, about 130 mg / ml, about 140 mg / ml, about 150 mg / ml, about 160 mg / ml, about 170 mg / ml, about 180 mg / ml, about 190 mg / ml, or about 100 mg / ml of the stabilizer.

[0264] In some embodiments, in addition to an amount of the DR IL-18 polypeptide, an amount of one or more ICIs, or amounts of both, the composition further comprises a surfactant. In some embodiments, the surfactant is an anionic surfactant. Non-limiting examples of anionic surfactants include docusate, perfluorooctanesulfonate, perfluorobutanesulfone, alkyl-aryl ester phosphate, and alkyl ether phosphate. In some embodiments, the surfactant is a cationic surfactant. Non-limiting examples of cationic surfactants include cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide. In some embodiments, the surfactant is a non-ionic surfactant. Non-limiting examples of non-ionic surfactants include octaethylene glycol monododecyl ether, Triton X-100, polyethoxylated tallow amine, cocamide monoethanolamine, poloxamer, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tri stearate, Tween 20, Tween 80, decyl glucoside, octyl glucoside, and polysorbate 80. In some embodiments, the surfactant is polysorbate 80.

[0265] In some embodiments, the composition comprises between 0.01 mg / ml to about 10 mg / ml of the surfactant. In some embodiments, the composition comprises between about 0.01 mg / ml to about 0.5 mg / ml, between 0.01 mg / ml to about 1 mg / ml, between about 0.01 mg / ml to about 5 mg / ml, between about 0.5 mg / ml to about 1 mg / ml, between about 1 mg / ml to about 5 mg / ml, or between about 5 mg / ml to about 10 mg / ml of the surfactant.

[0266] In some embodiments, the composition comprises at least about 0.01 mg / ml, at least about 0.05 mg / ml, at least about 0.1 mg / ml, at least about 0.2 mg / mg, at least about 0.3 mg / ml, at least about 0.4 mg / ml, at least about 0.5 mg / ml, at least about 0.6 mg / ml, at least about 0.7 mg / ml, at least about 0.8 mg / ml, at least about 0.9 mg / ml, at least about 1 mg / ml, at least about 2 mg / ml, at least about 3 mg / ml, at least about 4 mg / ml, at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml, or more of the surfactant. In some embodiments, the composition comprises at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, at most about 4 mg / ml, at most about 3 mg / ml, at mostabout 2 mg / ml, at most about 1 mg / ml, at most about 0.9 mg / ml, at most about 0.8 mg / ml, at most about 0.7 mg / ml, at most about 0.6 mg / ml, at most about 0.5 mg / ml, at most about 0.4 mg / ml, at most about 0.3 mg / ml, at most about 0.2 mg / ml, at most about 0.1 mg / ml, at most about 0.05 mg / ml, at most about 0.01 mg / ml, or less of the surfactant.

[0267] In some embodiments, the composition comprises about 0.01 mg / ml, about 0.05 mg / ml, about 0.1 mg / ml, about 0.2 mg / ml, about 0.3 mg / ml, about 0.4 mg / ml, about 0.5 mg / ml, about 0.6 mg / ml, about 0.7 mg / ml, about 0.8 mg / ml, about 0.9 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, or about 10 mg / ml of the surfactant.

[0268] In some embodiments, in addition to an amount of the DR IL-18 polypeptide, an amount of one or more ICIs, or amounts of both, the composition further comprises an anti-oxidation agent. In some embodiments, the anti -oxidation agent is selected from the group consisting of ascorbic acid, glutathione, lipoic acid, uric acid, carotene, a-tocopherol, ubiquinol, and L- Methionine. In some embodiments, the anti-oxidation agent is L-Methionine.

[0269] In some embodiments, the composition comprises between about 0.01 mg / ml to about 10 mg / ml of the anti-oxidation agent. In some embodiments, the composition comprises between about 0.01 mg / ml to about 0.5 mg / ml, between 0.01 mg / ml to about 1 mg / ml, between about 0.01 mg / ml to about 5 mg / ml, between about 0.5 mg / ml to about 1 mg / ml, between about 1 mg / ml to about 5 mg / ml, or between about 5 mg / ml to about 10 mg / ml of the anti-oxidation agent.

[0270] In some embodiments, the composition comprises at least about 0.01 mg / ml, at least about 0.05 mg / ml, at least about 0.1 mg / ml, at least about 0.15 mg / ml, at least about 0.2 mg / mg, at least about 0.25 mg / ml, at least about 0.3 mg / ml, at least about 0.35 mg / ml, at least about 0.4 mg / ml, at least about 0.45 mg / ml, at least about 0.5 mg / ml, at least about 0.55 mg / ml, at least about 0.6 mg / ml, at least about 0.65 mg / ml, at least about 0.7 mg / ml, at least about 0.75 mg / ml, at least about 0.8 mg / ml, at least about 0.85 mg / ml, at least about 0.9 mg / ml, at least about 0.95 mg / ml, at least about 1 mg / ml, at least about 2 mg / ml, at least about 3 mg / ml, at least about 4 mg / ml, at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml, or more of the anti-oxidation agent. In some embodiments, the composition comprises at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, at most about 4 mg / ml, at most about 3 mg / ml, at most about 2 mg / ml, at most about 1 mg / ml, at most about 0.95 mg / ml, at most about 0.9 mg / ml, at most about 0.85 mg / ml, at most about 0.8 mg / ml, at most about 0.75 mg / ml, at most about 0.7 mg / ml, at most about 0.65 mg / ml, at most about 0.6 mg / ml, at most about 0.55 mg / ml, at most about 0.5 mg / ml, at most about 0.45 mg / ml,at most about 0.4 mg / ml, at most about 0.35 mg / ml, at most about 0.3 mg / ml, at most about 0.25 mg / ml, at most about 0.2 mg / ml, at most about 0.15 mg / ml, at most about 0.1 mg / ml, at most about 0.05 mg / ml, at most about 0.01 mg / ml, or less of the anti-oxidation agent.

[0271] In some embodiments, the composition comprises about 0.01 mg / ml, about 0.05 mg / ml, about 0.1 mg / ml, about 0.15 mg / ml, about 0.2 mg / ml, about 0.25 mg / ml, about 0.3 mg / ml, about 0.35 mg / ml, about 0.4 mg / ml, about 0.45 mg / ml, about 0.5 mg / ml, about 0.55 mg / ml, about 0.6 mg / ml, about 0.65 mg / ml, about 0.7 mg / ml, about 0.75 mg / ml, about 0.8 mg / ml, about 0.85 mg / ml, about 0.9 mg / ml, about 0.95 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, or about 10 mg / ml of the anti -oxidation agent.

[0272] In some embodiments, in addition to an amount of the DR IL-18 polypeptide, an amount of one or more ICIs, or amounts of both, the composition further comprises a solvent. Nonlimiting examples of solvents include water, ethanol, methanol, acetone, tetracholoroethylene, toluene, methyl acetate, and ethyl acetate. In some embodiments, the solvent is water. In some embodiments, the composition comprises between about 0 mg / ml to about 10 mg / ml of the solvent. In some embodiments, the composition comprises between about 0 mg / ml to about 5 mg / ml, or between about 5 mg / ml to about 10 mg / ml of the solvent. In some embodiments, the composition comprises at least about 0.01 mg / ml, at least about 0.05 mg / ml, at least about 0.1 mg / ml, at least about 0.15 mg / ml, at least about 0.2 mg / mg, at least about 0.25 mg / ml, at least about 0.3 mg / ml, at least about 0.35 mg / ml, at least about 0.4 mg / ml, at least about 0.45 mg / ml, at least about 0.5 mg / ml, at least about 0.55 mg / ml, at least about 0.6 mg / ml, at least about 0.65 mg / ml, at least about 0.7 mg / ml, at least about 0.75 mg / ml, at least about 0.8 mg / ml, at least about 0.85 mg / ml, at least about 0.9 mg / ml, at least about 0.95 mg / ml, at least about 1 mg / ml, at least about 2 mg / ml, at least about 3 mg / ml, at least about 4 mg / ml, at least about 5 mg / ml, at least about 6 mg / ml, at least about 7 mg / ml, at least about 8 mg / ml, at least about 9 mg / ml, at least about 10 mg / ml of the solvent.

[0273] In some embodiments, the composition comprises at most about 10 mg / ml, at most about 9 mg / ml, at most about 8 mg / ml, at most about 7 mg / ml, at most about 6 mg / ml, at most about 5 mg / ml, at most about 4 mg / ml, at most about 3 mg / ml, at most about 2 mg / ml, at most about 1 mg / ml, at most about 0.95 mg / ml, at most about 0.9 mg / ml, at most about 0.85 mg / ml, at most about 0.8 mg / ml, at most about 0.75 mg / ml, at most about 0.7 mg / ml, at most about 0.65 mg / ml, at most about 0.6 mg / ml, at most about 0.55 mg / ml, at most about 0.5 mg / ml, at most about 0.45 mg / ml, at most about 0.4 mg / ml, at most about 0.35 mg / ml, at most about 0.3 mg / ml, at most about 0.25 mg / ml, at most about 0.2 mg / ml, at most about 0.15 mg / ml, at most about 0.1 mg / ml, at most about 0.05 mg / ml, at most about 0.01 mg / ml, or less of the solvent.

[0274] In some embodiments, the composition comprises about 0.01 mg / ml, about 0.05 mg / ml, about 0.1 mg / ml, about 0.15 mg / ml, about 0.2 mg / ml, about 0.25 mg / ml, about 0.3 mg / ml, about 0.35 mg / ml, about 0.4 mg / ml, about 0.45 mg / ml, about 0.5 mg / ml, about 0.55 mg / ml, about 0.6 mg / ml, about 0.65 mg / ml, about 0.7 mg / ml, about 0.75 mg / ml, about 0.8 mg / ml, about 0.85 mg / ml, about 0.9 mg / ml, about 0.95 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, or about 10 mg / ml of the solvent.Compositions comprising an immune checkpoint inhibitor

[0275] One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) an ICI, wherein the ICI is not pembrolizumab. In some embodiments, the ICI is a binding antagonist. In some embodiments, the ICI is a binding antagonist that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the binding antagonist is an antibody or antigen binding fragment thereof. In some embodiments, the antibody is a monoclonal antibody.

[0276] In some embodiments, the ICI is a PD-1 checkpoint inhibitor. In some embodiments, the PD-1 checkpoint inhibitor is a PD-1 antagonist (e.g., acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, or AMP -224). In some embodiments, the ICI is an anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the anti-PD-1 antibody is monoclonal.

[0277] In some embodiments, the PD-1 checkpoint inhibitor is a PD-L1 antagonist (e.g., adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, or BGB-A333). In some embodiments, the ICI is an anti-PD-Ll antibody or antigen binding fragment thereof. In some embodiments, the anti-PD-Ll antibody is monoclonal.

[0278] In some embodiments, the immune checkpoint or PD-1 checkpoint inhibitor is a PD-L2 antagonist. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the ICI is an anti-PD-L2 antibody or antigen binding fragment thereof. In some embodiments, the anti- PD-L2 antibody is monoclonal.

[0279] In some embodiments, the ICI is a CTLA-4 antagonist (e.g., botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, or zalifrelimab). In some embodiments, the ICI is an anti-CTLA-4 antibody or antigen binding fragment thereof. In some embodiments, the anti-CTLA-4 antibody is monoclonal.

[0280] In some embodiments, the ICI is a LAG-3 antagonist (e.g., encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, and tuparstobart). In some embodiments, the ICI is an anti-LAG-3 antibody or antigen binding fragment thereof. In some embodiments, the anti-LAG-3 antibody is monoclonal.

[0281] In some embodiments, the ICI is a B7-H3 antagonist (e.g., enoblituzumab, ifinatamab, mirzotamab, omburtamab, or vobramitamab). In some embodiments, the ICI is an anti-B7-H3 antibody or antigen binding fragment thereof. In some embodiments, the anti-B7-H3 antibody is monoclonal.

[0282] In some embodiments, the ICI is selected from the group consisting of zimberelimab, nivolumab, cemiplimab, dostarlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, pidilizumab, MEDI0680, SSI-361, AMP-224, cetrelimab, Prolgolimab, Retifanlimab, atezolizumab, avelumab, durvalumab, envafolimab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adebrelimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatlimab, enoblituzumab, and a variant of any of the foregoing.

[0283] In some embodiments, the ICI is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing.

[0284] One aspect of the present disclosure provides therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) a PD-L1 or PD-L2 antagonist. In some embodiments, the PD-L1 or PD-L2 antagonists is selected from the group consisting of adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.

[0285] In some embodiments, the therapeutic composition comprises a solution wherein the ICI is diluted at a concentration of at least about 1-250 mg / mL, about 1-10 mg / mL, 10-20 mg / mL, 20-30 mg / mL, 30-40 mg / mL, 40-50 mg / mL, 50-75 mg / mL, 75-100 mg / mL, 100-150 mg / mL, or 150-250 mg / mL solution.

[0286] In some embodiments, the therapeutic composition comprises a solution wherein the ICI is diluted at a concentration of least about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 200 mg / mL, or about 250 mg / mL solution.

[0287] In some embodiments, the therapeutic composition comprises a ratio of the ICI and DR IL-18 polypeptide of about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, about 1 : 15, about 1 :20, about 1 :30, about 1 :40, about 1 :50, about 1 :60, about 1 :70, about 1 :80, about 1 :90, about 1 : 100, about 1 : 120, about 1 : 140, about 1 : 160, about 1 : 180, about 1 :200, about 200: 1, about 180: 1, about 160: 1, about 140: 1, about 120: 1, about 100: 1, about 90: 1, about 80: 1, about 70: 1, about 60: 1, about 50: 1, about 40: 1, about 30: 1, about 20: 1, about 15: 1, about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3 : 1, or about 2: 1 mg.

[0288] In some embodiments, the therapeutic composition comprises at least about 5-1600 mg, at least about 5-10 mg, at least about 10-20 mg, at least about 20-40 mg, at least about 40-60 mg, at least about 60-80 mg, at least about 80-100 mg, at least about 100-200 mg, at least about 200- 300 mg, at least about 300-400 mg, at least about 400-500 mg, at least about 500-600 mg, at least about 700-800 mg, at least about 800-900 mg, at least about 900-1000 mg, at least about 1000-1200 mg, at least about 1200-1400 mg, or at least about 1400-1600 mg of the ICI.

[0289] In some embodiments, the therapeutic composition comprises at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, atleast about 55 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 560 mg, at least about 580mg, at least about 600 mg, at least about 640 mg, at least about 680 mg, at least about 720 mg, at least about 760 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 920 mg, at least about 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1080 mg, at least about 1120 mg, at least about 1160 mg, at least about 1200 mg, at least about 1280 mg, at least about 1360 mg, at least about 1440 mg, at least about 1520 mg, or at least about 1600 mg of the ICI.

[0290] In some embodiments, the therapeutic composition further comprises axitinib or lenvatinib. In some embodiments, the therapeutic composition further comprises 5mg of axitinib. In some embodiments, the therapeutic composition further comprises 20 mg lenvatinib.

[0291] One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) an ICI selected from the group consisting of Zimberelimab, Nivolumab, Cemiplimab, Dostarlimab, Vopratelimab, Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, INCMGA00012, Pidilizumab, MEDI0680, SSI-361, AMP -224, Cetrelimab, Prolgolimab, Retifanlimab, Atezolizumab, Avelumab, Durvalumab, Envafolimab, Cosibelimab, CA-170, BMS-986189, BMS-936559, Sugemalimab, Adebrelimab, CBT-502, BGB-A333, Pacmilimab, Ipilimumab, Tremelimumab, Relatlimab, Enoblituzumab, and a variant of any of the foregoing.

[0292] One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) an ICI selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart,quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing.Composition comprising an additional treatment

[0293] The present disclosure provides compositions, including compositions useful in combination therapies such as DR IL-18 compositions that includes a DR IL-18 polypeptide and an ICI composition that includes an ICI, wherein the ICI is not pembrolizumab. In addition to DR IL-18 compositions and ICI compositions, the disclosure further provides compositions for administering one or more additional treatments to the subject. Useful additional treatment compositions include prophylactic treatment compositions that prevent and / or reduce the display of the symptoms of CRS when administered to a subject when the subject is administered a DR IL- 18 composition or a DR IL- 18 composition and an ICI composition. Compositions of the present disclosure may be formulated separately, such as e.g., a DR IL- 18 composition formulated separately from an ICI composition formulated separately from an additional treatment composition or CRS prophylaxis composition. Compositions of the present disclosure may be co-formulated, such as e.g., a DR-IL18 composition co-formulated with an ICI composition, a DR-IL18 composition co-formulated with an additional treatment composition or CRS prophylaxis composition, an ICI composition co-formulated with an additional treatment composition or CRS prophylaxis composition, or a DR-IL18 composition co-formulated with an ICI composition co-formulated with an additional treatment composition or CRS prophylaxis composition.

[0294] One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide to a subject; (b) an ICI to the subject, wherein the ICI is not Pembrolizumab; and (c) an additional treatment. In some embodiments, the additional treatment is a prophylactic agent. In some embodiments, the additional treatment reduces the display of the symptoms of cytokine release syndrome (CRS). In some embodiments, therapeutic composition is for use in treating cancer and the additional treatment includes one or more CRS prophylactic agents and provides CRS prophylaxis that reduces the display of the symptoms of CRS.

[0295] In some embodiments, a single therapeutic composition comprises the prophylactic agent, the DR IL- 18 polypeptide, and the ICI. In some embodiments, two or more therapeutic compositions comprise the prophylactic agent, the DR IL- 18 polypeptide, and the ICI.

[0296] In some embodiments, the additional treatment is an agent or agents selected from the group consisting of a NSAID, acetaminophen, diphenhydramine, a histamine Hl antagonist, famotidine, and a H2 blocker. In some embodiments, the additional treatment is an agent or agents selected from the group consisting of a NSAID, acetaminophen, diphenhydramine, a histamine Hl antagonist, famotidine, an H2 blocker, tocilizumab, and any combination thereof.

[0297] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that is a NSAID. In some embodiments, the NSAID comprises indomethacin or ibuprofen. In some embodiments, the indomethacin is formulated to allow for administration to the subject of 25 mg three times daily. In some embodiments, the ibuprofen is formulated to allow for administration to the subject of between 200 mg to 600 mg every 6 to 8 hours. In some embodiments, the NSAID is formulated for oral administration. In some embodiments, the NSAID is formulated for intravenous administration.

[0298] Non-limiting examples of useful NSAIDs include ibuprofen, naproxen, diclofenac, difhmisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, celecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is indomethacin. In some embodiments, the NSAID is naproxen. In some embodiments, the NSAID is aspirin. In some embodiments, the NSAID is between about 25 mg to about 600 mg. In some embodiments, the NSAID is between about 25 mg to about 50 mg, between about 50 mg to about 75 mg, between about 75 mg to about 100 mg, between about 100 mg to about 125 mg, between about 125 mg to about 150 mg, between about 150 mg to about 175 mg, between about 175 mg to about 200 mg, between about 200 mg to about 225 mg, between about 225 mg to about 250 mg, between about 250 mg to about 275 mg, between about 275 mg to about 300 mg, between about 300 mg to about 325 mg, between about 325 mg to about 350 mg, between about 350 mg to about 375 mg, between about 375 mg to about 400 mg, between about 400 mg to about 425 mg, between about 425 mg to about 450 mg, between about 450 mg to about 475 mg, between about 475 mg to about 500 mg, between about 500 mg to about 525 mg, between about 525 mg to about 550 mg, between about 550 mg to about 575 mg, or between 575 mg to about 600 mg. In some embodiments, the NSAID is between about 200 mg to about 600 mg.

[0299] 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 leastabout 500 mg, at least about 525 mg, at least about 550 mg, at least about 575 mg, at least about 600 mg, or more.

[0300] In some embodiments, the NSAID is at most about 600 mg, at most about 575 mg, at most about 550 mg, at most about 525 mg, at most about 500 mg, at most about 475 mg, at most about 450 mg, at most about 425 mg, at most about 400 mg, at most about 375 mg, at most about 350 mg, at most about 325 mg, at most about 300 mg, at most about 275 mg, at most about 250 mg, at most about 225 mg, at most about 200 mg, at most about 175 mg, at most about 150 mg, at most about 125 mg, at most about 100 mg, at most about 75 mg, at most about 50 mg, at most about 25 mg, or less.

[0301] 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.

[0302] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that 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 formulated to allow for administration to the subject of 650 mg every 4 to 6 hours beginning 1 hour prior to administering a dose of the DR IL-18 composition. In some embodiments, the acetaminophen is formulated for continued administration for at least 48 hours after administering a dose of the DR IL- 18 composition. In some embodiments, the acetaminophen is formulated for oral administration. In some embodiments, the acetaminophen is formulated for intravenous administration.

[0303] In some embodiments, the acetaminophen is between about 200 mg to about 800 mg. In some embodiments, the acetaminophen is between about 600 mg to about 800 mg.

[0304] 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-n-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.

[0305] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that is a histamine Hl antagonist. In some embodiments the histamine Hl antagonist is formulated for administration of about 50 mg to the subject. In some embodiments, the histamine Hl antagonist is formulated for intravenous administration. In some embodiments, the histamine Hl antagonist is formulated for oral administration.

[0306] Non-limiting examples of histamine Hl antagonists include brompheniramine, clemastine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine, mepyramine, chlorpheniramine, promethazine, cyproheptadine. In some embodiments, the histamine Hl antagonist is between about 20 to about 100 mg. In some embodiments, the histamine Hl antagonist 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 histamine Hl 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 Hl antagonist 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 histamine Hl antagonist is about 50 mg.

[0307] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that is diphenhydramine. In some embodiments the diphenhydramine is formulated for administration of about 50 mg to the subject. In some embodiments, the diphenhydramine is formulated for intravenous administration. In some embodiments, the diphenhydramine is formulated for oral administration.

[0308] In some embodiments, the diphenhydramine is between 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.

[0309] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that is a histamine H2 antagonist (H2 blocker). In some embodiments, the H2 blocker is formulated for administration of 20 mg to a subject. In some embodiments, the H2 blocker is formulated for intravenous administration, including e.g., for intravenous administration of 20 mg. In some embodiments, the H2 blocker is formulated for administration of 20 mg to 40 mg to a subject. In some embodiments, the H2 blocker is formulated for oral administration, including e.g., oral administration of 20 mg to 40 mg.

[0310] In some embodiments, the H2 blocker is famotidine, cimetidine, ranitidine, or nizatidine. In some embodiments, the H2 blocker is famotidine. 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 between 10 mg to about 60 mg. In some embodiments, the H2 blocker is between 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.

[0311] In some embodiments, a composition of the present disclosure includes an additional treatment agent, such as a CRS prophylactic agent, that is famotidine. In some embodiments, the famotidine is formulated for administration of 20 mg to a subject. In some embodiments, the famotidine is formulated for intravenous administration, including e.g., for intravenous administration of 20 mg. In some embodiments, the famotidine is formulated for administration of 20 mg to 40 mg. In some embodiments, the famotidine is formulated for oral administration, including e.g., for oral administration of 20 mg to 40 mg.

[0312] In some embodiments, the famotidine is between 10 mg to about 60 mg. In some embodiments, the famotidine is between 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.

[0313] In some embodiments, the additional treatment is tocilizumab. In some embodiments, the tocilizumab is between about 400 mg to about 1000 mg. In some embodiments, the tocilizumab is between about 500 mg to about 900 mg. In some embodiments, the tocilizumab is 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, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, or more. In some embodiment, the tocilizumab is at most about 1000 mg, at most about 950 mg, at most about 900 mg, at most about 850 mg, 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 least about 400 mg, or less. In some embodiments, the tocilizumab is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.

[0314] Compositions of the present disclosure include compositions that comprise a combination of two or more CRS prophylactic agents. Any of the herein described groups of CRS prophylactic agents and individual CRS prophylactic agents may be combined into a useful CRS prophylaxis combination and formulated together in a single composition (with or without additional components such as e.g., a DR IL-18 polypeptide, one or more ICIs, or both).

[0315] For example, in some embodiments, CRS prophylaxis composition will include at least a NSAID and at least a histamine Hl antagonist; at least acetaminophen and at least a histamine Hl antagonist; at least a NSAID and at least acetaminophen; or at least a NSAID, at least a histamine Hl antagonist, and at least acetaminophen. Such NSAID, histamine Hl antagonist, and acetaminophen may be formulated together, as practical and appropriate, in such combinations according to the dosages and delivery methods of each agent as described herein. In some embodiments, CRS prophylaxis compositions will include 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 may be formulated together, as practical and appropriate, in such combinations according to the dosages and delivery methods of each agent as described herein. In some embodiments, such combinations will further include an H2 blocker, including e.g., where the H2 blocker used is famotidine and the famotidine is formulated according to the dosages and administration described herein.

[0316] In some embodiments, a CRS prophylaxis composition will include at least two or more of an NSAID, a histamine Hl antagonist, and acetaminophen, including e.g., where (i) theNSAID is oral or intravenous indomethacin at 50 mg to 100 mg per day (inc., e.g., at 75 mg per day), or oral or intravenous ibuprofen at 600 mg to 2,400 mg per day (inc. e.g., at 800 mg to 1,800 mg per day); (ii) the histamine Hl antagonist is intravenous or oral diphenhydramine at a dose of 25 mg to 100 mg (inc. e.g., a dose of 50 mg); and (iii) the acetaminophen is oral or intravenous acetaminophen at 350 mg to 4,000 mg per day (inc. e.g., at 650 mg to 3,900 mg per day). In some embodiments, such a combination will further include an H2 blocker, including e.g., where the H2 blocker used is famotidine and the famotidine is at a dosage and administered as described herein.Examples of Non-Limiting Aspects of the Disclosure

[0317] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below.

[0318] SET A (aspects 1-56)1. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a prophylactic agent; (b) a decoy-resistant IL- 18 polypeptide or a nucleic acid encoding the decoy-resistant IL-18 polypeptide; and (c) an effective amount of an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is not pembrolizumab.2. A method of treating a disease, comprising: (a) administering a composition comprising a decoy-resistant IL-18 polypeptide or a nucleic acid encoding the decoy -resistant IL-18 peptide to a subject; and (b) administering a composition comprising an immune checkpoint inhibitor selected from the group consisting of Zimberelimab, Nivolumab, Cemiplimab, Dostarlimab, Vopratelimab, Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, INCMGA00012 , Pidilizumab, MEDI0680, SSI-361, AMP- 224, Cetrelimab, Prolgolimab, Retifanlimab, Atezolizumab, Avelumab, Durvalumab, Envafolimab, Cosibelimab, CA-170, BMS-986189, BMS-936559, Sugemalimab, Adebrelimab, CBT-502, BGB-A333, Pacmilimab, Ipilimumab, Tremelimumab, Relatlimab, Enoblituzumab, and a variant of any of the foregoing.3. The method of SET A aspect 1, wherein the prophylactic agent comprises a pain medication.The method of SET A aspect 3, wherein the pain medication is a non-steroidal antiinflammatory drug (NS AID). The method of SET A aspect 4, wherein the NSAID is selected from the group consisting of ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. The method of SET A aspect 5, wherein the NSAID is ibuprofen. The method of SET A aspect 5, wherein the NSAID is diclofenac. The method of SET A aspect 4, wherein the NSAID is from about 25 mg to about 60 mg. The method of SET A aspect 4, wherein the NSAID is from about 200 mg to about 600 mg. The method of SET A aspect 3, wherein the pain medication comprises an analgesic. The method of SET A aspect 10, wherein the analgesic is selected from the group consisting of acetaminophen, aspirin, caffeine, butalbital, isometheptene mucate, magnesium salicylate, codeine, dihydrocodeine, hydrocodone, oxycodone, tramadol, co- codamol, co-codaprin, co-dydramol, alfentanil, fentanyl, hydromorphone, methadone, morphine, meperidine, and oxymorphone. The method of SET A aspect 11, wherein the analgesic is acetaminophen. The method of SET A aspect 11, wherein the analgesic is at least about 500 mg. The method of SET A aspect 11, wherein the analgesic is at least about 600 mg. The method of SET A aspect 1, wherein the prophylactic agent comprises an antihistamine. The method of SET A aspect 15, wherein the antihistamine is a H-l receptor antagonist or a H-2 receptor antagonist. The method of SET A aspect 16, wherein the antihistamine is a H-l receptor antagonist. The method of SET A aspect 17, wherein the H-l receptor antagonist is selected from the group consisting of brompheniramine, chlorpheniramine, clemastine, cypropheptadine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine. The method of SET A aspect 18, wherein the H-l receptor antagonist is diphenhydramine. The method of SET A aspect 16, wherein the antihistamine is a H-2 receptor antagonist.The method of SET A aspect 20, wherein the H-2 receptor antagonist is selected from the group consisting of cimetidine, famotidine, nizatidine, and ranitidine. The method of SET A aspect 20, wherein the H-2 receptor antagonist is famotidine. The method of SET A aspect 16, wherein the antihistamine is at least about 20 mg. The method of SET A aspect 16, wherein the antihistamine is at least about 40 mg. The method of SET A aspect 1, wherein the prophylactic agent comprises an antiinfection drug. The method of SET A aspect 25, wherein the anti-infection drug is a cytokine inhibitor. The method of SET A aspect 26, wherein the cytokine inhibitor targets the cytokine receptor. The method of SET A aspect 27, wherein the cytokine receptor is for TNFa, TNFP, IFNa, IFN , TFNy, IL-6, or IL-12. The method of SET A aspect 26, wherein the cytokine receptor is IL-6 receptor. The method of SET A aspect 25, wherein the anti-infection drug is an antibody or a small molecule. The method of SET A aspect 25, wherein the anti-infection drug is at least about 500 mg. The method of SET A aspect 1, wherein the prophylactic agent comprises a supplemental fluid. The method of SET A aspect 32, wherein the supplemental fluid is selected from the group consisting of normal saline solution, lactated ringer’s solution, dextrose in water solution, sodium chloride solution, and any combinations thereof. The method of SET A aspect 32, wherein the supplemental fluid is at most about 3 liters. The method of SET A aspect 1, wherein the prophylactic agent comprises a steroid. The method of SET A aspect 35, wherein the steroid is selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone. The method of SET A aspect 36, wherein the steroid is prednisone. The method of SET A aspect 35, wherein the steroid is at most about 10 mg / day. The method of SET A aspect 1, wherein the prophylactic agent is administered at least two hours prior to the decoy-resistant IL- 18 polypeptide and the effective amount of the immune checkpoint inhibitor. The method of SET A aspect 1, wherein the prophylactic agent is administered at least one hour prior to the decoy -resistant IL-18 polypeptide and the effective amount of the immune checkpoint inhibitor.41. The method of SET A aspect 1, wherein the prophylactic agent is administered intravenously, intramuscularly, subcutaneously, or orally.42. The method of SET A aspect 1 or 2, wherein the disease comprises cancer.43. The method of SET A aspect 42, wherein the cancer is a solid tumor or a liquid tumor.44. The method of SET A aspect 43, wherein the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, renal cell carcinoma, urothelial, nonsmall cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of head and neck (SCCHN), microsatellite instability high (MSI-H) tumors, high tumor mutation burden (TMB-H) tumors, mismatch repair deficient tumors, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof.45. The method of SET A aspect 43, wherein the solid tumor is melanoma, renal cell carcinoma, TNBC, NSCLC, SCCHN, or MSI-H tumors.46. The method of SET A aspect 43, wherein the solid tumor is melanoma.47. The method of SET A aspect 43, wherein the solid tumor is renal cell carcinoma.48. The method of SET A aspect 43, wherein the solid tumor is TNBC.49. The method of SET A aspect 43, wherein the solid tumor is NSCLC.50. The method of SET A aspect 43, wherein the solid tumor is SCCHN.51. The method of SET A aspect 43, wherein the solid tumor is MSI-H tumors.52. The method of SET A aspect 1 or SET A aspect 2, wherein the decoy-resistant IL-18 polypeptide is administered intravenously or subcutaneously.53. The method of SET A aspect 1 or SET A aspect 2, wherein the decoy-resistant is administered weekly.54. The method of SET A aspect 1 or SET A aspect 2, wherein the method results in reduction in tumor size or tumor number in the subject.55. The method of SET A aspect 1 or 2, wherein the decoy -resistant IL-18 polypeptide comprises a plurality of mutations relative to wild-type IL-18, as set forth in SEQ ID NO: 13.56. The method of SET A aspect 55, wherein the plurality of mutations comprise a plurality of amino acid substitutions.

[0319] SET B (aspects 1-104)1. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a decoy -resistant (DR) IL-18 composition comprising a DR IL- 18 polypeptide or a nucleic acid encoding the DR IL- 18 polypeptide; and (b) an immune checkpoint inhibitor (ICI) composition comprising an ICI, wherein the ICI is notpembrolizumab; and optionally wherein (c) the ICI is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI- 361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing; (d) the method comprises administering to the subject an additional treatment that reduces the display of symptoms of cytokine release syndrome (CRS); or (e) both (c) and (d). The method of SET B aspect 1, wherein the method comprises the additional treatment and the additional treatment comprises CRS prophylaxis administered with or before the DR IL-18 composition. The method of SET B aspect 1 or 2, wherein the method comprises administering successive doses of the DR IL-18 composition and administering the additional treatment with or before each dose of the successive doses of the DR IL-18 composition. The method of any one of the preceding SET B aspects, wherein the additional treatment comprises at least one of a nonsteroidal anti-inflammatory drug (NS AID), acetaminophen, histamine Hl antagonist, H2 blocker, or fluids administered to the subject. The method of any one of the preceding SET B aspects, where in the additional treatment comprises an NSAID, optionally wherein the NSAID is an oral NSAID. The method of SET B aspect 5, wherein the additional treatment is administered before the DR IL- 18 composition or before each dose of the successive doses of the DR IL- 18 composition, optionally at least 1 hour before, optionally 1 to 2 hours before.The method of SET B aspect 5 or 6, wherein the NS AID is further administered for at least 24 hours, optionally at least 48 hours, following the DR IL- 18 composition or each dose of the successive doses of the DR IL- 18 composition. The method of any one of SET B aspects 5-7, wherein the NS AID is indomethacin, optionally oral indomethacin. The method of SET B aspect 8, wherein the indomethacin is administered at 50 mg to 100 mg per day, optionally at 75 mg per day. The method of SET B aspect 8 or 9, wherein the indomethacin is administered in 25 mg doses, optionally three times per day. The method of any one of SET B aspects 5-7, wherein the NS AID is ibuprofen, optionally oral ibuprofen. The method of SET B aspect 11, wherein the ibuprofen is administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day. The method of SET B aspect 11 or 12, wherein the ibuprofen is administered in 200 mg to 600 mg doses, optionally with 6 to 8 hours between ibuprofen doses. The method of any one of the preceding SET B aspects, where in the additional treatment comprises a histamine Hl antagonist, optionally wherein the histamine Hl antagonist is an intravenous histamine Hl antagonist or an oral histamine Hl antagonist. The method of SET B aspect 14, wherein the histamine Hl antagonist is administered before the DR IL- 18 composition or each dose of the successive doses of the DR IL- 18 composition, optionally at least 30 minutes before, optionally 30 to 60 minutes before. The method of SET B aspect 14 or 15, wherein the histamine Hl antagonist is diphenhydramine, optionally intravenous diphenhydramine or oral diphenhydramine. The method of SET B aspect 16, wherein 25 mg to 100 mg of diphenhydramine is administered, optionally wherein 50 mg of diphenhydramine is administered. The method of any one of the preceding SET B aspects, where in the additional treatment comprises acetaminophen, optionally wherein the acetaminophen is oral acetaminophen. The method of SET B aspect 18, wherein the acetaminophen is administered before the DR IL- 18 composition or each dose of the successive doses of the DR IL- 18 composition, optionally within 2 hours before or 1 hour before. The method of SET B aspect 19, wherein the acetaminophen is further administered for at least 2 days following the DR IL- 18 composition or each dose of the successive doses of the DR IL- 18 composition.The method of SET B aspect 18, wherein the acetaminophen is administered within 24 hours of the DR IL- 18 composition or each dose of the successive doses of the DR IL- 18 composition. The method of any one of SET B aspects 18-21, wherein 350 mg to 4,000 mg of acetaminophen is administered per day, optionally wherein 650 mg to 3,900 mg of acetaminophen is administered per day. The method of any one of SET B aspects 18-22, wherein the acetaminophen is administered in one or more 650 mg doses, optionally with 4 to 6 hours between doses. The method of any one of the preceding SET B aspects, wherein the additional treatment comprises a H2 blocker, optionally wherein the H2 blocker is an oral H2 blocker or an intravenous H2 blocker. The method of SET B aspect 24, 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. The method of SET B aspect 24 or 25, wherein the H2 blocker is famotidine, optionally oral famotidine or intravenous famotidine. The method of SET B aspect 26, wherein 20 mg to 40 mg of oral famotidine is administered. The method of SET B aspect 26, wherein 20 mg of intravenous famotidine is administered. The method of any one of the preceding SET B aspects, wherein the method comprises administering multiple doses of a CRS prophylactic agent to the subject comprising at least a dose of a NSAID and at least a dose of a histamine Hl antagonist; at least a dose of acetaminophen and at least a dose of a histamine Hl antagonist; at least a dose of a NSAID and at least a dose of acetaminophen; or at least a dose of a NSAID, at least a dose of a histamine Hl antagonist, and at least a dose of acetaminophen; optionally wherein the NSAID is selected from indomethacin and ibuprofen and the histamine Hl antagonist is diphenhydramine. The method of SET B aspect 29, further comprising at least a dose of an H2 blocker, optionally wherein the H2 blocker is famotidine, optionally wherein the famotidine is oral famotidine administered at a 20 mg to 40 mg dose or intravenous famotidine administered at a 20 mg dose. The method of SET B aspect 29 or 30, wherein:(i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionallyat 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 Hl 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. The method of any one of the preceding SET B aspects, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS as compared to an equivalent subject having not received the CRS prophylactic agent. The method of any one of the preceding SET B aspects, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS as compared to a subject receiving an equivalent treatment comprising administration of about 30 pg / kg or more of the DR IL-18 composition without having received the CRS prophylactic agent. The method of any one of the preceding SET B aspects, wherein the subject does not experience grade 4 or higher CRS, optionally wherein the subject does not experience grade 3 or higher CRS. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 polypeptide comprises a plurality of mutations relative to wild-type IL- 18, as set forth in SEQ ID NO: 13. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 polypeptide comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid substitutions relative to wild-type IL- 18, as set forth in SEQ ID NO: 13. The method of SET B aspect 35 or 36, wherein the plurality of mutations comprise mutations at positions selected from: Yl, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, DUO, Nl l l, M113, V153, and N155. The method of any of the proceeding SET B aspects, wherein the DR IL- 18 polypeptide comprises one or more substitutions, relative to wild-type IL-18 as set forth in SEQ ID NO: 13, selected from the group consisting of: Y1H, Y1R, LSH, L51, LSY, K8Q, K8R, M51T, M51K, M51D, M51N, M51E, M51R, K53R, K53G, K53S, K53T, S55K, S55R, Q56E, Q56A, Q56R, Q56V, Q56G, Q56K, Q56L, P57L, P57G, P57A, P57K, G59T, G59A, M60K, M60Q, M60R, M60L, E77D, Q103E, Q103K, Q103P, Q103A, Q103R, S105R, S105D, S105K, S105N, S105A, DI 10H, DI 10K, DI 10N, DI 10Q, DI 10E,D1 IOS, DI 1OG, N111H, N111 Y, N11 ID, N111R, N11 IS, N111G, Ml 13V, Ml 13R, M113T, M113K, V1531, V153T, V153A, N155K, and N155H. The method of any of the proceeding SET B aspects, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 1-12. The method of any of the proceeding SET B aspects, wherein the DR IL- 18 polypeptide comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 1-12. The method of any of the proceeding SET B aspects, wherein the DR IL- 18 polypeptide comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 1-12. The method of any of the proceeding SET B aspects, wherein the DR IL- 18 polypeptide comprises an amino acid sequence selected from SEQ ID NOs: 1-12. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 polypeptide is a modified IL-18 polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 5. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 polypeptide is a modified IL-18 polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 5. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 polypeptide is administered at a concentration of about 30 mg / mL. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 15 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 20 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL-18 composition comprises at least about 30 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 90 pg of the DR IL- 18 polypeptide per kg body weight of the subject.The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 180 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 360 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein of the DR IL-18 composition comprises at least about 600 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition comprises at least about 900 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL-18 composition comprises at least about 1200 pg of the DR IL-18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition, or each dose of the successive doses of the DR IL- 18 composition, comprises about 15 pg to about 1200 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition, or each dose of the successive doses of the DR IL- 18 composition, comprises about 15 pg to about 30 pg, about 30 pg to about 90 pg, about 90 pg to about 180 pg, about 180 pg to about 360 pg, about 360 pg to about 600 pg, about 600 pg to about 900 pg, or about 900 pg to about 1200 pg of the DR IL-18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition, or each dose of the successive doses of the DR IL- 18 composition, comprises about 15 pg, about 30 pg, about 90 pg, about 180 pg, about 360 pg, about 600 pg, about 900 pg, or about 1200 pg of the DR IL- 18 polypeptide per kg body weight of the subject. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition is administered to the subject weekly. The method of any one of the preceding SET B aspects, wherein the DR IL- 18 composition is administered to the subject about every 7 days.The method of any one of the preceding SET B aspects, wherein a next dose of the DR IL-18 composition is administered to the subject at least 6 days after a previous dose of the DR IL- 18 composition. The method of SET B aspect 60, wherein the next dose of the DR IL-18 composition is administered to the subject at most 9 days after the previous dose of the DR IL- 18 composition. The method of any one of the preceding SET B aspects, wherein the method comprises administering successive doses of the ICI composition. The method of any one of the preceding SET B aspects, wherein a dose of the ICI 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. The method of any one of the preceding SET B aspects, wherein a dose of the DR IL- 18 composition is administered to the subject at least 60 minutes after a dose of the ICI composition is administered to the subject. The method of any one of the preceding SET B aspects, wherein (a) and (b) are performed sequentially. The method of any one of the preceding SET B aspects, wherein (a) is performed before (b). The method of any one of SET B aspects 1-65, wherein (b) is performed before (a). The method of any one of SET B aspects 1-64, wherein (a) and (b) are performed simultaneously. The method of any one of the preceding SET B aspects, wherein a dose of the ICI composition is administered to the subject by intravenous infusion. The method of any one of the preceding SET B aspects, wherein each dose of the ICI composition is administered to the subject by intravenous infusion. The method of any one of the preceding SET B aspects, wherein a dose of the DR IL- 18 composition is administered to the subject by subcutaneous injection. The method of any one of the preceding SET B aspects, wherein each dose of the DR IL- 18 composition is administered to the subject by subcutaneous injection. The method of any one of the preceding SET B aspects, wherein the disease comprises cancer. The method of SET B aspect 73, wherein the cancer is a solid tumor or a liquid tumor. The method of SET B aspect 74, wherein the cancer is a solid tumor selected from the group consisting of melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer (HNSCC), classical Hodgkin Lymphoma(cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient cancer (dMMR) cancer, microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophageal or gastroesophageal junction cancer, esophageal or gastroesophageal junction adenocarcinoma, locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinoma, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial carcinoma, liver cancer, tumor mutational burden-high (TMB-H) cancer, cutaneous squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof. The method of any one of SET B aspects 73-75, wherein the cancer is resistant to one or more ICIs. The method of any one of SET B aspects 73-76, wherein the cancer is selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (with no 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, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof, and wherein the cancer is resistant to one or more ICIs. The method of any one of SET B aspect 73-76, wherein the cancer is selected from platinum -resistant ovarian cancer or microsatellite stable colorectal cancer. The method of SET B aspect 73, wherein the cancer is a liquid tumor selected from the group consisting of a leukemia, a lymphoma, a myelodysplastic syndrome, a myeloproliferative disorder, and myeloma. The method of SET B aspect 79, wherein the liquid tumor is a myeloma. The method of SET B aspect 79, wherein the liquid tumor is a lymphoma, optionally B cell lymphoma. The method of SET B aspect 79, wherein the liquid tumor is a leukemia, optionally acute myeloid leukemia. The method of any one of the preceding SET B aspects, comprising administering one or more doses of a CRS prophylactic agent to the subject with or before each dose of the successive doses of the DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of a NSAID, a histamine Hl antagonist, acetaminophen, or a H2 blocker, and wherein:(i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the aminoacid sequence set forth in SEQ ID NO: 5;(ii) the dose of the DR IL-18 composition comprises at least about 30 pg of the polypeptide per kg body weight of the subject; and(iii) the disease comprises a ICI resistant solid tumor selected from the group consisting of: melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI- H tumor, TMB-H or mismatch repair deficient tumor, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof; or platinum -resistant ovarian cancer or microsatellite stable colorectal cancer. The method of any one of the preceding SET B aspects, wherein the ICI is an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3. The method of SET B aspect 84, wherein the ICI is an anti-LAG-3 antibody or antigen binding fragment thereof. The method of SET B aspect 85, wherein the anti-LAG-3 antibody or antigen binding fragment thereof is encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, or tuparstobart. The method of SET B aspect 84, wherein the ICI is a PD-1 checkpoint inhibitor, optionally a PD-1 antagonist, a PD-L1 antagonist, or a PD-L2 inhibitor. The method of SET B aspect 87, wherein the PD-1 checkpoint inhibitor is selected from the group consisting of: acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB- A333. The method of any one of SET B aspects 73-88, comprising administering one or more CRS prophylactic agents to the subject with or before the DR IL- 18 composition, wherein the one or more CRS prophylactic agents comprise a NSAID, a histamine Hl antagonist, acetaminophen, a H2 blocker, or a combination thereof, and wherein:(i) the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;(ii) the DR IL-18 composition comprises at least about 30 pg of the polypeptide per kg body weight of the patient;(iii) the ICI composition comprises an ICI that binds to at least one of PD-1, PD-L1, PD- L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3; and(iv) the disease comprises a ICI checkpoint inhibitor resistant solid tumor selected from the group consisting of: melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumor, TMB-H or mismatch repair deficient tumor, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof; or platinum-resistant ovarian cancer or microsatellite stable colorectal cancer. The method of any one of SET B aspects 73-89, wherein the ICI is an anti-LAG-3 antibody or antigen binding fragment thereof, optionally wherein the cancer is selected from colorectal cancer, myeloma, B cell lymphoma, and acute myeloid leukemia. The method of any one of SET B aspects 73-89, wherein the ICI is a PD-1 checkpoint inhibitor, optionally wherein the cancer is selected from colorectal cancer, myeloma, B cell lymphoma, and acute myeloid leukemia. The method of any one of the preceding SET B aspects, wherein the disease is a cancer or a tumor and the method thereby causes one or more improvements in the patient’s cancer or tumor. The method of SET B aspect 92, wherein the one or more improvements comprise stable disease for at least 12 weeks. The method of SET B aspect 92 or 93, wherein the one or more improvements comprise an immunotherapy -induced regression of the cancer or tumor in the patient. The method of any one of SET B aspects 92-94, wherein the one or more improvements comprise a partial response as assessed by RECIST Version 1.1. The method of any one of SET B aspects 92-95, wherein the one or more improvements comprise a complete response as assessed by RECIST Version 1.1. Use of an ICI composition, DR IL-18 composition, or a combination thereof, in a method of treating cancer, according to any one of the preceding SET B aspects. A therapeutic composition comprising: (a) an effective amount of decoy -resistant (DR) IL-18 polypeptide; and (b) and effective amount of an ICI, wherein the ICI is not pembrolizumab, optionally wherein the the ICI is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab,pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI- 361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing. The therapeutic composition of SET B aspect 98, wherein the ICI is a PD-1 antagonist, optionally wherein the PD-1 antagonist is selected from the group consisting of: acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI- 361, and AMP-224. . The therapeutic composition of SET B aspect 98, wherein the ICI is a PD-L1 antagonist, optionally wherein the PD-L1 antagonist is selected from the group consisting of: adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333. . The therapeutic composition of SET B aspect 98, wherein the ICI is a LAG3 antagonist, optionally wherein the LAG3 antagonist is selected from the group consisting of: encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, or tuparstobart. . The therapeutic composition of SET B aspect 98, wherein the ICI is a CTLA4 antagonist, optionally wherein the CTLA4 antagonist is selected from the group consisting of: botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug,nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, or zalifrelimab.103. The therapeutic composition of any one of SET B aspects 98 to 102, wherein the therapeutic composition is formulated for intravenous administration.104. The therapeutic composition of any one of SET B aspects 98 to 103, further comprising a buffering agent, a stabilizer, surfactant, an anti-oxidation agent, solvent, or any combination thereof.EXAMPLESEXAMPLE #1: Anti-PD-1 treatment as monotherapy

[0320] In an exemplary embodiment, a subject is administered an anti-PD-1 monoclonal antibody by infusion (200 mg Q3W) for at most 2 years to treat tumors associated with nonsmall cell lung cancer but is not administered a decoy -resistant IL-18 polypeptide. The tumors will shrink initially but a resistance to the anti-PD-1 treatment develops, resulting in disease recurrence and disease progression after being administered the anti-PD-1 monotherapy for 2 years.EXAMPLE #2: Anti-PD-1 antibody combination therapy with a DR IL-18 polypeptide

[0321] In an exemplary embodiment, a subject is administered an anti-PD-1 monoclonal antibody by infusion (200 mg Q3W) and a DR IL- 18 polypeptide by subcutaneous injection (e.g., 30 pg / kg subject’s body weight QW) with mandatory CRS prophylaxis given with every dose of DR IL- 18 polypeptide.

[0322] To determine the maximum tolerated dose, each subject will receive an initial dose of 30 pg / kg the DR IL-18 polypeptide and the dose will be escalated as in the Table A below in the absence of >Grade 2 treatment-related AEs. If the first dose level (30 pg / kg) is not tolerated, a lower dose (10, 15, or 20 pg / kg) or a less intense dosing schedule at 30 pg / kg will be assessed.Table A: Initial Dose Levels for Dose Escalation

[0323] Once a desirable dose is determined, the subject is administered such for at most 2 years to treat tumors associated with non-small cell lung cancer. The tumors will shrink throughout the course of the treatment, resulting in reductions in tumor size and tumor number until the patient exhibits signs of complete disease remission after being administered the combination treatment for 2 years.EXAMPLE #3: CRS prophylaxis in patients treated with DR IL- 18 polypeptide plus pembrolizumab combination therapy

[0324] A risk of CRS when DR IL- 18 polypeptide is administered subcutaneously as a monotherapy has been observed. All patients are now given prophylaxis before each injection.

[0325] Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS is as follows: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

[0326] A three-patient cohort, that previously experienced an insufficient response to PD-1 checkpoint inhibitor therapy, received combination therapy of weekly subcutaneous DR IL-18 polypeptide at 30 pg / kg plus 200 mg pembrolizumab intravenously every three weeks. DR IL-18 polypeptide was administered with CRS prophylaxis, given with each dose, that included administration of (a) an oral nonsteroidal anti-inflammatory drug (NSAID) 1-2 hours prior to DR IL-18 polypeptide dosing and continuing for at least 48 hours post-dose (using indomethacin at 25 mg 3 times daily or oral ibuprofen at 200 mg to 600 mg every 6 to 8 hours); (b) intravenous or oral diphenhydramine at 50 mg (or comparable dose of next-generation histamine Hl antagonist) 30-60 minutes prior to dosing with DR IL-18 polypeptide; (c) 650 mg oral acetaminophen every 4 to 6 hours as needed for the first 24 hours post-dose; and (d) if indicated after initial DR IL-18 polypeptide dosing, famotidine (or other H2 blocker) at 20 mg intravenously or 20-40 mg orally 30-60 minutes prior to subsequent DR IL-18 polypeptide dosing. If not contraindicated by vital signs post-dose, any blood pressure medications were withheld for 24 hours before and at least 48 hours after DR IL-18 polypeptide dosing. For subjects with contraindications to NSAIDs, 650 mg oral acetaminophen every 4-6 hours beginning 1 hour prior to DR IL-18 polypeptide dosing was used and continued for at least 48 hours post-dose. For subjects with or at risk for hypotension, up to 3 liters of oral and / or intravenous fluids were administered within 24 hours post-dose.

[0327] All patients in the cohort remained on study through the dose limiting toxicity (DLT) period (i.e., through 21 days with 3 doses of DR IL-18 polypeptide). No patient in the cohort experienced grade 3 or higher CRS and no patients in the cohort required steroid administration for CRS.EXAMPLE #4: Efficacy in patients treated with DR IL-18 polypeptide plus ICI combination therapy

[0328] Cohorts of patients, as described below, are administered (with CRS prophylaxis given with each dose as described in Example #3) weekly subcutaneous DR IL-18 polypeptide at 30 pg / kg, 60 pg / kg, or other recommended dose (such as the recommended phase 2 dose obtained from DR IL- 18 polypeptide dose finding studies) plus ICI intravenously every one, two, or three weeks.

[0329] Subjects in the cohort will include subjects, with histologically or cytologically confirmed diagnosis of 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 head and neck (SCCHN), any microsatellite instabilityhigh (MSI-H), any high tumor mutation burden (Hi-TMB) or mismatch repair deficient, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, and hepatocellular carcinoma cancer (HCC) cancer / tumor(s), which experienced an insufficient response to a prior ICI therapy, such as checkpoint inhibitor programmed cell death receptor- 1 (PD-1) therapy. TNBC is diagnosed in a tumor which does not express estrogen receptor or progesterone receptor, is not human epidermal growth factor receptor 2 (HER2) 3+ on immunohistochemistry (IHC) or is negative by fluorescence in situ hybridization (FISH). MSI high tumors have mutations in 30% or more microsatellites by PCR or are negative for MSH1 / 2 / 6 or PMS-2 by IHC. TMB-H high tumor has 10 mutations per megabase (mut / Mb) or greater calculated from whole genome sequencing or whole exome sequencing. The following tumors are allowed in expansion cohorts: platinum resistant ovarian cancer and microsatellite stable colorectal cancer.

[0330] Disease assessments will be made using a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis (and other relevant areas if they include target lesions). Determinations of the magnitude and duration of changes in tumor size will be based on well-established response and progression criteria (Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1; see Eisenhauer et al. (2009) European Journal of Cancer 45:228-247) as applied to radiographic measurements. Disease assessments will be done every 6 weeks for the first 24 weeks then every 12 weeks. Clinical laboratory, pharmacodynamic, pharmacogenomic, pharmacokinetic, and other assessments will also be performed.

[0331] The cohort is expected to display evidence of pharmacodynamic activity as well as substantial evidence of tumor regressions including objective responses (CR and PR) as assessed by RECIST Version 1.1. Stable disease for > 12 weeks will be considered clinically relevant in this population of patients.EXAMPLE #5: DR IL-18 polypeptide and anti-PD-1 ICI antibody combination therapy reduces tumor growth in CT26 murine colorectal tumor model

[0332] A CT26 murine colorectal cancer model was used to evaluate the anti-tumor activity in colorectal cancer of decoy resistant (DR) IL- 18 polypeptide, alone and in combination with an anti-PD-1 immune checkpoint inhibitor (ICI). CT26 is an N-nitroso-N-methylurethane-(NNMU) induced undifferentiated colon carcinoma cell line established from BALB / c mice with aggressive colon carcinoma. CT26 is considered a “warm” tumor model, meaning it generally resides between an immunogenic “hot” and a nonimmunogenic “cold” tumor.

[0333] To establish the models, CT26 cells were transplanted into host mice as a xenograft and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (dosed five times by intraperitoneal injection (IP) at 0.32 milligrams per kilogram (mpk) biweekly (BIW), last dosed on study day 15), anti-PD-1 antibody alone (dosed 10 mpk BIW for 5 doses) or with DR IL-18 polypeptide in combination with anti-PD-1 (dosed the same as each corresponding monotherapy). Untreated “vehicle” controls were dosed with delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI). As an assay for cancer growth, tumor size was measured (in cubic millimeters (mm3)) in each animal over time during the course of the study.

[0334] As can be seen in FIG. 2, tumors grew rapidly in untreated vehicle control mice and mice administered anti-PD-1 monotherapy. Tumor growth was substantially reduced in mice treated with DR IL-18 polypeptide monotherapy as compared to vehicle control mice and anti-PD-1 monotherapy treated mice. However, tumor growth in mice treated with DR IL-18 polypeptide and anti-PD-1 combination was substantially reduced, if not halted, as compared to either of the monotherapy treatment conditions. Accordingly, this example demonstrates that combination therapy that includes DR IL- 18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-tumor activity, greatly reducing, if not halting, colorectal tumor growth. The antitumor activity of the combination therapy was substantially greater than either DR IL- 18 polypeptide monotherapy or anti-PD-1 ICI monotherapy.EXAMPLE #6: DR IL-18 polypeptide and anti-LAG3 ICI antibody combination therapy reduces tumor growth in CT26 murine colorectal tumor model

[0335] The CT26 murine colorectal cancer model described in Example #5 was used to evaluate the anti -turn or activity in colorectal cancer of decoy resistant IL- 18 (DR- 18) in combination with an anti-LAG3 immune checkpoint inhibitor (ICI).

[0336] Mice, with established tumors, were treated with DR-18 alone (dosed five times IP at 0.32 mpk BIW, last dosed on study day 15), anti-LAG3 antibody alone (dosed 10 mpk BIW for 5 doses), or with DR- 18 in combination with anti-LAG3 (dosed the same as each corresponding monotherapy). Untreated “vehicle” controls were dosed with delivery vehicle only (i.e., without DR- 18 or any ICI). As an assay for cancer growth, tumor size was measured (in cubic millimeters (mm3)) in each animal over time during the course of the study.

[0337] As can be seen in FIG. 3, tumors grew rapidly in untreated vehicle control mice and mice administered anti-LAG3 monotherapy. Tumor growth was substantially slower in mice treated with DR- 18 monotherapy as compared to vehicle control mice and anti-LAG3 monotherapy treated mice. However, tumor growth in mice treated with DR- 18 and anti-LAG3 combinationwas substantially slower, if not halted, as compared to either of the monotherapy treatment conditions. Accordingly, this example demonstrates that combination therapy that includes DR- 18 in combination with an anti-LAG3 antibody ICI has effective anti -tumor activity, greatly reducing, if not halting, colorectal tumor growth. The anti-tumor activity of the combination therapy was substantially greater than either DR-18 or anti-LAG3 ICI monotherapy alone.EXAMPLE #7: DR IL- 18 polypeptide and anti-PD-1 ICI antibody combination therapy reduces tumor growth in MC38 murine colorectal tumor model

[0338] A MC38 murine colorectal cancer model was used to evaluate the anti -turn or activity in colorectal cancer of DR IL- 18 polypeptide, alone and in combination with an anti-PD-1 ICI. The MC38 tumorigenic epithelial cell line is isolated from mice 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.

[0339] To establish the models, MC38 cells were transplanted into host mice as a xenograft and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (dosed five times IP at 0.32 mpk BIW, last dosed on study day 15), anti-PD-1 antibody alone (dosed 10 mpk BIW for 5 doses), or with DR IL- 18 polypeptide in combination with anti-PD-1 (dosed the same as each corresponding monotherapy). Untreated “vehicle” controls were dosed with delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI). As an assay for cancer growth, tumor size was measured (in mm3) in each animal over time during the course of the study.

[0340] As can be seen in FIG. 4, tumors grew, on average, to over 2000 mm3 in untreated vehicle control mice. Mice administered anti-PD-1 monotherapy showed a reduction in MC38 tumor growth as compared to vehicle control. Tumor growth was reduced in mice treated with DR IL- 18 polypeptide monotherapy as compared to anti-PD-1 monotherapy treated mice. However, MC38 tumor growth more substantially reduced, as compared with either monotherapy, in mice treated with DR IL-18 polypeptide and anti-PD-1 combination.Accordingly, this example demonstrates that combination therapy that includes DR IL- 18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-colorectal tumor activity that is superior to both DR IL-18 polypeptide monotherapy and anti-PD-1 ICI monotherapy.EXAMPLE #8: DR IL-18 polypeptide and anti- LAG3 ICI antibody combination therapy reduces tumor growth in MC38 murine colorectal tumor model

[0341] The MC38 murine colorectal cancer model described in Example #7 was used to evaluate the anti -turn or activity in colorectal cancer of DR- 18, alone and in combination with an anti-LAG3 ICI.

[0342] Mice with established MC38 tumors were treated with DR- 18 alone (dosed five times IP at 0.32 mpk BIW, last dosed on study day 15), anti-LAG3 antibody alone (dosed 10 mpk BIW for 5 doses), or with DR- 18 in combination with anti-LAG3 (dosed the same as each corresponding monotherapy). Untreated “vehicle” controls were dosed with delivery vehicle only (i.e., without DR-18 or any ICI). As an assay for cancer growth, tumor size was measured (in mm3) in each animal over time during the course of the study.

[0343] As can be seen in FIG. 5, tumors grew rapidly in untreated vehicle control mice and mice administered anti-LAG3 monotherapy. In comparison, tumor growth was greatly reduced in mice administered combination therapy that included DR-18 and anti-LAG3 antibody. However, it is noted that DR-18 monotherapy also greatly reduced tumor growth as compared to either vehicle control or anti-LAG3 monotherapy. Collectively, this example demonstrates that combining DR-18 with anti-LAG3 ICI therapy has effective anti -colorectal tumor activity that is superior to anti-LAG3 ICI therapy alone.EXAMPLE #9: DR IL-18 polypeptide and anti-PD-1 ICI antibody combination therapy reduces tumor growth and improves therapeutic response in murine heme tumor models

[0344] Various heme tumor murine models, including MPC-11 (myeloma), A-20 (B cell lymphoma), and Cl 498 (acute myeloid leukemia), were used to evaluate the anti -turn or activity in blood cancers of DR IL- 18 polypeptide, alone and in combination with an anti-PD-1 ICI. MPC-11 (Merwin Plasma Cell tumor-11) is a mouse plasma cell myeloma with a H-2d haplotype that is commercially available and commonly used for anti-cancer immunotherapeutic efficacy and other studies. A-20 is a cell line derived from a spontaneous mouse reticulum cell sarcoma that is commercially available and commonly used for B cell lymphoma studies including anti-cancer immunotherapeutic efficacy and other studies. C1498 is an aggressive acute myeloid leukemia (AML) cell line which originated spontaneously in a C57BL / 6 mouse that is commercially available and commonly used for AML studies including anti-cancer immunotherapeutic efficacy and other studies.

[0345] To establish the models, MPC-11, A-20, or C1498 cells were transplanted into host mice as xenografts and allowed to engraft, forming tumors. Mice were treated with DR IL- 18polypeptide alone (dosed five times IP at 0.32 mpk BIW, last dosed on study day 15), anti-PD-1 antibody alone (dosed 10 mpk BIW for 5 doses), or with DR IL- 18 polypeptide in combination with anti-PD-1 (dosed the same as each corresponding monotherapy). Untreated “vehicle” controls were dosed with delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI).

[0346] Both DR IL- 18 polypeptide monotherapy and DR IL- 18 polypeptide plus anti-PD-1 antibody ICI combination therapy demonstrated reductions in tumor growth as compared to vehicle controls and anti-PD-1 antibody ICI monotherapy. In addition to tumor growth inhibition, mice were also evaluated for treatment response using a pseudo-clinical scoring criteria that correlated with scoring used for partial response (PR) and complete response (CR) in human clinical trials. In the A-20 tumor model, improvements in response were observed in mice treated with combination therapy (DR IL- 18 polypeptide plus anti-PD-1 antibody ICI) as compared to DR IL- 18 polypeptide monotherapy. Treatment with DR IL- 18 polypeptide monotherapy resulted in 60% CR and 40% PR, whereas treatment with combination therapy resulted in 87.5% CR and 12.5% PR. Collectively, this example demonstrates that combining 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 anti- PD-1 ICI and results in treatment responses that are improved as compared to DR IL- 18 polypeptide monotherapy.

[0347] While preferred embodiments of the present invention have been shown and described herein, it will be obvious 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. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Amino Acid SequencesSEQ ID NO:! variant of SEQ ID NO: 10 (C38S / C68S) YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARG LAVTISVKSEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSS YEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: !)SEQ ID NO: 2 variant of SEQ ID NO: 10 (C38S / C68G)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKGEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 2)SEQID NO: 3 variant of SEQ ID NO: 10 fC38S / C68A)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKAEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 3)SEQID NO: 4 variant of SEQ ID NO: 10 (C38S / C68V)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKVEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 4)SEQ ID NO: 5 variant of SEQ ID NO: 10 (C38S / C68D)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKDEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 5)SEQID NO: 6 variant of SEQ ID NO: 10 (C38S / C68E)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKEEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 6)SEQID NO: 7 variant of SEQ ID NO: 10 (C38S / C68N)YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKNEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 7)SEQID NO: 8 variant of SEQ ID NO: 13YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYGDSGARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFERDVPGHSGKVQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 8)SEQID NO: 9 variant of SEQ ID NO: 13YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYGDSRPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRAVPGHNRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 9)SEQID NO: 10 variant of SEQ ID NO: 13YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSLARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 10)SEQID NO: 11 variant of SEQ ID NO: 13YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSRARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFARSVPGHGRKTQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 11)SEQID NO: 12 variant of SEQ ID NO: 13YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSRARGLAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRNVPGHGRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 12)SEQID NO: 13 wild-type IL- 18YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 13)Table 3: Immune checkpoint targeting antibody and antibody-derived therapeutics-Ill-

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a decoy -resistant (DR) IL-18 composition comprising a DR IL- 18 polypeptide or a nucleic acid encoding the DR IL- 18 polypeptide; and (b) an immune checkpoint inhibitor (ICI) composition comprising an ICI, wherein the ICI is not pembrolizumab; and optionally wherein (c) the ICI is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI- 361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing; (d) the method comprises administering to the subject an additional treatment that reduces the display of symptoms of cytokine release syndrome (CRS); or (e) both (c) and (d).

2. The method of claim 1, wherein the method comprises the additional treatment and the additional treatment comprises CRS prophylaxis administered with or before the DR IL- 18 composition.

3. The method of claim 2, wherein the method comprises administering multiple doses of a CRS prophylactic agent to the subject comprising at least a dose of a NSAID and at least a dose of a histamine Hl antagonist; at least a dose of acetaminophen and at least a dose of a histamine Hl antagonist; at least a dose of a NSAID and at least a dose of acetaminophen; or at least a dose of a NSAID, at least a dose of a histamine Hl antagonist, and at least a dose of acetaminophen; optionally wherein the NSAID is selected from indomethacin and ibuprofen and the histamine Hl antagonist is diphenhydramine.

4. The method of claim 3, wherein:(i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally at 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 Hl 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. The method of any one of the preceding claims, wherein administering the CRS prophylactic agent reduces the display of one or more symptoms of CRS as compared to: an equivalent subject having not received the CRS prophylactic agent; a subject receiving an equivalent treatment comprising administration of about 30 pg / kg or more of the DR IL- 18 composition without having received the CRS prophylactic agent; or both.

6. The method of any one of the preceding claims, wherein the DR IL-18 polypeptide comprises a plurality of mutations relative to wild-type IL-18, as set forth in SEQ ID NO: 13.

7. The method of any of the proceeding claims, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or 100% sequence identity to any one of SEQ ID NOs: 1-12.

8. The method of any one of the preceding claims, wherein the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO: 5.

9. The method of any one of the preceding claims, wherein the DR IL-18 composition comprises at least about 15 pg, at least about 20 pg, or at least about 30 pg of the DR IL- 18 polypeptide per kg body weight of the subject.

10. The method of any one of the preceding claims, wherein the disease comprises cancer.

11. The method of claim 10, wherein the cancer is selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (with no 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, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof, and wherein the cancer is resistant to one or more ICIs; or thecancer is selected from platinum-resistant ovarian cancer or microsatellite stable colorectal cancer.

12. The method of claim 10, wherein the cancer is a liquid tumor selected from the group consisting of: a myeloma, a lymphoma, and a leukemia.

13. The method of any one of the preceding claims, comprising administering one or more doses of a CRS prophylactic agent to the subject with or before each dose of the successive doses of the DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of a NSAID, a histamine Hl antagonist, acetaminophen, or a H2 blocker, and wherein:(i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5;(ii) the dose of the DR IL-18 composition comprises at least about 30 pg of the polypeptide per kg body weight of the subject; and(iii) the disease comprises a ICI resistant solid tumor selected from the group consisting of: melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI- H tumor, TMB-H or mismatch repair deficient tumor, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof; or platinum -resistant ovarian cancer or microsatellite stable colorectal cancer.

14. The method of any one of the preceding claims, wherein the ICI is an ICI that binds to at least one ofPD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3.

15. The method of claim 14, wherein the ICI is an anti-LAG-3 antibody or antigen binding fragment thereof, optionally wherein the anti-LAG-3 antibody or antigen binding fragment thereof is encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, or tuparstobart.

16. The method of claim 14, wherein the ICI is a PD-1 checkpoint inhibitor, optionally a PD- 1 antagonist, a PD-L1 antagonist, or a PD-L2 inhibitor, optionally wherein the PD-1 checkpoint inhibitor is selected from the group consisting of: acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab,opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA- 170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.

17. The method of any one of claims 10-16, comprising administering one or more CRS prophylactic agents to the subject with or before the DR IL- 18 composition, wherein the one or more CRS prophylactic agents comprise a NSAID, a histamine Hl antagonist, acetaminophen, a H2 blocker, or a combination thereof, and wherein:(i) the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;(ii) the DR IL-18 composition comprises at least about 30 pg of the polypeptide per kg body weight of the patient;(iii) the ICI composition comprises an ICI that binds to at least one of PD-1, PD-L1, PD- L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3; and(iv) the disease comprises a ICI checkpoint inhibitor resistant solid tumor selected from the group consisting of: melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumor, TMB-H or mismatch repair deficient tumor, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, HCC, or any combination thereof; or platinum-resistant ovarian cancer or microsatellite stable colorectal cancer.

18. The method of any one of the preceding claims, wherein the disease is a cancer or a tumor and the method thereby causes one or more improvements in the patient’s cancer or tumor.

19. Use of an ICI composition, DR IL-18 composition, or a combination thereof, in a method of treating cancer, according to any one of the preceding claims.

20. A therapeutic composition comprising: (a) an effective amount of decoy -resistant (DR) IL-18 polypeptide; and (b) and effective amount of an ICI, wherein the ICI is not pembrolizumab, optionally wherein the ICI is selected from the group consisting of acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarlimab, enlonstobart, ezabenlimab, fmotonlimab, geptanolimab, iparomlimab, lipustobart, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, retifanlimab, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zeluvalimab, zimberelimab, INCMGA00012, MEDI0680, SSI- 361, AMP -224, adebrelimab, atezolizumab, avelumab, benmelstobart, betifisolimab, cosibelimab, durvalumab, envafolimab, garivulimab, lesabelimab, lodapolimab, manelimab, opucolimab, pacmilimab, socazolimab, sudubrilimab, sugemalimab,tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botensilimab, evalstotug, firastotug, gotistobart, ipilimumab, muzastotug, nurulimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tuvonralimab, vilastobart, zalifrelimab, encelimab, favezelimab, fianlimab, ieramilimab, miptenalimab, negalstobart, relatlimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vobramitamab, and a variant of any of the foregoing, optionally wherein the therapeutic composition is formulated for intravenous administration, optionally further comprising a buffering agent, a stabilizer, surfactant, an anti-oxidation agent, solvent, or any combination thereof.

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