Drug delivery compositions and uses thereof

Abstract

To provide a medication delivery composition and a device useful for treatment and / or prevention of cancer and metastatic tumor, for example, to provide a medication delivery device including a biodegradable scaffold for transporting one or more anti-cancer therapeutic agents which activate a natural immunity system (STING agonist) and / or an adaptive immunity (for example, anti PD-1 antibody), the composition and device may include cytokine (for example, IL-15 super agonist).SOLUTION: A medication delivery device can be transplanted in void capacity of an excised tumor for preventing re-propagation and spread of the tumor, and there are provided: a method for producing a medication delivery composition and a device; and a kit including materials for providing the composition and the device.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Government Interest Statement This invention was made with government support under Grant No. P50CA168504 awarded by the National Cancer Institute of the National Institutes of Health. The government has certain rights in this invention.

[0002] FIELD OF THE INVENTION The present invention relates to implantable drug delivery compositions and devices that provide local administration of therapeutic agents (e.g., activators of the innate immune response system and / or activators of the adaptive immune response system), and methods of treating diseases such as cancer using such compositions and devices. [Background technology]

[0003] Background of the Invention Systemic administration of pharmaceuticals, nutrients, or other substances into the circulatory system affects the entire body. Systemic routes of administration include enteral (e.g., oral administration, which results in absorption of the drug through the digestive tract) and parenteral (e.g., intravenous, intramuscular, and subcutaneous injection) administration. The administration of immunotherapeutic agents typically relies on these systemic administration routes. However, immunotherapeutic agents often induce unwanted toxicity in unaffected tissues, and systemic administration can therefore result in undesirable side effects. In some instances, certain promising therapeutic agents are extremely difficult to develop due to the associated toxicity and limitations of current administration methods and systems. For example, systemic administration of immunotherapeutic agents for cancer treatment is often associated with immune-related adverse events (e.g., skin rash, hepatitis, diarrhea, colitis, hypophysitis, thyroiditis, and adrenal insufficiency). These adverse events may be due, in part, to exposure of non-tumor-specific immune cells to the drug and the higher doses required by systemic administration to achieve sufficient concentrations to induce the desired response in tumors. In addition to enhancing safety, localizing the delivery of immunotherapeutic agents can improve efficacy by concentrating the drug's action where it is needed.

[0004] Surgery is often the first-line treatment for solid tumor cancers and is typically used in combination with systemic anti-cancer therapy. However, surgery-induced immunosuppression has been associated with the development of postoperative septic complications and tumor metastasis due to alterations in a variety of metabolic and endocrine responses, ultimately resulting in the death of many patients (Smyth, MJ et al. (Nature Reviews Clinical Oncology, 2016, 13, 143-158). Therefore, there is a need to effectively and safely administer immunotherapeutic agents in combination with surgical approaches to achieve antimetastatic efficacy and reduce tumor regrowth. Summary of the Invention

[0005] As mentioned above, systemic administration of immunotherapeutic agents can cause adverse side effects, and surgical removal of tumors can cause immunosuppression. However, the present invention provides a targeted drug delivery system (e.g., targeting a specific tissue or cell type, or targeting a specific diseased tissue but not normal tissue) that can reduce the amount of drug present in non-targeted body tissues (e.g., non-diseased tissues), and is particularly useful when treating cancer in locations where it is desirable to deliver an effective dose of drug to cancer tissue while minimizing the impact on surrounding non-cancerous tissues. In particular, the drug delivery system delivers one or more therapeutic agents that act on the immune system to treat cancer and prevent tumor recurrence and / or metastasis, while minimizing adverse side effects.

[0006] In one aspect, provided are drug delivery compositions and devices comprising a biomaterial (e.g., a hydrogel) and an innate immune response activator (e.g., a STING agonist). In some embodiments, the innate immune response activator is a stimulator of interferon genes (STING) agonist, a cytoplasmic DNA sensor (CDS) agonist, a Toll-like receptor (TLR) agonist, a C-type lectin receptor (CLR) agonist, a NOD-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, or an inflammasome inducer. Some innate immune response activators can induce anti-tumor responses.

[0007] In another aspect, provided are drug delivery compositions and devices comprising a biomaterial, an activator of the innate immune response, and a cytokine (e.g., an IL-15 superagonist). Certain cytokines act as immunomodulators, for example, by activating T cells and NK cells and inducing their proliferation, causing T cells and NK cells to secrete interferon-γ, and endowing T cells and NK cells with the ability to kill malignant cells in the absence of antigenic stimulation. In another aspect, provided are drug delivery compositions and devices comprising a biomaterial and a cytokine (e.g., an IL-15 superagonist).

[0008] In one embodiment, provided are drug delivery compositions and devices comprising a biomaterial, an activator of the innate immune response, and a chemokine (e.g., CXCL9). Certain chemokines can regulate cells of the immune system during the process of immune surveillance and can recruit immune cells to the site of tumor burden. They can serve to guide cells of both the innate and adaptive immune systems. In another embodiment, provided are drug delivery compositions and devices comprising a biomaterial and a chemokine (e.g., CXCL9).

[0009] In some embodiments, the drug delivery compositions and devices further comprise an activator of the adaptive immune response (e.g., an anti-PD-1 antibody, an anti-CTLA-4 antibody, an agonist anti-CD137 antibody). Some activators of the adaptive immune response can activate therapeutic anti-tumor immunity, including blocking immune checkpoints or activating costimulatory molecules.

[0010] In another aspect, provided are drug delivery compositions and devices comprising a biomaterial and an activator of the adaptive immune response (e.g., an anti-PD-1 antibody, an anti-CTLA-4 antibody, an agonist anti-CD137 antibody).

[0011] In some embodiments, the drug delivery compositions and devices further comprise one or more additional activators of the adaptive immune response. In some embodiments, the activator of the adaptive immune response is an antibody (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an agonist anti-CD137 antibody), a bispecific antibody (e.g., a bifunctional fusion protein targeting PD-L1 and TGFβ), an antibody-drug conjugate (e.g., trastuzumab emtansine, inotuzumab ozogamicin), or a small molecule (e.g., celecoxib, bortezomib).

[0012] In some embodiments, the biomaterial is a hydrogel. The hydrogel can provide a scaffold that allows the components of the composition or device to be effectively combined to form an implantable drug delivery system in a surgical setting. In some embodiments, the hydrogel is prepared from hyaluronic acid. Hyaluronic acid is a biocompatible material that biodegrades in vivo over time, allowing the drug to be released from the drug delivery system. .

[0013] In some embodiments, the drug delivery compositions and devices further comprise an oncolytic virus, a radioisotope, a chemotherapeutic agent, or a combination thereof. In some embodiments, the drug delivery compositions and devices comprise at least one excipient.

[0014] In some embodiments, the drug delivery compositions and devices further comprise an oncolytic virus, a radioisotope, an immunomodulatory chemotherapeutic agent, a targeted agent, or a combination thereof.

[0015] In certain embodiments, the drug delivery compositions and devices comprise at least one excipient.

[0016] In some embodiments, the biomaterials (e.g., hydrogels) of the drug delivery compositions and devices are biodegradable in vivo. It has a storage modulus of about 3000 Pa.

[0017] In another aspect, provided is a method for treating and / or preventing cancer by surgically implanting a drug delivery composition or device. In some embodiments, the cancer is sarcoma, carcinoma, lymphoma, germ cell tumor, or blastoma. In another aspect, provided is a method for preventing regrowth of a primary tumor by surgically implanting a drug delivery composition. In another aspect, provided is a method for preventing tumor recurrence and / or metastasis by surgically implanting a drug delivery composition. In some embodiments, the method further comprises implanting the drug delivery composition after surgical resection of the tumor. In some embodiments, the method further comprises implanting the drug delivery composition at the site of tumor resection.

[0018] Also provided are methods of using and preparing the drug delivery compositions and devices, as well as kits that provide the drug delivery compositions and devices.

[0019] The details of certain aspects of the invention are described herein. Other features, objects, and advantages of the invention will become apparent from the detailed description, drawings, examples, and claims.

[0020] definition As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts.

[0021] The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., "Pharmaceutically Acceptable Salts," incorporated herein by reference. Pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivatate, thiamin ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-terminated salts. + (C1-C4 alkyl)4 - Typical alkali or alkaline salts Earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0022] "Polymer" is given its ordinary meaning as used in the art, i.e., a molecular structure comprising one or more repeating units (monomers) linked by covalent bonds. The repeating units may all be identical, or in some cases, there may be more than one type of repeating unit present in the polymer. In some embodiments, a polymer is a compound comprising 11 or more covalently linked repeating units. In some embodiments, a polymer is naturally occurring. In some embodiments, a polymer is synthetic (i.e., not naturally occurring).

[0023] The term "crosslinker" refers to a compound that links one polymer chain to another by a covalent or ionic bond.

[0024] The term "solvate" refers to a form of a compound or its salt associated with a solvent, usually through a solvolysis reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some instances, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0025] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R x HO, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, such as a monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), such as a hemihydrate (R 0.5 H2O)), and polyhydrates (where x is a number greater than 1, such as dihydrates (R2H2O) and hexahydrates (R6H2O)).

[0026] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a pair of tautomers) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0027] It should also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0028] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0029] The term "co-crystal" refers to a crystal structure consisting of at least two components. In certain embodiments, a co-crystal includes a compound of the present invention and one or more other components, including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal includes a compound of the present invention and one or more solvent molecules. In certain embodiments, a co-crystal includes a compound of the present invention and one or more acids or bases. In certain embodiments, a co-crystal includes a compound of the present invention and one or more components related to said compound, including, but not limited to, isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of said compound.

[0030] The term "prodrug" refers to a compound that has a cleavable group and that, upon solvolysis or under physiological conditions, becomes a compound described herein that is pharmaceutically active in vivo. The term "prodrug" refers to a compound. Examples include, but are not limited to, choline ester derivatives and N-alkylmorpholine esters. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but often offer the advantages of solubility, tissue compatibility, or delayed release in mammals in the acid-sensitive form (see, for example, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups present in the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds described herein include C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 Substituted aryl and C7-C 12 Aryl alkyl esters may be preferred.

[0031] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or older adult)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); industrial mammals, e.g., cows, pigs, horses, sheep, goats, cats, dogs, and / or birds (e.g., industrial birds, e.g., chickens, ducks, geese, and / or turkeys). In some embodiments, the animal is a mammal. The animal may be male or female, at any stage of development. The non-human animal may be a transgenic or genetically engineered animal.

[0032] The term "biological sample" refers to tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (such as cytological smears (such as Pap smears or blood smears) or samples obtained by microdissection). a sample of cells isolated from a sample of a whole organism (such as a yeast or bacterial sample); or a cellular fraction, fragment, or organelle (such as obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, a swab (such as a buccal swab), or any material containing biomolecules derived from a first biological sample.

[0033] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a drug delivery composition as described herein.

[0034] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a "pathological condition" (e.g., a disease, disorder, or condition, including one or more signs or symptoms thereof) as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or are observed. Treatment may continue after symptoms have resolved, for example, to delay or prevent recurrence and / or spread.

[0035] The terms "condition," "disease," and "disorder" are used interchangeably.

[0036] An "effective amount" is an amount sufficient to elicit a desired biological response, i.e., to treat a condition. As will be apparent to one skilled in the art, the effective amount of a drug delivery composition can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent in the composition, the condition being treated, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments. For example, in treating cancer, an effective amount of the composition of the present invention can prevent tumor regrowth, reduce tumor burden, or stop tumor growth or spread.

[0037] A "therapeutically effective amount" is an amount sufficient to provide a therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a composition of the invention means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the cause of a symptom or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0038] A "prophylactically effective amount" is an amount sufficient to prevent a condition, or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a composition means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0039] "Proliferative disease" refers to a disease caused by abnormal growth or expansion of cells through proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with: 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of hydrolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as that in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis or angiogenesis-related diseases, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0040] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to the growth of an abnormal mass of tissue that outpaces and is uncoordinated with the growth of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, characteristically grow slower than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous gland hyperplasia. In some cases, a "benign" tumor may later give rise to a malignant neoplasm, which may result from additional genetic alterations in a subpopulation of the tumor's neoplastic cells; these tumors are referred to as "premalignant neoplasms." An example of a premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites.

[0041] The terms "metastasis," "metastatic," or "metastatic" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the histological type of the primary or original tumor that is not of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is said to be metastatic prostate cancer, and includes the proliferation of cancerous prostate cancer cells growing in bone tissue.

[0042] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl et al.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include: These include, but are not limited to: acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma) (hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g. for example, cholangiocarcinoma; bile duct carcinoma; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast carcinoma, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ductal carcinoma in situ in situ); ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., cancers of the hematopoietic system (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CML, T-cell CML), LL, T-cell CLL); lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B lymphoma, cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom hypergammaglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more of the above leukemias / lymphomas; multiple myeloma; heavy chain disease (e.g., alpha-amyloid leukemia ... α-chain disease, gamma-chain disease, mu-chain disease); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); melanoma; midline tract carcinoma; multiple endocrine neoplasia syndrome; muscle cancer; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); nasopharyngeal carcinoma; neuroblastoma; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine carcinomas (e.g., enteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancer (e.g., For example, cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma; papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet tumor); parathyroid carcinoma; papillary adenocarcinoma; penile cancer (e.g., Paget's disease of the penis and scrotum); pharyngeal carcinoma; pinealoma; pituitary carcinoma; pleuropulmonary blastoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., adenocarcinoma of the prostate); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small vowel cancer (e.g., appendix cancer); soft tissue sarcoma ( For example, malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma; sebaceous gland carcinoma; gastric cancer; small intestine cancer; sweat gland cancer carcinoma; synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thymic carcinoma; thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0043] The term "immunotherapeutic agent" refers to a therapeutic agent that promotes disease treatment by inducing, enhancing, or suppressing an immune response. Immunotherapeutics designed to induce or amplify an immune response are classified as activating immunotherapeutics, while immunotherapeutics that reduce or suppress an immune response are classified as suppressing immunotherapeutics. Immunotherapeutics are typically, but not necessarily, biological drugs. Numerous immunotherapeutics are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapeutics include, but are not limited to, inducers of type I interferon, interferons, stimulators of interferon genes (STING) agonists, TLR7 / 8 agonists, IL-15 superagonists, anti-PD-1 antibodies, anti-CD137 antibodies, and anti-CTLA-4 antibodies.

[0044] The terms "biologic," "biologic drug," and " "Biological product" refers to a wide range of products, including vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biological agents may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living organisms such as cells and tissues. Biological agents may be isolated from a variety of natural sources (e.g., humans, animals, microorganisms), or may be reproduced by bioengineering methods and other techniques.

[0045] The term "antibody" refers to a functional component of serum and is often referred to as a collection of molecules (antibodies or immunoglobulins) or as a single molecule (antibody molecule or immunoglobulin molecule). Antibodies can bind to or react with a specific antigenic determinant (antigen or antigenic epitope), which can then lead to the induction of immunological effector mechanisms. Individual antibodies are usually considered to be monospecific, and antibody composition can be monoclonal (i.e., consisting of identical antibody molecules) or polyclonal (i.e., consisting of two or more different antibodies reacting with the same or different epitopes on the same antigen, or, in some cases, on distinct, different antigens). Each antibody has a unique structure that allows it to specifically bind to its corresponding antigen, and all naturally occurring antibodies have the same overall basic structure of two identical light chains and two identical heavy chains. Antibodies are also collectively known as immunoglobulins.

[0046] The term "antibody" or "antibodies," as used herein, is also intended to include chimeric and single-chain antibodies (e.g., nanobodies or Fcabs), as well as binding fragments of antibodies, such as Fab, Fv fragments, or single-chain Fv (scFv) fragments, and multimeric forms, such as dimeric IgA or pentavalent IgM molecules. Also included are bispecific antibodies, bispecific T cell engagers (BiTEs), immune mobilizing monoclonal T cell receptors against cancer (ImmTACs), dual-affinity re-targeting (DART); alternative scaffolds, or antibody mimetics. substances (e.g., anticalins, FN3 monobodies, DARPins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Avimers, Fynomers, Im7, VLR, V NAR, Trimab, CrossMab, Trident); nanobodies, binanobodies , F(ab')2, Fab', di-sdFv, single domain antibodies, trifunctional antibodies, diabodies, and minibodies. Antibodies are of human origin. The antibodies may be of human or non-human origin, such as antibodies of murine or other rodent origin, or chimeric, humanized, or reshaped, for example, based on murine antibodies. The antibody may be an antibody produced by the method described above.

[0047] The term "small molecule" or "small molecule therapeutic" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., via chemical synthesis). Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, and the like). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol, or about 100 g / mol or less. In some embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol but not more than about 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this example, the small molecule is also referred to as an "organometallic small molecule." Preferred small molecules are biologically active in that they provide a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In some embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug has already been deemed safe and effective for use in humans or animals by the appropriate government agency or regulatory authority.For example, drugs approved for use in humans or animals are listed by the FDA under 21 CFR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 CFR §§ 500-589, which are incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0048] The term "therapeutic agent" refers to any substance that has therapeutic properties and produces a desired, usually beneficial, effect. For example, a therapeutic agent can treat, ameliorate, and / or prevent a disease. The therapeutic agents disclosed herein can be biologic agents or small molecule therapeutic agents.

[0049] The term "chemotherapeutic agent" refers to a therapeutic agent known for use in chemotherapy for cancer.

[0050] The term "targeted agent" refers to an anticancer drug that blocks the growth and spread of cancer by interfering with specific molecules ("molecular targets") involved in cancer growth, progression, and spread. Targeted agents are sometimes referred to as "targeted cancer therapy," "molecularly targeted drugs," "molecularly targeted therapy," or "precision medicine." Targeted agents differ from standard chemotherapy in that targeted agents act on specific molecular targets associated with cancer, whereas standard chemotherapy acts on all rapidly dividing normal and cancerous cells. Targeted agents are deliberately selected or designed to interact with their targets, whereas many standard chemotherapy agents are identified because they kill cells.

[0051] The term "biomaterial" refers to any biocompatible substance engineered to interact with biological systems for medical purposes (e.g., therapeutic, diagnostic). Biomaterials can be naturally derived or synthetic.

[0052] The term "hydrogel" refers to a network of hydrophilic polymer chains, sometimes found as colloidal particles in which water is the dispersion medium. Hydrogels are highly absorbent (may contain more than 90% water) natural or synthetic polymer networks. Hydrogels also possess a degree of flexibility similar to that of natural tissue due to their significant water content.

[0053] The terms "implantable," "implant," "implanting," and "graft" refer to the placement of a drug delivery composition in a specific location in a subject, for example, within a tumor reaction site or in a sentinel lymph node, typically by conventional surgical methods.

[0054] The term "biocompatible" means substantially non-toxic in the in vivo environment of the intended use. Biocompatibility refers to a material that is not substantially rejected by a patient's physiological systems (i.e., is non-antigenic). This can be measured by the material's ability to pass biocompatibility tests set forth in International Organization for Standardization (ISO) Standard No. 10993 and / or United States Pharmacopeia (USP) 23 and / or U.S. Food and Drug Administration (FDA) Blue Book Memorandum No. G95-1, entitled "Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing." Typically, these tests test the material's toxicity, infectivity, pyrogenicity, irritant potential, reactivity, hemolytic activity, carcinogenicity, and / or immunogenicity. A biocompatible structure or material, when introduced into the majority of patients, does not elicit an undesirable, harmful, long-lasting, or exaggerated biological reaction or response that is distinguishable from the mild, transient inflammation typically associated with surgery or the implantation of a foreign substance in a living body.

[0055] The term "inhibit" or "inhibition," with respect to an enzyme, refers to a decrease in the activity of the enzyme. In some embodiments, the term refers to a decrease in the level of enzyme activity to a level that is statistically significantly lower than the initial level (which may be, for example, the baseline level of enzyme activity). In some embodiments, the term refers to a decrease in the level of enzyme activity to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level (which may be, for example, the baseline level of enzyme activity).

[0056] The term "activator of the innate immune response" refers to an agent that activates the innate immune system. Such activation can stimulate the expression of molecules that help initiate inflammatory responses and / or induce adaptive immune responses, leading to the development of antigen-specific adaptive immunity. Activation of the innate immune system can result in cytokine production, proliferation, and survival, as well as improved T cell priming through enhanced antigen presentation and the expression of costimulatory molecules by antigen-presenting cells.

[0057] The term "activator of the adaptive immune response" refers to an agent that activates the adaptive immune system. Such activation can restore anti-tumor function by neutralizing inhibitory immune checkpoints or by triggering costimulatory receptors, ultimately generating helper and / or effector T cell responses against immunogenic antigens expressed by cancer cells and generating memory B cell and / or T cell populations. In some embodiments, an activator of the adaptive immune response involves modulation of the adaptive immune response and / or leukocyte trafficking.

[0058] The term "modulator of macrophage effector function" refers to an agent that activates macrophage effector function or depletes immunosuppressive macrophages or macrophage-derived suppressor cells. Such enhancement can recruit macrophages and bone marrow components to destroy tumors and their stroma, including tumor vasculature. Macrophages can be induced to secrete antitumor cytokines and / or perform phagocytosis, including antibody-dependent cellular phagocytosis.

[0059] As used herein, the terms "sustained release" and "extended release" are equivalent terms. The compositions and devices of the present disclosure may release a therapeutic agent upon in vivo implantation following tumor resection. The terms "sustained" and "extended" may mean that any of the therapeutic agents is released over a time scale ranging from 1 minute to 1 month. In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of any of the therapeutic agents is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 1 minute after implantation of the composition or device. In some embodiments, one of the therapeutic agents 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of any of these is released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 1 minute after implantation of the composition or device. [Brief explanation of the drawings]

[0060] [Figure 1]FIG. 1 is an image of an exemplary drug delivery device F conjugated with ALEXA FLUOR® 750 dye.

[0061] [Figure 2] Figure 2 shows images of individual mice after tumor seeding and resection followed by implantation of exemplary drug delivery device F. The images show the degradation of the fluorescent dye-loaded hydrogel over a 13-week period.

[0062] [Figure 3] FIG. 3 is a graph showing the biodegradation over time of the exemplary drug delivery device F implanted in FIG.

[0063] [Figure 4] Figure 4 shows Kaplan-Meier curves for female BALB / cJ mice orthotopically seeded with 4T1-Luc2 cells and whose tumors were either untreated or surgically resected.

[0064] [Figure 5] Figure 5 shows images of individual mice after implantation of exemplary drug delivery device F through the mammary fat pad without tumor seeding and resection. The images show the degradation of the fluorescent dye-loaded hydrogel over a 24-week period.

[0065] [Figure 6] FIG. 6 is a graph showing the biodegradation over time of the exemplary drug delivery device F implanted in FIG.

[0066] [Figure 7] FIG. 7 shows images of individual mice after topical administration of ALEXA FLUOR® 750 dye in solution and fluorescence IVIS imaging at the indicated time points.

[0067] [Figure 8]FIG. 8 is a graph comparing the biodegradation of exemplary drug delivery device F from FIG. 6 with the in vivo diffusion of free dye in FIG.

[0068] [Figure 9] FIG. 9 shows a confocal image of an exemplary drug delivery device 1 (fluorescently labeled 2′3′-cGAMP+anti-PD-1 antibody+IL-15 superagonist).

[0069] [Figure 10] FIG. 10 shows a confocal image of exemplary drug delivery device 2 (fluorescently labeled anti-PD-1 antibody + IL-15 superagonist).

[0070] [Figure 11] FIG. 11 is a series of graphs showing the release rates of therapeutic agents (celecoxib, anti-PD-1 antibody, IL-15 superagonist) from drug delivery devices 3, 4, and 5 using various excipients (Tween, PBS, RPMI+10% FBS).

[0071] [Figure 12] FIG. 12 is a graph showing the release rates of c-di-GMP from drug delivery device 6 and 2′3′-cGAMP from drug delivery devices 1 and 7 using various excipients (PBS, RPMI+10% FBS).

[0072] [Figure 13] Figure 13 is a series of graphs showing the release rates of: 2'3'-cGAMP from drug delivery devices 1 and 7 in different media (PBS, RPMI+10% FBS); IL-15 superagonist from drug delivery devices 1 and 5 in different media (PBS, RPMI+10% FBS); and anti-PD-1 antibody from drug delivery devices 1 and 4 in different media (PBS, RPMI+10% FBS).

[0073] [Figure 14]FIG. 14 shows images of individual mice following administration of fluorescently labeled 2′3′-cGAMP in solution or exemplary drug delivery device 7 implanted next to the fourth mammary fat pad of tumor-free female BALB / cJ mice.

[0074] [Figure 15] Figure 15 shows images of individual mice following administration of fluorescently labeled IL-15 superagonist (IL-15sa) in solution or exemplary drug delivery device 5 implanted adjacent to the fourth mammary fat pad of tumor-free female BALB / cJ mice.

[0075] [Figure 16] Figure 16 shows images of individual mice following administration of fluorescently labeled anti-PD-1 antibody in solution or exemplary drug delivery device 4 implanted adjacent to the fourth mammary fat pad of tumor-free female BALB / cJ mice.

[0076] [Figure 17] Figure 17 is a series of graphs quantifying the release kinetics for 2'3'-cGAMP, IL-15sa, and anti-PD-1 from the experiments in Figures 14-16. The fold difference is shown for each time point. Data are expressed as mean ± SEM. *p≦0.05, **p≦0.01, ***p≦0.001, ****p≦0.0001.

[0077] [Figure 18] Figure 18 shows images of individual mice after inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0078] [Figure 19] Figure 19 shows images of individual mice following implantation of a non-drug-containing hydrogel, Device 8, after inoculation and excision of a tumor derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0079] [Figure 20] Figure 20 shows images of individual mice following implantation of exemplary drug delivery device 2 (anti-PD-1 antibody + IL-15 superagonist) after inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0080] [Figure 21] Figure 21 shows images of individual mice after implantation of an exemplary drug delivery device 9 (STING agonist + anti-PD-1 antibody) following inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0081] [Figure 22] 22 shows images of individual mice after implantation of an exemplary drug delivery device 10 (STING agonist + IL-15 superagonist) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0082] [Figure 23] Figure 23 shows images of individual mice after implantation of exemplary drug delivery device 1 (STING agonist + IL-15 superagonist + anti-PD-1 antibody) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0083] [Figure 24] Figure 24 shows images of individual mice after implantation of an exemplary drug delivery device 11 (STING agonist + IL-15 superagonist + agonist anti-CD137 antibody) following seeding and resection. The images show the appearance / disappearance of tumors over a 6-week period.

[0084] [Figure 25]Figure 25 shows images of individual mice after implantation of exemplary drug delivery device 12 (STING agonist + IL-15 superagonist + agonist anti-CD40 antibody) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0085] [Figure 26] Figure 26 shows images of individual mice following implantation of exemplary drug delivery device 13 (STING agonist + IL-21 + anti-PD-1 antibody) after inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0086] [Figure 27] Figure 27 shows images of individual mice after implantation of exemplary drug delivery device 14 (resiquimod + IL-15 superagonist + anti-PD-1 antibody) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0087] [Figure 28] Figure 28 shows images of individual mice after implantation of an exemplary drug delivery device 15 (poly(I:C) + IL-15 superagonist + anti-PD-1 antibody) following inoculation and excision of a tumor derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0088] [Figure 29] Figure 29 shows images of individual mice following implantation of an exemplary drug delivery device 16 (CpG oligonucleotide + IL-15 superagonist + anti-PD-1 antibody) after inoculation and resection of a tumor derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period.

[0089] [Figure 30]Figure 30 shows images of individual mice after implantation of a device containing a hydrogel containing an IL-15 superagonist, anti-PD-1, and a small molecule therapeutic agent (celecoxib or EW7197 dissolved in DMSO) following inoculation and resection of a tumor derived from 4T1-Luc2 syngeneic breast cancer cells. Figure 30 also shows images of individual mice after administration via topical administration of a solution containing an IL-15 superagonist, anti-PD-1, and a small molecule therapeutic agent (celecoxib or EW7197 dissolved in DMSO) following inoculation and resection of a tumor derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 3-week period.

[0090] [Figure 31] Figure 31 shows images of different cohorts of mice after implantation of a series of devices: (c-di-GMP + IL-15 superagonist + anti-PD-1 antibody), (c-di-GMP + IL-15 superagonist + anti-PD-1 antibody + DMSO), or (DMSO) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. Images show the appearance / disappearance of tumors over a period of 1 to 3 weeks.

[0091] [Figure 32] Figure 32 shows images of individual mice after intraperitoneal (IP) or intravenous (IV) injection of a solution of an exemplary composition (STING agonist + IL-15 superagonist + anti-PD-1 antibody) following inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells and tumor resection. The images show the appearance / disappearance of tumors over a 6-week period.

[0092] [Figure 33] Figure 33 shows images of individual mice following topical administration of a solution of an exemplary composition (STING agonist + IL-15 superagonist + anti-PD-1 antibody) following inoculation with a tumor derived from 4T1-Luc2 syngeneic breast cancer cells and tumor resection. The images show the appearance / disappearance of tumors over a 6-week period.

[0093] [Figure 34] Figure 34 shows images of individual mice following implantation of exemplary drug delivery device 1 (STING agonist + IL-15 superagonist + anti-PD-1 antibody) after inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period among NK cell-depleted mice.

[0094] [Figure 35] Figure 35 shows images of individual mice after implantation of exemplary drug delivery device 1 (STING agonist + IL-15 superagonist + anti-PD-1 antibody) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period among mice that were depleted of CD8+ T cells.

[0095] [Figure 36] Figure 36 shows images of individual mice after implantation of exemplary drug delivery device 1 (STING agonist + IL-15 superagonist + anti-PD-1 antibody) following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period among mice that were depleted of CD4+ T cells.

[0096] [Figure 37] Figures 37A-37C demonstrate that biodegradable hydrogel scaffolds in situ prolong localized release of payloads, enabling focused perioperative cancer immunotherapy. Figure 37A shows a photograph of a representative scaffold loaded with R848. Figure 37B shows fluorescent IVIS imaging depicting the in vivo release profile of a model small molecule payload (Cy7 carboxylic acid). Figure 37C shows quantification of the in vivo release profile of Cy7 carboxylic acid. Experiments were performed once with n=5 biological replicates. Fold differences are shown for each time point. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SD. *p≦0.05, ***p≦0.001, ****p≦0.0001

[0097] [Figure 38] Figures 38A-38F show that hydrogel scaffolds prolong the release of biologic drugs and small molecules in vitro. Scaffolds were placed in PBS (pH 7.4), and drug release was measured using a fluorescent plate reader or HPLC. The following payloads were evaluated: anti-PD-1 (Figure 38A), IL-15sa (Figure 38B), lenalidomide (Figure 38C), celecoxib (Figure 38D), 2'3'-cGAMP (2'3'-c-di-AM(PS)2(Rp,Rp), a model compound for "STING-RR") (Figure 38E), and R848 (Figure 38F). Experiments were performed three times with biological replicates (n=4+). Data are presented as mean ± SD.

[0098] [Figure 39] Figure 39 shows images of individual mice following implantation of exemplary drug delivery devices 17 (STING agonist), 18 (IL-15 superagonist), or 19 (anti-PD-1 antibody) after inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 6-week period. Doubling the dose of the STING agonist or IL-15 superagonist resulted in significant efficacy, indicating the use of these compounds as monotherapeutics, whereas doubling the dose of anti-PD-1 did not.

[0099] [Figure 40] FIG. 40 is an image of Device 1 showing the mechanical integrity of the hydrogel.

[0100] [Figure 41] Figure 41 shows images of a device loaded with ALEXA FLUOR® 750 dye (left) and a control device without fluorescent dye (right). The fluorescent images show that the loaded small molecules are uniformly distributed throughout the hydrogel.

[0101] [Figure 42] Figure 42 shows images of individual mice after implantation of an exemplary drug delivery device 1 following inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The following groups were evaluated: no treatment (sham), empty hydrogel, intraperitoneal injection of the triple combination (2'3'-cGAMP, IL-15sa, and anti-PD-1), intravenous injection of the triple combination (2'3'-cGAMP, IL-15sa, and anti-PD-1), topical administration of the triple combination (2'3'-cGAMP, IL-15sa, and anti-PD-1), or Device 1. Hydrogel was placed at the site of the tumor reaction, as was topical administration of the triple combination in solution.

[0102] [Figure 43] Figure 43 shows a series of graphs showing that sustained local release of 2'3'-cGAMP, IL-15sa, and anti-PD-1 (Device 1) prevents tumor recurrence and metastasis in the majority of mice, as illustrated by the total flux of bioluminescent 4T1-Luc2 cells. Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0103] [Figure 44] Figure 44 shows Kaplan-Meier curves for all groups described in Figure 42. The number of mice (n) per group and median survival (ms) are listed. Statistics were calculated relative to the group treated with hydrogel containing the triplicate combination using the log-rank (Mantel-Cox) test. **p≦0.01, ***p≦0.001, ****p≦0.0001.

[0104] [Figure 45] Figure 45 shows images of individual mice after implantation of exemplary drug delivery devices 11-16 and 20 following inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The devices were placed at the site of the tumor reaction.

[0105] [Figure 46] Figure 46 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells following administration of devices 11, 12, and 20 compared to device 1 (containing anti-PD-1 as the antibody in combination with IL-15sa and 2'3'-cGAMP) from the experiment described in Figure 45. Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0106] [Figure 47] Figure 47 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells following administration of Device 13 compared to Device 1 (containing IL-15sa as a cytokine in combination with 2'3'-cGAMP and anti-PD-1) from the experiment described in Figure 45. Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0107] [Figure 48] Figure 48 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells following administration of devices 14-16 from Figure 45 compared to device 1 (containing 2'3'-cGAMP as an innate immune activator in combination with IL-15sa and anti-PD-1). Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0108] [Figure 49]Figures 49A-49C show a series of Kaplan-Meier curves for devices 1, 11, 12, and 20 (Figure 49A); devices 1 and 13 (Figure 49B); and devices 1 and 14-16 (Figure 49C). The number of mice per group (n) and median survival (ms) are listed. Statistics were calculated using the log-rank (Mantel-Cox) test compared to groups treated with hydrogels containing anti-PD-1 (Device 1) (Figure 49A), IL-15sa (Device 1) (Figure 49B), or 2'3'-cGAMP (Device 1) (Figure 49C). *p≦0.05, **p≦0.01, ***p≦0.001.

[0109] [Figure 50] Figure 50 shows images of individual mice after implantation of exemplary drug delivery devices 2, 9, and 10 following inoculation and excision of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The devices were placed at the site of the tumor reaction.

[0110] [Figure 51] Figure 51 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells following administration of exemplary drug delivery devices 2, 9, and 10 from the experiment described in Figure 50, compared to device 1. Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0111] [Figure 52] Figure 52 shows a series of Kaplan-Meier curves for devices 1, 2, 9, and 10. The number of mice per group (n) and median survival (ms) are listed. Statistics were calculated using the log-rank (Mantel-Cox) test compared to the group treated with device 1. *p≦0.05, **p≦0.01, ***p≦0.001.

[0112] [Figure 53]Figure 53 is a series of plots showing flow cytometry analysis of leukocytes isolated from blood 10 days after surgery. The plots confirm that NK cells, CD8+ T cells, and CD4+ T cells are depleted after administration of the appropriate antibody to the mice.

[0113] [Figure 54] Figure 54 shows images of individual mice following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells, followed by implantation of an exemplary drug delivery device 1. The images show the appearance / disappearance of tumors over a 4-week period among mice depleted of NK cells, CD8+ T cells, or CD4+ T cells; or mice in which innate immune signaling (IFNAR1) was inhibited.

[0114] [Figure 55] Figure 55 shows Kaplan-Meier curves for all groups in the experiment described in Figure 54. The number of mice per group (n) and median survival (ms) are listed. Statistics were calculated relative to the groups treated with the triplicate combination hydrogel (Device 1) and PBS (control) using the log-rank (Mantel-Cox) test. *p≦0.05, ***p≦0.001

[0115] [Figure 56] Figure 56 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device 1 from the experiment described in Figure 54. Data for individual mice are shown for tumors that recurred locally or metastasized to the lungs after the indicated treatments.

[0116] [Figure 57]Figures 57A-57F are a series of graphs showing that sustained local release of 2'3'-cGAMP, IL-15sa, and anti-PD-1 increases the number of innate and adaptive anti-tumor immune cells and cytokines. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice, and device 1 was placed at the site of the reaction. Three or 14 days after surgery, spleens were collected from mice for flow cytometry analysis, and 14 days after surgery, blood was collected from mice for cytokine analysis. Figures 57A-57C show that numerous leukocytes with activated effector phenotypes were observed. Quantification of flow cytometry gating of subsets of NK cells (day 3) (Figure 57A), dendritic cells (day 3) (Figure 57B), and CD4+ and CD8+ T cells (day 14) (Figure 57C) is shown. Figures 57D-57E show that T cells producing proinflammatory cytokines and cytolytic molecules were observed in large numbers. Quantification of flow cytometry gating for CD4+ and CD8+ T cells (day 14) is shown. Splenocytes were cultured for 5 hours in the presence of phorbol ester, ionomycin, and brefeldin A (Figure 57D) or a specific immunodominant peptide (survivin 66-74) expressed by 4T1 cells and brefeldin A, followed by flow cytometry (Figure 57E). Figure 57F shows that elevated cytokine concentrations were observed in plasma collected 14 days after surgery. Levels of type I interferon are shown (see Figure 57F). Data were generated using multiplexing laser bead technology. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SEM. *p≦0.05, **p≦0.01, ***p≦0.001, ****p≦0.0001

[0117] [Figure 58]Figure 58 is a graph showing that elevated concentrations of cytokines were observed in plasma collected 14 days after surgery for the experiment described in Figures 57A-57F. Levels of a panel of cytokines are shown. Data were generated by multiplex laser bead technology. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SEM. *p≦0.05, **p≦0.01, ***p≦0.001, ****p≦0.0001

[0118] [Figure 59] Figure 59 is a graph showing that sustained local release of 2'3'-cGAMP, IL-15sa, and anti-PD-1 increased the numbers of several leukocyte subsets in the lung. Lungs were harvested 14 days after surgery for the experiment described in Figures 57A-57F, and single-cell suspensions were prepared for flow cytometry. Data are presented as mean ± SEM. *p≦0.05, **p≦0.01

[0119] [Figure 60] Figure 60 is a Kaplan-Meier curve showing that the efficacy of exemplary drug delivery device 1 against parental 4T1 (lacking the luc2 transgene) is comparable to the efficacy of exemplary drug delivery device 1 against 4T1-luc2 in mice bearing tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The number of mice per group (n) and median survival (ms) are listed.

[0120] [Figure 61] Figure 61 shows images of individual mice after implantation of an exemplary drug delivery device 1 following inoculation with a tumor derived from 4T1-Luc2 syngeneic breast cancer cells, compared to an untreated mouse. The tumor was not resected, and the device was implanted around the tumor. The images show the appearance / disappearance of the tumor over a 4-week period.

[0121] [Figure 62]Figure 62 shows Kaplan-Meier curves for all groups from the experiment described in Figure 61. The number of mice (n) per group and median survival (ms) are listed. Figure 62 also shows a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of exemplary drug delivery device 1 from the experiment described in Figure 61. Data for individual mice are shown for tumors that recurred locally or metastasized to the lung after the indicated treatments.

[0122] [Figure 63] Figure 63 shows images of individual mice after implantation of an exemplary drug delivery device 21 following inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a four-week period. Figure 63 also shows a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells following administration of the exemplary drug delivery device 21.

[0123] [Figure 64] Figure 64 shows Kaplan-Meier curves for mice implanted with exemplary drug delivery device 21 compared to exemplary drug delivery device 1 after inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The number of mice per group (n) and median survival (ms) are listed.

[0124] [Figure 65] Figure 65 is a series of graphs showing the in vitro release rates of: 2'3'-cGAMP (25 μg, 50 μg, 100 μg) from drug delivery device 7 in PBS (pH 7.4); resiquimod (R848; 100 μg, 200 μg) from drug delivery device 22 in PBS (pH 7.4); anti-PD-1 antibody (150 μg, 300 μg) from drug delivery device 4 in PBS (pH 7.4); and IL-15sa (1.5 μg, 3.0 μg) from drug delivery device 5 in PBS (pH 7.4).

[0125] [Figure 66]Figure 66 shows images of individual mice following implantation of exemplary drug delivery devices 7 (50 μg or 100 μg of S), 23 (50 μg of STING-RR), or STING-RR (100 μg)-loaded alginate following inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0126] [Figure 67] Figure 67 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 66. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0127] [Figure 68] Figure 68 shows images of individual mice after implantation of an exemplary drug delivery device 22 (50 μg, 100 μg, or 200 μg of resiquimod (R848, Invivogen) was dissolved in water to form the device); an exemplary drug delivery device 22 (200 μg of resiquimod (R848, Sigma) was dissolved in DMSO to form the device). The devices were implanted after inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0128] [Figure 69] Figure 69 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 68. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0129] [Figure 70]Figure 70 shows images of individual mice following implantation of exemplary drug delivery devices 5 (3 μg IL-15sa), 4 (300 μg anti-PD-1 antibody), 24 (15 μg IFN-α), 25 (3 μg IFN-β), and 26 (30 μg IFN-γ) after inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0130] [Figure 71] Figure 71 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 70. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0131] [Figure 72] Figure 72 shows images of individual mice following implantation of exemplary drug delivery devices 27 (150 μg each of anti-PD-1 antibody and anti-CTLA4 antibody), 28 (50 μg of resiquimod + 150 μg each of anti-PD-1 antibody and anti-CTLA4 antibody), 29 (300 μg of M-TriDAP), 30 (200 μg of lenalidomide, where lenalidomide was dissolved in water for device formation), and 30 (200 μg of lenalidomide, where lenalidomide was dissolved in DMSO for device formation) following inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0132] [Figure 73] Figure 73 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 72. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0133] [Figure 74] Figure 74 shows images of individual mice after implantation of exemplary drug delivery devices 23 (100 μg of STING-RR) or 8 (hydrogel 4) following inoculation with tumors derived from 4T1-Luc2 syngeneic breast cancer cells. Device 8 was implanted in combination with local administration of STING-RR (100 μg). A control group receiving no treatment after tumor resection was also evaluated. The images show the appearance / disappearance of tumors over a 4-week period. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0134] [Figure 75] Figure 75 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 74. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0135] [Figure 76] Figure 76 shows images of individual mice after implantation of an exemplary drug delivery device 23 following inoculation and resection of tumors derived from 4T1-Luc2 syngeneic breast cancer cells. The images show the appearance / disappearance of tumors over a 4-week period among mice depleted of NK cells, CD8+ T cells, or CD4+ T cells; or mice in which innate immune signaling (IFNAR1) was inhibited. The top image monitors the site of resection (local tumor recurrence), while the bottom image shows lung metastases.

[0136] [Figure 77] Figure 77 is a series of graphs showing the total flux of bioluminescent 4T1-Luc2 cells after administration of the exemplary drug delivery device described in Figure 76. The top image shows the site of resection (local tumor recurrence), while the bottom image shows lung metastasis.

[0137] [Figure 78]Figure 78 is a series of graphs showing that sustained local release of STING-RR increases cytokine levels in the blood. 10 days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice and device 23 was placed at the reaction site. Blood was collected from mice 3 days (top graph) or 14 days (bottom graph) after surgery for cytokine analysis.

[0138] [Figure 79] Figure 79 is a series of graphs showing that sustained local release of 2'3'-cGAMP, IL-15sa, and anti-PD-1 (Device 1) did not alter blood composition. After placing Device 1 at the reaction site, blood was collected 14 days after surgery. WBC, white blood cells; NE, neutrophils; LY, lymphocytes; MO, monocytes; EO, eosinophils; BA, basophils; HCT, hematocrit; RBC, red blood cells; MCV, mean corpuscular volume; RDW, red blood cell distribution width; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MPV, mean platelet volume; PLT, platelets. Data are presented as mean ± SEM. Dashed lines indicate established normal ranges.

[0139] [Figure 80] Figures 80A-80B are a series of graphs showing that the sustained local release of 2'3'-cGAMP, IL-15sa, and anti-PD-1 following tumor resection was well tolerated after implantation of a variety of different devices (1, 2, 9, 10) or administration via different routes (IP, IV, topical). None of the listed conditions had a long-term effect on liver enzyme levels measured 15 days after surgery (Figure 80A) or mouse body weight (Figure 80B). The weight loss observed during the first week was observed in all groups, including the untreated and empty hydrogel negative controls, and was therefore related to the stress of the surgery itself. Data in Figure 80A are presented as mean ± SEM. The dashed line indicates the established normal range.

[0140] [Figure 81]Figure 81 is a series of graphs showing that sustained local release of STING-RR (device 23) did not alter blood composition. After placement of device 23 at the reaction site, blood was collected 14 days after surgery. WBC, white blood cells; NE, neutrophils; LY, lymphocytes; MO, monocytes; EO, eosinophils; BA, basophils; HCT, hematocrit; RBC, red blood cells; MCV, mean corpuscular volume; RDW, red blood cell distribution width; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MPV, mean platelet volume; PLT, platelets. Data are presented as mean ± SEM. Dashed lines indicate established normal ranges.

[0141] [Figure 82] Figures 82A-83B are a series of graphs showing that sustained local release of STING-RR after implantation or local administration of Device 23 following tumor resection was well tolerated. None of the listed routes of administration or devices had a long-term effect on liver enzyme levels measured 15 days after surgery (Figure 82A) or mouse body weight (Figure 82B). The weight loss observed in the first week was observed in all groups, including the untreated negative control, and was therefore related to the stress of the surgery itself. "Hydrogel (RR)" refers to loading of STING-RR into a hydrogel prepared from hyaluronic acid (Device 23); "Hydrogel (Alginate)" refers to loading of STING-RR (100 μg) into a hydrogel prepared from alginate. Data in Figure 82A are presented as mean ± SEM. The dashed line indicates the established normal range.

[0142] [Figure 83]Figures 83A-83D show that long-term local release of an innate immune agonist prevented tumor recurrence and distant metastasis, curing the majority of mice after perioperative treatment. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice and hydrogels loaded with the following payloads were evaluated: anti-PD-1, anti-CTLA-4, IL-15sa, lenalidomide, celecoxib, STING-RR, or R848. No hydrogel was tested as a negative control. Figure 83A shows IVIS imaging of 4T1-Luc2 cells for all groups, illustrating tumor burden. Figure 83B shows Kaplan-Meier curves comparing antibodies inducing immune checkpoint blockade (Device 19 or 31 (300 μg anti-CTLA-4)) with no hydrogel. Figure 83C shows Kaplan-Meier curves comparing the potent cytokine IL-15sa (Device 18) with no hydrogel. Figure 83D shows Kaplan-Meier curves comparing immunomodulatory small molecules (Device 3 (1500 μg celecoxib), 22, 23, or 30) with no hydrogel. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test compared to the group treated with no hydrogel. **p≦0.01, ***p≦0.001.

[0143] [Figure 84]Figures 84A-84F show that innate immune agonists are effective only when released locally from the hydrogel. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells (see Figures 84A-84B). Figure 84A shows Kaplan-Meier curves for all groups described: no hydrogel, weekly intraperitoneal (IP) injection of R848, weekly intravenous (IV) injection of R848, empty hydrogel + local administration of R848 in solution, or R848-loaded hydrogel (Device 22). Figure 84B shows Kaplan-Meier curves for all groups described: no hydrogel, empty hydrogel + local administration of STING-RR in solution, or STING-RR-loaded hydrogel (Device 23). Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were intratumorally injected (IT) with a single dose of R848 or STING-RR (see Figures 84C-84D). Tumor volume (Figure 84C) and mouse survival rate (Figure 84D) were measured. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells (see Figures 84E-84F). Figure 84E shows Kaplan-Meier curves for all groups indicated: no hydrogel, Ccl4 (device 32), Ccl5 (device 33), or Cxcl10 (device 34). Figure 84F shows Kaplan-Meier curves for all groups indicated: no hydrogel, paclitaxel (device 35), or doxorubicin (device 36). The number of mice (n) per group and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test compared to the group treated with hydrogel containing the indicated innate immune agonist. *p≦0.05, **p≦0.01, ***p≦0.001.

[0144] [Figure 85]Figures 85A-85B show that multiple systemic administrations of R848 failed to confer a significant survival benefit and were much less tolerated than R848 released from hydrogels. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells. Figure 85A shows Kaplan-Meier curves for IP injections of R848 (200 μg) without hydrogel and three consecutive daily injections. Figure 85B shows mouse weights for each treatment group. The number of mice per group (n) and median survival rates (ms) are listed. Experiments were performed with at least three biological replicates.

[0145] [Figure 86] Figure 86 shows that STING-RR confers superior efficacy over 2'3'-cGAMP in the perioperative setting through prolonged release from hydrogel (devices 23 or 7 (100 μg of S)) for a given loaded dose. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells. Kaplan-Meier curves illustrate the relative survival benefit. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test compared to no hydrogel. **p≦0.01

[0146] [Figure 87] Figure 87 shows that the efficacy of STING-RR loaded in hydrogel is maintained after refrigerated storage at 4°C for one week. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells. Kaplan-Meier curves are shown for no hydrogel, STING-RR-loaded hydrogel (Device 23), or STING-RR-loaded hydrogel stored at 4°C for seven days. The number of mice per group (n) and median survival rate (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test compared to no hydrogel. **p≦0.01

[0147] [Figure 88] Figures 88A-88B show that intraoperative placement of immunotherapeutic-loaded hydrogels into the tumor reaction site is required for therapeutic efficacy. Local release of innate immune agonists (as monotherapy) from hydrogels does not confer therapeutic efficacy, even when the hydrogels are placed around the tumor in the absence of tumor removal. R848 (Device 22) (Figure 88A) or STING-RR-loaded hydrogels (Device 23) (Figure 88B) were placed around the tumor 10 days after orthotopic seeding of 4T1-Luc2 cells. Kaplan-Meier curves for the control and treatment groups are shown. The number of mice per group (n) and median survival rate (ms) are listed. Experiments were performed with at least three biological replicates.

[0148] [Figure 89] Figure 89 shows that prolonged local release of combined immune checkpoint blockade confers a limited survival benefit. Tumors were excised from mice 10 days after orthotopic seeding of 4T1-Luc2 cells. Kaplan-Meier curves are shown for no hydrogel or anti-PD-1 and anti-CTLA-4 loaded hydrogels (devices loaded with 300 μg of each antibody). The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates.

[0149] [Figure 90]Figures 90A-90B demonstrate that both innate and adaptive immune system readiness are critical to the observed efficacy. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice, and Device 22 (R848) (Figure 90A) or Device 23 (STING-RR) (Figure 90B) was placed at the site of the reaction. To investigate their relative contribution to the observed efficacy, specific immune cell subsets (NK cells, CD8+ T cells, or CD4+ T cells) were depleted or innate immune signaling (IFNAR1) was inhibited. Kaplan-Meier curves are shown for all groups listed. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test, comparing groups treated with the indicated innate immune agonist-containing hydrogels with groups treated with PBS (no depletion control). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0150] [Figure 91]Figures 91A-91G show that prolonged local release of R848 increases the number of innate and adaptive antitumor immune cells and cytokines. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice, and device 22 was placed at the site of the reaction. Spleens were collected from mice 3 and 14 days after surgery for flow cytometry analysis, and blood was collected from mice 1.5 hours, 6 hours, 3 days, and 14 days after surgery for cytokine analysis. As shown in Figures 91A-91C, numerous activated leukocytes with effector phenotypes were observed. Quantification of flow cytometry gating of subsets of NK cells (day 3) (Figure 91A), dendritic cells (day 3) (Figure 91B), and CD4+ and CD8+ T cells (day 14) (Figure 91C) is shown. Figure 91D shows numerous central memory-like CD8+ T cells. Figure 91E shows that numerous T cells producing proinflammatory cytokines and cytolytic molecules were observed. Quantification of flow cytometry gating of CD4+ and CD8+ T cells (day 14) is shown. Splenocytes were cultured for 6 hours in the presence of a specific immunodominant peptide (gp70423-431) expressed by 4T1 cells and brefeldin A, followed by flow cytometry. High concentrations of cytokines were observed in plasma collected at various time points after surgery (see Figures 91F-91G). Figure 91F shows the level of type I interferon. Figure 91G shows the level of a panel of cytokines. Data were generated using multiplex laser bead technology. Experiments were performed once with n=5 biological replicates. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SEM. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001.

[0151] [Figure 92]Figures 92A-92B show that prolonged local release of STING-RR increases the number of innate immune cells. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice, and the device 23 was placed at the reaction site. Three days after surgery, spleens were harvested from mice for flow cytometry analysis. Large numbers of activated leukocytes with effector phenotypes were observed. Quantification of flow cytometry gating of subsets of NK cells (Figure 92A) and dendritic cells (Figure 92B) is shown.

[0152] [Figure 93] Figures 93A-93B show that prolonged local release of R848 increases the numbers of several leukocyte subsets in the lung. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice and device 22 was placed at the reaction site. Lungs were harvested on days 3 (Figure 93A) and 14 (Figure 93B) after surgery, and single-cell suspensions were prepared for flow cytometry. Data are presented as mean ± SEM. *p≦0.05, **p≦0.01.

[0153] [Figure 94] Figures 94A-94B show that the induction of an adaptive antitumor memory response is confirmed by the rejection of 4T1-Luc2 cells seeded as a rechallenge. Kaplan-Meier curves demonstrate that 100% of naive mice succumbed to the lethal challenge, whereas 100% of mice achieving durable survival benefits after treatment with R848 (Figure 94A) or STING-RR (Figure 94B)-loaded hydrogels survived the rechallenge. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed once with biological replicates. Statistics were calculated using log-rank (Mantel-Cox) compared to rechallenged mice. ***p≦0.001, ****p≦0.0001.

[0154] [Figure 95]Figures 95A-95B show that long-term local release of an innate immune agonist does not alter blood composition. Blood was collected on days 3 and 14 after surgery for treatment with R848 (Device 22) (Figure 95A) or STING-RR (Device 23) (Figure 95B). WBC, white blood cells; NE, neutrophils; LY, lymphocytes; MO, monocytes; EO, eosinophils; BA, basophils; HCT, hematocrit; RBC, red blood cells; MCV, mean corpuscular volume; RDW, red blood cell distribution width; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MPV, mean platelet volume; PLT, platelets. Experiments were performed once with n=5 biological replicates. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SEM. Dashed lines indicate established normal ranges.

[0155] [Figure 96] Figures 96A-96B demonstrate that long-term local release of innate immune agonists is safe. None of the listed conditions affected liver enzyme levels measured on postoperative day 3 (R848, Device 22) (Figure 96A) or postoperative day 15 (STING-RR, Device 23) (Figure 96B). Data are presented as mean ± SD (n = 6+ per group, performed twice as biological replicates). Dashed lines indicate established normal ranges.

[0156] [Figure 97] Figure 97 shows that long-term local release of an innate immune agonist is very well tolerated. None of the listed conditions had a long-term effect on mouse weight after administration of R848 (Device 22). The weight loss observed in week 1 was related to the stress of the surgery itself, as it was observed in all groups, including the no hydrogel and empty hydrogel negative controls. Data are presented as mean values ​​± (sample size for each group is provided in Figure 2d, with biological replicates performed at least three times).

[0157] [Figure 98]Figure 98 shows that the response of parental 4T1 cells to R848 released locally from hydrogel is similar to that of Luc2-expressing 4T1 cells. Kaplan-Meier curves for female BALB / cJ mice orthotopically seeded with wild-type 4T1 cells and administered either no hydrogel or R848-loaded hydrogel (device 22). These data are similar to those presented in Figure 84A, which contains 4T1-Luc2 cells. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using log-rank (Mantel-Cox) compared to no hydrogel. *p≦0.05.

[0158] [Figure 99A-C] Figures 99A-99C show that localized delivery of perioperative immunotherapy is effective in a further model of spontaneous metastasis. After subcutaneous inoculation with B16-BL6 melanoma cells (Figure 99A) or LLC lung cancer cells (Figures 99B-99C), tumors were excised from mice when tumor volume reached approximately 600 mm. Figures 99A-99C show Kaplan-Meier curves for no hydrogel or for R848 (Device 22) (Figures 99A-99B) or STING-RR (Device 23) (Figure 99C).

[0159] [Figure 99D] Figure 99D shows that additional biomaterials can be used to achieve long-term local release of immunotherapeutic agents in the perioperative setting, resulting in significant survival benefits. Figure 99D shows Kaplan-Meier curves for mice after orthotopic 4T1-Luc2 tumor resection and treatment with no hydrogel, DMSO vehicle-loaded alginate hydrogel ("empty"), or alginate R848-loaded hydrogel. The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated using the log-rank (Mantel-Cox) test compared to the group treated with hydrogels containing the indicated innate immune agonists. *p≦0.05.

[0160] [Figure 100] Figure 100 shows that alginate-derived hydrogel scaffolds prolong the release of R848 in vitro. The scaffolds were placed in PBS (pH 7.4) and drug release was measured using HPLC. Experiments were performed three times with biological replicates (n=4+). Data are presented as mean ± values.

[0161] [Figure 101] Figure 101 shows Kaplan-Meier curves demonstrating the survival benefit for the NOD1 / NOD2 agonist M-TriDAP (Device 29) versus no hydrogel. The number of mice per group (n) and median survival (ms) are listed. Statistics were calculated relative to the group treated with hydrogel containing the triple combination using the log-rank (Mantel-Cox) test. *p≦0.05.

[0162] [Figure 102] Figures 102A-102C demonstrate the efficacy of perioperative localized delivery of immunotherapeutic agents in a further model of spontaneous metastasis. Tumors were excised from mice 10 days after orthotopic inoculation of parental 4T1 breast cancer cells (Figure 102A), when tumor volumes reached approximately 600 mm3 after subcutaneous inoculation of B16-BL6 melanoma cells (Figure 102B), or when tumor volumes reached approximately 600 mm3 after subcutaneous inoculation of LLC lung cancer cells (Figure 102C). Figures 102A-102C show Kaplan-Meier curves for no hydrogel or the triple combination of 2'3'-cGAMP, IL-15sa, and anti-PD-1 (Device 1). The number of mice per group (n) and median survival (ms) are listed. Experiments were performed with at least three biological replicates. Statistics were calculated relative to the group treated with the hydrogel containing triple combination using the log-rank (Mantel-Cox) test. *p≦0.05.

[0163] [Figure 103]Figures 103A-103C show that for a given loaded dose of R848, hydrogels (derived from cross-linked hyaluronic acid or alginate) confer superior survival benefits to poly(lactic-co-glycolic acid) (PLGA) scaffolds. For a 200 μg loaded dose of R848, the majority of the R848 must be released within a few hours to be effective. Figure 103A shows photographs of PLGA scaffolds when dry (top) or wet (bottom). PLGA scaffolds were prepared by weighing 100 mg of PLGA (50:50, ester end-capped, Mn ∼50,000 Da; Akina AP121) per scaffold, mixing it overnight with 200 μg of solid R848 (per 100 mg of PLGA), compressing it at 1500 psi (5000 lbs) for 1 minute, and foaming it overnight with 850 psi carbon dioxide. Figure 103B shows cumulative drug release after scaffold placement in PBS (pH 7.4). Drug release was measured by HPLC. Release of R848 from PLGA scaffolds took weeks rather than hours. Figure 103C demonstrates that this delayed release attenuates the efficacy of localized delivery of innate immune agonists. Kaplan-Meier curves for control and treatment groups are shown. The number of mice (n) per group and median survival (ms) are listed.

[0164] [Figure 104]Figures 104A-104B show that prolonged local release of STING-RR increases cytokine levels in the blood. Ten days after orthotopic seeding of 4T1-Luc2 cells, tumors were excised from mice and device 23 was placed at the reaction site. Elevated concentrations of cytokines were observed in plasma collected on days 3 (Figure 104A) and 14 (Figure 104B) after surgery. Levels of a panel of cytokines are shown. Data were generated using multiplex laser bead technology. Experiments were performed once with n=5 biological replicates. Statistics were calculated using a two-tailed unpaired t-test. Data are presented as mean ± SEM. *p≦0.05, **p≦0.01, ***p≦0.001, ****p≦0.0001.

[0165] [Figure 105] Figure 105 shows Kaplan-Meier curves demonstrating the survival benefit for Ifn-α (Device 24) versus no hydrogel. The number of mice per group (n) and median survival (ms) are listed. DETAILED DESCRIPTION OF THE INVENTION

[0166] Detailed Description of Certain Aspects of the Invention Provided herein are drug delivery compositions and devices. The drug delivery compositions and devices may comprise a biomaterial and an activator of innate immune response. The drug delivery compositions and devices may comprise a biomaterial, an activator of innate immune response, and a cytokine. The drug delivery compositions and devices may comprise a biomaterial, an activator of innate immune response, and a chemokine. The drug delivery compositions and devices may comprise a biomaterial and a cytokine. The drug delivery compositions and devices may comprise a biomaterial and a chemokine. The drug delivery compositions and devices may further comprise one or more activators of adaptive immune response.

[0167] The drug delivery compositions and devices may comprise a biomaterial and an activator of the adaptive immune response. The drug delivery compositions and devices may further comprise an additional activator of the adaptive immune response. The drug delivery compositions and devices may further comprise an additional therapeutic agent (e.g., a modulator of macrophage effector function or a chemotherapeutic agent).

[0168] The therapeutic agents provided in the drug delivery compositions and devices can activate the innate and / or adaptive immune response systems, thereby providing a unique tool for the treatment of cancer, particularly solid tumors. The compositions, devices, methods, systems, and kits provided herein are also advantageous over existing methods in that they do not require the administration of cells (e.g., adoptive cell transfer) or the incorporation of additional components such as microparticles, peptides, or tumor antigens.

[0169] The drug delivery compositions and devices are useful for treating cancer in the perioperative setting. In particular, the compositions and devices can deliver immunotherapeutic agents by implantation at the site of need in a subject in need thereof. The drug delivery compositions and devices are particularly advantageous over existing immunotherapeutic agents because they can be delivered directly to the site of tumor resection, avoiding systemic administration. Thus, the drug delivery compositions and devices provide a vehicle for drug delivery at the site of tumor resection, avoiding potential toxicity that may be associated with traditional systemic administration of immunotherapeutic agents. Efficacy can also be improved by concentrating the immunotherapeutic agent at the site of tumor resection. In some embodiments, the drug delivery compositions and devices are useful for delaying and / or preventing tumor growth, preventing cancer recurrence, preventing tumor metastasis, and / or preventing regrowth of the primary tumor.

[0170] Drug delivery compositions and devices Biomaterials / Hydrogels The drug delivery compositions and devices include biomaterials. In some embodiments, the biomaterial is a scaffold or depot. The scaffold or depot includes any synthetic or naturally occurring material suitable for containing any therapeutic agent in the drug delivery compositions and devices described herein and for promoting its sustained or long-term release. Thus, the biomaterial possesses properties that provide advantageous properties of the compositions and devices described herein (e.g., storage modulus, biodegradation, release profile of the therapeutic agent). In some embodiments, the biomaterial prolongs the release of the therapeutic agent at the tumor reaction site compared to administration of the same therapeutic agent in solution. In certain embodiments, the biomaterial extends the release of a therapeutic agent at a tumor reaction site by at least 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 4 weeks compared to administration of the same therapeutic agent in solution.

[0171] In some embodiments, the biomaterial is selected from the group consisting of hyaluronic acid, alginate, chitosan, chitin, chondroitin sulfate, dextran, gelatin, collagen, starch, cellulose, polysaccharides, fibrin, ethylene vinyl acetate (EVA), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), PEG diacrylate (PEGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), polydioxanone (PDO), polyhydroxybutyric acid (PHB), poly(2-hydroxyethyl methacrylate) (pHEMA), polycaprolactone (PCL), poly(beta-amino ester) (PBAE), poly(ester amide), poly(propylene glycol) (PPG), poly(aspartic acid), Poly(glutamic acid), poly(propylene fumarate) (PPF), poly(sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl ester carbonate) (PDTE), poly[bis(trifluoroethoxy)phosphazene], polyoxymethylene, single-walled carbon nanotubes, polyphosphazenes, polyanhydrides, poly(N-vinyl-2-pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), polyacetals, poly(alpha esters), poly(ortho esters), polyphosphoesters, polyurethanes, polycarbonates, polyamides, polyhydroxyalkanoates, polyglycerols, polyglucuronic acid, derivatives thereof, and / or combinations thereof.

[0172] In some embodiments, the biomaterial is a hydrogel. In some embodiments, the hydrogel comprises hyaluronic acid, alginate, chitosan, chondroitin sulfate, dextran, gelatin, collagen, starch, cellulose, polysaccharides, fibrin, polyethylene glycol (PEG), PEG diacrylate (PEGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), poly(2-hydroxyethyl methacrylate) (pHEMA), poly(beta-amino ester) (PBAE), poly(aspartic acid), poly(glutamic acid), poly(propylene glycol) (PPG), poly(vinyl alcohol) (PVA), polyacetal, polyglycerol, or polyglucuronic acid. In some embodiments, when the biomaterial is a hydrogel, the therapeutic agent of the composition or device is a hydrophilic molecule. In some embodiments, when the biomaterial is a hydrogel, the therapeutic agent of the composition or device is a hydrophobic molecule. In some embodiments, when the biomaterial is a hydrogel, the therapeutic agent of the composition or device is a hydrophobic or hydrophilic molecule. In some embodiments, when the biomaterial is a hydrogel, the therapeutic agent of the composition or device is a hydrophobic and hydrophilic molecule.

[0173] In some embodiments, the biomaterial is hyaluronic acid or alginate. In some embodiments, the biomaterial is cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the biomaterial comprises hyaluronic acid or alginate. In some embodiments, the biomaterial comprises cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the hydrogel is hyaluronic acid or alginate. In some embodiments, the hydrogel is cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the hydrogel comprises hyaluronic acid or alginate. In some embodiments, the hydrogel comprises cross-linked hyaluronic acid or cross-linked alginate.

[0174] In some embodiments, the biomaterial comprises hyaluronic acid. In some embodiments, the biomaterial comprises cross-linked hyaluronic acid. In some embodiments, the biomaterial is hyaluronic acid. In some embodiments, the biomaterial is cross-linked hyaluronic acid. In some embodiments, the hydrogel comprises hyaluronic acid. In some embodiments, the hydrogel comprises cross-linked hyaluronic acid. In some embodiments, the hydrogel is hyaluronic acid. In some embodiments, the hydrogel is cross-linked hyaluronic acid.

[0175] Hyaluronic acid, also known as hyaluronan, is an anionic, non-sulfated glycosaminoglycan that is widely distributed throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is non-sulfated, it forms in the cell membrane rather than the Golgi, and it can grow to be very large, often reaching molecular weights of several million.

[0176] Hyaluronic acid, one of the main components of the extracellular matrix, contributes greatly to cell proliferation and migration, and therefore plays an important role in cancer metastasis. In some cancers, the level of hyaluronic acid correlates with malignancy and poor prognosis. Hyaluronic acid is often used as a tumor marker for certain cancers (e.g., prostate cancer and breast cancer), and can also be used to monitor the progression of disease in individuals. Therefore, the use of hyaluronic acid as a biomaterial in the disclosed drug delivery compositions and devices provides unexpectedly useful and effective cancer treatments.

[0177] In some embodiments, hyaluronic acid is substituted with thiols (EXTRACEL®, HYSTEM®), methacrylates, hexadecylamides (HYMOVIS®), and thiols. Min (CORGEL®) Hyaluronic acid can also be crosslinked directly with formaldehyde (HYLAN-A®) or with divinyl sulfone (HYLAN-B®).

[0178] In some embodiments, the hyaluronic acid comprises a thiol-modified hyaluronic acid and a crosslinker. In some embodiments, the hydrogel comprises a thiol-modified hyaluronic acid (e.g., GLYCOSIL®) and a thiol-reactive PEGDA crosslinker (e.g., EXTRALINK®). In some embodiments, thiol-modified hyaluronic acid and a thiol-reactive PEGDA crosslinker are combined to form a crosslinked hydrogel useful in the drug delivery compositions and devices described herein.

[0179] In some embodiments, the amounts and concentrations of thiol-modified hyaluronic acid, thiol-reactive hyaluronic acid, and crosslinker can be adjusted to provide drug delivery compositions and devices with desired physical properties (e.g., having a storage modulus of about 500 Pa to about 3000 Pa).

[0180] In some embodiments, the biomaterial comprises alginate. In some embodiments, the biomaterial comprises cross-linked alginate. In some embodiments, the biomaterial is alginate. In some embodiments, the biomaterial is cross-linked alginate. In some embodiments, the hydrogel comprises alginate. In some embodiments, the hydrogel comprises cross-linked alginate. In some embodiments, the hydrogel is alginate. In some embodiments, the hydrogel is cross-linked alginate. In some embodiments, the biomaterial does not comprise alginate. In some embodiments, the biomaterial is not alginate. In some embodiments, the hydrogel is not alginate. In some embodiments, the hydrogel does not comprise alginate.

[0181] In some embodiments, the alginate can be ionically crosslinked by adding a salt (eg, calcium chloride) that promotes crosslinking.

[0182] In some embodiments, the alginate comprises an alginate and a crosslinker (e.g., calcium chloride). In some embodiments, the hydrogel comprises an alginate and a crosslinker (e.g., calcium chloride). In some embodiments, the alginate and calcium chloride (e.g., an ionic crosslinker) are combined to form a crosslinked hydrogel useful in the drug delivery compositions and devices described herein.

[0183] In certain embodiments, the amounts and concentrations of alginate and calcium chloride can be adjusted to provide drug delivery compositions and devices with desired physical properties (such as having a storage modulus of about 500 Pa to about 3000 Pa).

[0184] In some embodiments, the biomaterial is a hydrophobic polymer. In some embodiments, the hydrophobic polymer is ethylene vinyl acetate (EVA), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polydioxanone (PDO), polyhydroxybutyric acid (PHB), polycaprolactone (PCL), poly(ester amide), poly(propylene fumarate) (PPF), poly(sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl tyrosine alkyl ester) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl tyrosine alkyl ester) (PSA ... Examples of suitable biomaterials include poly(estercarbonate) (PDTE), poly[bis(trifluoroethoxy)phosphazene], polyoxymethylene, single-walled carbon nanotubes, polyphosphazenes, polyanhydrides, poly(N-vinyl-2-pyrrolidone) (PVP), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), poly(alpha esters), poly(ortho esters), polyphosphoesters, polyurethanes, polycarbonates, polyamides, and polyhydroxyalkanoates. The use of hydrophobic polymers as biomaterials is particularly useful when the therapeutic agent in the composition or device is hydrophilic. Hydrophobic therapeutic agents are expected to be released over a longer period (e.g., days / weeks) rather than within a release timescale (e.g., hours) that contributes to the therapeutic effect. Thus, in some embodiments, when the biomaterial is a hydrophobic polymer, the therapeutic agent in the composition or device is a hydrophilic molecule.

[0185] In some embodiments, the biomaterial comprises a crosslinked biological agent. In some embodiments, the biological agent is crosslinked with the self-immolative crosslinker dithio-bis(ethyl 1H-imidazole-1-carboxylate) (DIC). In some embodiments, the resulting hydrogel is loaded with a small molecule.

[0186] Activators of the innate immune response The drug delivery compositions and devices may include activators of the innate immune response. The drug delivery compositions and devices may include more than one activator of the innate immune response. The primary functions of the innate immune response include: recruiting immune cells to the site of infection through the production of chemical factors, including specialized chemical mediators (e.g., cytokines); activating the complement cascade, which identifies bacteria, activates cells, and promotes the clearance of antibody complexes or dead cells; identifying and removing foreign substances present in organs, tissues, blood, and lymph by specialized white blood cells; activating the adaptive immune system through a process known as antigen presentation; and acting as a physical and chemical barrier against infectious agents (e.g., epithelial surfaces, gastrointestinal tract). Typically, leukocytes are white blood cells that perform the functions of the innate immune system. These cells include natural killer cells, mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. These cells function within the immune system by identifying and eliminating pathogens that may cause infection.

[0187] In some embodiments, the activator of the innate immune response is a ligand of a pattern recognition receptor (PRR).

[0188] In some embodiments, the activator of the innate immune response is an agonist of a pattern recognition receptor (PRR).

[0189] In some embodiments, the activator of the innate immune response is an inducer of type I interferon. In some embodiments, the activator of the innate immune response is recombinant interferon.

[0190] In certain embodiments, the activator of the innate immune response is an effective inducer of NK cell activation and / or proliferation. In certain embodiments, an "effective inducer" refers to an activator of the innate immune response that directly induces NK cell activation and / or proliferation.

[0191] In certain embodiments, the activator of the innate immune response is an effective inducer of dendritic cell activation and / or maturation. In certain embodiments, an "effective inducer" refers to an activator of the innate immune response that directly induces dendritic cell activation and / or maturation.

[0192] In certain embodiments, the activator of the innate immune response is an effective inducer of type I interferon by dendritic cells. In certain embodiments, an "effective inducer" refers to an activator of the innate immune response that directly induces type I interferon by dendritic cells.

[0193] In some embodiments, the activator of the innate immune response is a small molecule or a biological agent. In some embodiments, the activator of the innate immune response is a small molecule. In some embodiments, the activator of the innate immune response is a biological agent.

[0194] In some embodiments, the activator of the innate immune response is a stimulator of interferon genes (STING) agonist, a cytoplasmic DNA sensor (CDS) agonist, a Toll-like receptor (TLR) agonist, a C-type lectin receptor (CLR) agonist, a NOD-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, or an inflammasome inducer.

[0195] In some embodiments, the activator of innate immune response is a stimulator of interferon genes (STING) agonist, a Toll-like receptor (TLR) agonist, or a NOD-like receptor (NLR) agonist. In some embodiments, the activator of innate immune response is a stimulator of interferon genes (STING) agonist, or a Toll-like receptor (TLR) agonist. In some embodiments, the activator of innate immune response is a stimulator of interferon genes (STING) agonist, a TLR7 agonist, or a TLR8 agonist.

[0196] In some embodiments, the activator of the innate immune response is 3'3'-cGAMP, 2'3'-cGAMP, 2'3'-cGAM(PS)2(Rp / Rp), 2'3'-cGAM(PS)2(Rp / Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AMP(PS)2(Rp / Rp), 2'3'-c-di-AMP(PS)2(Rp / Sp), c-di-GMP, c-di-IMP, HSV-60, ISD, VACV-70, poly(dA:dT), poly(dG:dC), heat-killed bacteria, lipoproteins, Lican, lipopolysaccharide (LPS), lipoteichoic acid, peptidoglycan (PGN), synthetic lipoprotein, poly(A:U), poly(I:C), monophosphoryl lipid A (MPLA), GSK1795091, G100, SD-101, MGN1703, CMP-001, flagellin (FLA), polyU, poly(dT), gardikimod, imiquimod (R837), base analogs, adenine analogs, guanosine analogs, purine derivatives, benzazepine analogs, imidazoquinolines, thiazoquinolines, loxoribine, resiquimod (R848) ), dactolisib, sumanirole, N1-glycinyl[4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)benzoyl]spermine (CL307), CL264, CL097, CL075, MEDI9197, MEDI5083, hypoxanthine, TL8-506, PF-4878691, isatoribine, SM-324405, SM-324406, AZ12441970, AZ12443988, CpG oligonucleotides, bacterial DNA, betaglycan, fungal and bacterial cell walls betaglycan derived from erythrocytes, γ-D-Glu-mDAP (iE-DAP), iE-DAP derivatives, muramyl dipeptide (MDP), MDP derivatives, 5' triphosphate double-stranded RNA, poly(dA:dT), ATP, chitosan, potassium aluminum sulfate, dehydrated calcium pyrophosphate, silicon dioxide, MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), xanthenone analogs (e.g., DMXAA; vadimezan), TREX1 inhibitors, cyclic dinucleotides, derivatives thereof, or pharmaceutically acceptable salts thereof.

[0197] In some embodiments, the activator of the innate immune response is a fluorinated derivative of any of the above activators. In some embodiments, the activator of the innate immune response is an O-methylated derivative of any of the above activators.

[0198] In some embodiments, the activator of the innate immune response is 3'3'-cGAMP, 2'3'-cGAMP, 2'3'-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AM(PS)2(Rp,Rp), 2'3'-c-di-AM(PS)2(Rp,Sp), c-di-GMP, 2'3'-c-di-GMP, 2'3'-c-di-GM(PS)2(Rp,Rp), 2'3'-c-di-GM(PS)2(Rp,Sp), c-di-IMP, resiquimod, CpG oligonucleotide, polyinosinic:polycytidylic acid, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the activator of the innate immune response is a fluorinated derivative of 3'3'-cGAMP, 2'3'-cGAMP, 2'3'-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AM(PS)2(Rp,Rp), 2'3'-c-di-AM(PS)2(Rp,Sp), c-di-GMP, 2'3'-c-di-GMP, 2'3'-c-di-GM(PS)2(Rp,Rp), 2'3'-c-di-GM(PS)2(Rp,Sp), c-di-IMP, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the activator of the innate immune response is an O-methylated derivative of 3'3'-cGAMP, 2'3'-cGAMP, 2'3'-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AM(PS)2(Rp,Rp), 2'3'-c-di-AM(PS)2(Rp,Sp), c-di-GMP, 2'3'-c-di-GMP, 2'3'-c-di-GM(PS)2(Rp,Rp), 2'3'-c-di-GM(PS)2(Rp,Sp), c-di-IMP, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), c-di-GMP, or resiquimod. In some embodiments, the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), or resiquimod. In some embodiments, the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), or resiquimod. In some embodiments, the activator of the innate immune response is 2'3'-c-di-AM(PS)2 (Rp,Rp) or resiquimod.

[0202] In some embodiments, the activator of innate immune response is 2'3'-cGAMP or its pharmaceutically acceptable salt.In particular, 2'3'-cGAMP (cyclic [G(2',5')pA(3',5')p]) has been described to function as an endogenous second messenger, including STING-dependent type I interferon response.2'3'-cGAMP has also been shown to be an effective adjuvant for boosting the production of antigen-specific antibodies and T cell responses in mice.2'3'-cGAMP exerts antiviral function in the cells in which it is produced, but can also act on neighboring cells by passive diffusion across the cell membrane. [ka]

[0203] In some embodiments, the activator of the innate immune response is 2'3'-c-di-AM(PS)2(Rp,Rp), or a pharmaceutically acceptable salt thereof. 2'3'-c-di-AM(PS)2(Rp,Rp) is the Rp,Rp-isomer of the 2'3'-bisphosphorothioate analog of 3'3'-cyclic adenosine monophosphate (c-di-AMP). It is also a STING agonist. [ka]

[0204] In some embodiments, the activator of the innate immune response is a STING agonist, wherein the STING agonist is a cyclic dinucleotide. In some embodiments, the cyclic dinucleotide is any cyclic dinucleotide disclosed in U.S. patent application Ser. No. 15 / 234,182, filed Aug. 11, 2016, the entire contents of which are incorporated herein by reference.

[0205] In some embodiments, the activator of the innate immune response is a cytoplasmic DNA sensor (CDS) agonist. In some embodiments, the CDS agonist is a cyclic GMP-AMP synthase (cGAS) agonist.

[0206] In some embodiments, the activator of the innate immune response is any STING agonist or cGAS agonist disclosed in U.S. patent application USSN 14 / 653,586, filed December 16, 2013, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any STING agonist or cGAS agonist disclosed in U.S. patent application USSN 14 / 268,967, filed May 2, 2014, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any STING agonist or cGAS agonist disclosed in U.S. patent application USSN 14 / 787,611, filed April 29, 2014, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist or cGAS agonist disclosed in U.S. patent application Ser. No. 14 / 908,019, filed July 31, 2014, the entire contents of which are incorporated herein by reference.

[0207] In one embodiment, the activator of the innate immune response is any STING agonist disclosed in U.S. patent application USSN 13 / 057,662, filed June 14, 2011, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in U.S. patent application USSN 14 / 106,687, filed December 13, 2013, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in U.S. patent application USSN 15 / 035,432, filed May 19, 2016, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in International Patent Application PCT / US2017 / 013049, filed January 11, 2017, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in International Patent Application PCT / US2017 / 013066, filed January 11, 2017, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in International Patent Application PCT / US2014 / 038525, filed May 14, 2014, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in U.S. Patent Application No. USSN 13 / 912,960, filed June 7, 2013, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any STING agonist disclosed in International Patent Application No. PCT / IB2016 / 057265, filed January 12, 2016, the entire contents of which are incorporated herein by reference.

[0208] In some embodiments, the innate immune response activator is MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP) or a pharmaceutically acceptable salt thereof. M-TriDAP is a peptidoglycan (PGN) degradation product found primarily in Gram-negative bacteria. M-TriDAP is recognized by the intracellular sensor NOD1 (CARD4) and, to a lesser extent, NOD2 (CARD15). Recognition of M-TriDAP by NOD1 / NOD2 induces a signal transduction cascade involving the serine / threonine RIP2 (RICK, CARDIAK) kinase, which interacts with IKK, leading to the activation of NF-κB and the production of inflammatory cytokines such as TNF-α and IL-6. M-TriDAP induces NF-κB activation at a level similar to that of Tri-DAP.

[0209] In some embodiments, the activator of the innate immune response is a TLR7 agonist. In some embodiments, the activator of the innate immune response is a TLR8 agonist. In some embodiments, the activator of the innate immune response is a TLR7 agonist and a TLR8 agonist.

[0210] In some embodiments, the activator of the innate immune response is an immune response modifier (IRM).

[0211] In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 08 / 620,779, filed March 22, 1996, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 08 / 957,192, filed October 24, 1997, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 09 / 528,620, filed March 20, 2000, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 06 / 798,385, filed November 15, 1985, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 08 / 303,216, filed September 8, 1994, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 09 / 210,114, filed December 11, 1998, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in U.S. patent application USSN 09 / 361,544, filed July 27, 1999, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any IRM disclosed in International patent application PCT / US2004 / 032480, filed October 1, 2004, the entire contents of which are incorporated herein by reference.

[0212] In one embodiment, the activator of the innate immune response is CL307 (N1-glycinyl[4-((6-amino-2-(butylamino)-8-hydroxy-9H-purin-9-yl)methyl)benzoyl]spermine), or a pharmaceutically acceptable salt thereof. CL307 is a highly potent TLR7 agonist. Titration experiments showed that CL307 induces potent NF-κB activation even at a concentration of only 20 nM (10 ng / ml). [ka]

[0213] In one embodiment, the activator of the innate immune response is CL264 or a pharmaceutically acceptable salt thereof. CL264 induces NF-κB activation and IFN-α secretion in TLR7-expressing cells. CL264 is a TLR7-specific ligand and does not stimulate TLR8, even at high concentrations (>10 μg / ml). In TLR7-transfected HEK293 cells, CL264 induces NF-κB activation at a concentration of 0.1 μM, which is 5-10 times lower than imiquimod. [ka]

[0214] In some embodiments, the innate immune response activator is loxoribine or a pharmaceutically acceptable salt thereof. Loxoribine is a guanosine analogue derivatized at positions N7 and C8. This nucleoside is a highly potent stimulator of the immune system. Loxoribine activates the innate immune system through TLR7, which requires endosomal maturation. Loxoribine recognition is limited to TLR7. [ka]

[0215] In certain embodiments, the activator of the innate immune response is hypoxanthine, or a pharmaceutically acceptable salt thereof. Hypoxanthine is a naturally occurring purine derivative. [ka]

[0216] In one embodiment, the innate immune response activator is TL8-506, or a pharmaceutically acceptable salt thereof. TL8-506 is a benzazepine compound, an analog of the Toll-like receptor 8 (TLR8) agonist VTX-2337. TL8-506 activates TLR8 more potently than R848 and CL075. TL8-506 is approximately 50-fold and approximately 25-fold more potent than R848 and CL075, respectively, in inducing NF-κB activation in TLR8-transfected HEK293 cells. TL8-506 is a selective agonist of TLR8. [ka]

[0217] In some embodiments, the activator of the innate immune response is PF-4878691, isatoribine, SM-324405, SM-324406, AZ12441970, AZ12443988, or a pharmaceutically acceptable salt thereof. PF-4878691, isatoribine, SM-324405, SM-324406, AZ12441970, and AZ12443988 are TLR7 agonists.

[0218] In some embodiments, the activator of the innate immune response is an imidazoquinoline derivative, including dactolisib, imiquimod, gardikimod, resiquimod, sumanirole, and pharmaceutically acceptable salts thereof.

[0219] In some embodiments, the activator of the innate immune response is CL097, or a pharmaceutically acceptable salt thereof. CL097 is a highly water-soluble (≧20 mg / ml) derivative of resiquimod. CL097 is a ligand for TLR7 and TLR8. It induces NF-κB activation at 0.4 μM (0.1 μg / ml) in TLR7-transfected HEK293 cells and at 4 μM (1 μg / ml) in TLR8-transfected HEK293 cells. [ka]

[0220] In some embodiments, the activator of the innate immune response is CL075 or a pharmaceutically acceptable salt thereof. CL075 (3M002) is a thiazoloquinolone derivative that stimulates TLR8 in human peripheral blood mononuclear cells. It activates NF-κB and preferentially induces the production of TNF-α and IL-12. CL075 also induces IFN-α secretion, albeit to a lesser extent, through TLR7. It induces NF-κB activation at 0.4 μM (0.1 μg / ml) in TLR8-transfected HEK293 cells, whereas approximately 10-fold more CL075 is required to activate NF-κB in TLR7-transfected HEK293 cells. [ka]

[0221] In some embodiments, the activator of the innate immune response is MEDI9197, or a pharmaceutically acceptable salt thereof. MEDI9197 (3M052) is an injectable TLR7 and TLR8 agonist. It is an imidazoquinoline immune response modifier (IRM) with a C18 lipid moiety and designed for slow diffusion from the site of application. [ka]

[0222] In some embodiments, the activator of the innate immune response is resiquimod (R848), or a pharmaceutically acceptable salt thereof. In particular, resiquimod is an agent that acts as an immune response modifier and has antiviral and antitumor activity. It is used as a topical gel in the treatment of skin lesions such as those caused by herpes simplex virus and cutaneous T-cell lymphoma. It is also used as an adjuvant to increase the efficacy of vaccines. It has several mechanisms of action and is both an agonist for toll-like receptors 7 (TLR7) and 8 (TLR8) and an upregulator of opioid growth factor receptors. [ka]

[0223] In some embodiments, the activator of the innate immune response is a TLR7-selective antedrug. In some embodiments, the activator of the innate immune response is SM-324405, AZ12441970, or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the activator of innate immune response is inflammasome inducer.Inflammasome is a multimeric protein complex that is important for host defense against infection and endogenous danger signals.They promote the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and cause a rapid and pro-inflammatory cell death form called pyroptosis.

[0225] In some embodiments, the activator of the innate immune response is an inducer of the NLRP3, AIM2, NLRC4, or NLRP1 inflammasome.

[0226] In some embodiments, the activator of the innate immune response is [ka] or a pharmaceutically acceptable salt thereof, wherein R 1is H and R 2 Is H;R 1 is a butyl group, and R 2 Is H;R 1 is H and R 2 is -CO2CH3; or R 1 is a butyl group, and R 2 is -CO2CH3.

[0227] In certain embodiments, the activator of the innate immune response is an imidazoquinoline; an imidazonaphthyridine; a pyrazolopyridine; an aryl-substituted imidazoquinoline; a compound having a 1-alkoxy 1H-imidazo ring system; an oxazolo[4,5-c]-quinolin-4-amine; a thiazolo[4,5-c]-quinolin-4-amine; a selenazolo[4,5-c]-quinolin-4-amine; an imidazonaphthyridine; an imidazoquinoline Amines;Mono- and di-substituted 1H-imidazo[4,5-c]quinolin-4-amines;Fused cycloalkylimidazopyridines;1H-Imidazo[4,5-c]quinolin-4-amines;1-substituted 1H-imidazo-[4,5-c]quinolin-4-amines;Imidazo-[4,5-c]quinolin-4-amine;2-Ethyl 1H-imidazo[4,5-c]quinolin-4-amine;Olefinic 1H-imidazo[4,5-c] 6,7-dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid; pyridoquinoxaline-6-carboxylic acid; 6,7-dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid; substituted naphtho[ij]quinolizine; substituted pyridoquinoxaline-6-carboxylic acid; 7-hydroxy-benzo[ij]quinolizine-2-carboxylic acid derivatives; substituted benzo[ij]quinolizine-2-carboxylic acid; 7-hydroxy-benzo[ij]quinolizine-2-carboxylic acid; substituted pyrido[1,2,3,-de]-1,4-benzoxazine; N-methylenemalonic acid esters of tetrahydroquinoline, or pharmaceutically acceptable salts thereof.

[0228] In some embodiments, the activator of the innate immune response is any NLRP3 agonist disclosed in U.S. patent application Ser. No. 15 / 253,215, filed Aug. 31, 2016, the entire contents of which are incorporated herein by reference.

[0229] In some embodiments, the activator of the innate immune response is a RORy agonist. A RORy agonist is an agent that promotes the activity of RORy, for example, by binding to and activating RORy or by increasing the expression of RORy in a patient or a population of cells. A RORy agonist can be, for example, a small organic molecule, a polypeptide, or a nucleic acid. Various RORy agonists are described in U.S. Patent Application, USSN 14 / 398,774; Zhang et al. in Mol. Pharmacol. (2012) Vol. 82, pp. 583-590; and ACS Chem. Biol. (2010), Vol. 5, pp. 1029-1034. and in other publications such as Wang et al., each of which is hereby incorporated by reference.

[0230] In some embodiments, the activator of the innate immune response is [ka] [ka] and pharmaceutically acceptable salts thereof.

[0231] In some embodiments, the activator of the innate immune response is a general or specific compound described in U.S. patent application USSN 14 / 398,774, such as a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is independently halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -N(R 4 )(R 5 ), -CO2R 6 , -C(O)R 6 , -CN, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-4 Alkylene-N(R 4 )(R 5 ), -C 1-4 Alkylene-CO2R 6 , -OC 1-6 Alkylene-N(R 4 )(R 5 ), -N(R 4 )C(O)-C 1-6 Alkylene-N(R 4 )(R 5 ), -S(O)pC 1- 6 alkyl, -SO2N(R 4 )(R 5 ), -N(R 4 )SO2(C 1-6 alkyl), -C(O)N(R 4 )(R 5 ), and -N(R 4 )C(O)N(R 4 )(R 5 Optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: X is -O-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -OC(R 6 )2-C(R 6 )(R 7 )-C(R 6 )2-Ψ, -OC(R 6 )2-C(R 6 )(R 7 )-Ψ, -C(R6 )2-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -C(O)-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -C(R 6 )2-N(R 8 )-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -C(R 6 )=N-Ψ, -C(R 6 )2C(R 6 )=N-Ψ, -N=C(R 6 )-Ψ, or -N=C(R 6 )C(R 6 )2-Ψ; where Ψ is attached to the sulfonamide ring nitrogen atom in formula I; Y is -N(R 2 )(R 3 ) or -O-aralkyl, wherein said aralkyl is independently selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 4 )(R 5 ), -CN, -CO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R 4 )(R 5 ), -S(O) p C 1-6 Alkyl, -SO2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1-6 optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 1 is independently for each occurrence hydrogen, halogen, or C 1-6 represents alkyl; R 2is -C(O)-aryl, -C(O)-aralkyl, -C(O)-[C(R 6 )2] m -cycloalkyl, -C(O)-[C(R 6 )2] m -heterocyclyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkylene-C 1-6 Alkoxyl, -C(O)-C 1-6 Alkylene-cycloalkyl, or -C(O)-C 1-6 alkylene-heterocycloalkyl; each of which is independently selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 4 )(R 5 ), -CN, -CO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R 4 )(R 5 ), -S(O) p C 1-6 Alkyl, -SO2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1-6 optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 3 is hydrogen or C 1-6 is alkyl; R 4 and R 5 is independently for each occurrence hydrogen or C 1-6 represents alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring; R 6 is, independently for each occurrence, hydrogen or C 1-6 represents alkyl; R 7 is hydrogen, hydroxyl, C 1-6Hydroxyalkyl, C 1-6 Alkyl, C 1- 6 Haloalkyl, -CO2R 6 , C 1-6 Alkylene-CO2R 6 , C 1-4 Hydroxyalkylene-CO2R 6 , -N(R 4 )(R 5 ), C 1-6 Alkylene-N(R 4 )(R 5 ), C 1-6 Hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(O)R 9 , C 1-6 Alkylene-N(R 4 )C(O)R 9 , C 1-6 Alkylene-C(O)N(R 4 )(R 5 ), -N(R 4 )CO2-C 1-6 Alkyl or C 1-6 Alkylene-N(R 4 )(C(O)N(R 4 )(R 5 ) or R 7 is heterocycloalkyl or C 1-4 alkylene-heterocycloalkyl, where heterocycloalkyl is independently oxo, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, and C 1-6 optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkoxy; R 8 is hydrogen, C 1-6 Alkyl, or -C(O)-C 1-6 is alkyl; R 9 is hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Alkylene-N(R 4 )(R 5 ), or C 1-6 Alkylene-N(R 4 )C(O)-C 1-6 is alkyl; n is 1 or 2; and m and p independently represent 0, 1, or 2 for each occurrence.

[0232] In some embodiments, the activator of the innate immune response is any RORy agonist disclosed in U.S. patent application Ser. No. 14 / 398,774, filed Nov. 4, 2014, the entire contents of which are incorporated herein by reference. In some embodiments, the activator of the innate immune response is any RORy agonist disclosed in U.S. patent application Ser. No. 15 / 120,798, filed Aug. 23, 2016, the entire contents of which are incorporated herein by reference.

[0233] cytokines Drug delivery compositions and devices may contain cytokines. Cytokines are a broad category of small proteins (approximately 5-20 kDa) important in cell signaling. Their release influences the behavior of surrounding cells. As immunomodulators, cytokines participate in autocrine, paracrine, and endocrine signaling. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by a wide range of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells. They act through receptors and play an important role in the immune system. Cytokines regulate the balance between humoral and cell-based immune responses and control the maturation, proliferation, and responsiveness of specific cell populations. Some cytokines enhance or inhibit the actions of other cytokines in complex ways. Cytokines are important in the host's response to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

[0234] Furthermore, it is now known in the art that issues regarding delivery, administration and scheduling methods, as well as toxicity, must be addressed before the immune stimulatory functions of many cytokines and chemokines can be fully utilized.

[0235] In some embodiments, the cytokine is IL-1, IL-1α, IL-1β, IL-2, IL-2 superkine, IL-6, IL-7, IL-9, AM0010 , IL-12, IL-15, IL-15 superagonist, ALT-803, NIZ985, IL-16, IL-18, IL-21, IL-21 superagonist, denenicoquine, IL-21 superagonist antibody, IFN-α, IFN-β, IFN-γ, TNF-α, GM-CSF, cytokine fusion, RG7461, RG7813, or M9241.

[0236] In some embodiments, the cytokine is ALT-803, NIZ985, denenicoquine, RG7461, RG7813, M9241, IFN-α, IFN-β, or IFN-γ.

[0237] In some embodiments, the cytokine is an IL-15 superagonist or IL-21. In some embodiments, the cytokine is an IL-15 superagonist.

[0238] In some embodiments, the cytokine is an IL-15 superagonist, IL-21, IFN-α, IFN-β, IFN-γ, CCL4, CCL5, or CXCL10. In some embodiments, the cytokine is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ. In some embodiments, the cytokine is an IL-15 superagonist or IFN-α.

[0239] IL-15 (interleukin-15) is a cytokine with structural similarity to IL-2 that is secreted by mononuclear phagocytes after viral infection. IL-15 induces the proliferation of natural killer cells, whose primary role is to kill virus-infected cells. The combination of IL-15 with soluble IL-15Rα produces a complex called IL-15 superagonist (IL-15sa), which has greater biological activity than IL-15 alone. IL-15sa is an antitumor and antiviral agent due to its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes.

[0240] In some embodiments, the cytokine is ALT-803, an IL-15 superagonist known as an IL-15 superagonist. ALT-803 is believed to induce the proliferation of memory CD8+ T cells, upregulate receptors involved in innate immunity, secrete interferon-γ, and acquire the ability to kill malignant cells in the absence of antigenic stimulation. Thus, ALT-803 can promote the proliferation and activation of memory CD8+ T cells while converting them into innate immune effector cells that exhibit potent antitumor activity. ALT-803 is a fusion protein of an IL-15 mutant and an IL-15Rα / Fc complex, and has recently entered clinical trials as a direct immunomodulator. ALT-803 exhibits >25-fold enhanced biological activity compared to IL-15.

[0241] In one embodiment, the cytokine is NIZ985 (hetIL-15). Studies have shown that administration of hetIL-15 can promote increased tumor infiltration and retention of CD8+ T cells, including tumor-specific T cells, resulting in an increased CD8+ / Treg ratio. Tumor-resident CD8+ T cells exhibit effector cell characteristics, characterized by increased proliferation (Ki67+) and high cytotoxic potential (Granzyme B+). In the absence of hetIL-15, a smaller population of tumor-infiltrating T cells exhibits high levels of the exhaustion marker PD-1, potentially limiting their anti-cancer efficacy. Provision of hetIL-15 can result in a significant reduction in lymphocyte expression of PD-1, which alleviates one potential mechanism for the exhaustion phenotype. Preclinical cancer research supports the use of hetIL-15 in tumor immunotherapy approaches to promote the generation of anti-tumor responses by favoring effector over regulatory cells.

[0242] In some embodiments, the cytokine is interferon alpha (IFN-α). IFN-α proteins are produced by white blood cells. They are primarily involved in the innate immune response to viral infections.

[0243] In some embodiments, the cytokine is interferon beta (IFN-β). IFN-β comprises a protein produced by fibroblasts and is involved in the innate immune response. IFN-β stimulates both macrophages and NK cells to stimulate antiviral responses and is also active against tumors. In mice, IFN-β inhibits immune cells from producing growth factors, thereby slowing tumor growth, and inhibits other cells from producing growth factors that generate blood vessels, thereby blocking tumor angiogenesis and preventing tumors from connecting with the vasculature.

[0244] In some embodiments, the cytokine is interferon gamma (IFN-γ). IFN-γ, or type II interferon, is a cytokine useful for innate and adaptive immunity. IFN-γ is an important activator of macrophages and an inducer of class II major histocompatibility complex (MHC) molecule expression. Extensive in vitro studies of IFN-γ in cancer cells have shown that the antiproliferative activity of IFN-γ leads to growth inhibition or cell death, generally induced by apoptosis, but sometimes by autophagy. Clinical administration of IFN-γ has resulted in improved survival rates for patients with ovarian cancer, bladder cancer, and melanoma cancer.

[0245] In some embodiments, the cytokine is IL-1β. IL-1β is produced as a protein that is proteolytically processed to its active form by caspase 1. This cytokine is a key mediator of the inflammatory response and is involved in a variety of cellular activities.

[0246] In some embodiments, the cytokine is a chemokine. Chemokines are a family of small cytokines. The primary role of chemokines is to act as chemotactic factors that guide cell migration. Some chemokines regulate cells of the immune system during the process of immune surveillance, for example, directing lymphocytes to lymph nodes where they can screen for invading pathogens by interacting with antigen-presenting cells present in these tissues. These are known as homeostatic chemokines, and are produced and secreted without the need to stimulate their source cells. Some chemokines play a role in development, promoting angiogenesis (the growth of new blood vessels) or directing cells to express specific signals important for cell maturation. Other chemokines are inflammatory and are released by a wide range of cells in response to bacteria, viruses, and agents that cause physical damage, such as silica or uric acid crystals, which occur in gout. Their release is often stimulated by pro-inflammatory cytokines such as interleukin-1. Inflammatory chemokines function primarily as chemotactic factors for leukocytes, recruiting monocytes, neutrophils, and other effector cells from the blood to sites of infection or tissue damage. Some inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve as guide cells for both the innate and adaptive immune systems.

[0247] Furthermore, to ensure that the immune-stimulating functions of many chemokines can be fully utilized, It is now known in the art that issues regarding delivery, administration and scheduling methods, as well as toxicity, must be addressed.

[0248] In some embodiments, the chemokine is CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CCL21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, or CX3CL1.

[0249] activators of the adaptive immune response The drug delivery compositions and devices may include one or more activators of the adaptive immune response.

[0250] The adaptive immune response system, also known as the acquired immune system, is a subsystem of the overall immune system that includes highly specialized systemic cells and processes that eliminate or prevent the growth of pathogens. The adaptive immune system is one of the two main immune strategies found in vertebrates (the other being the innate immune system). Adaptive immunity creates immunological memory after an initial response to a specific pathogen, resulting in an enhanced response to subsequent encounters with that pathogen. This process of acquired immunity is the basis for vaccination. Like the innate immune system, the adaptive system contains both humoral and cell-mediated immune components. Unlike the innate immune system, the adaptive immune system is highly specific for particular pathogens.

[0251] The adaptive immune response system is triggered in vertebrates when a pathogen evades the innate immune response system, producing a threshold level of antigen and a "stranger" or "danger" signal that activates dendritic cells. The primary functions of the adaptive immune system include the recognition of specific "non-self" antigens in the presence of "self" during the process of antigen presentation; the generation of responses directed toward eliminating specific pathogens or pathogen-infected cells; and the development of immunological memory, in which pathogens are "remembered" through memory B cells and memory T cells.

[0252] A useful approach to activating the adaptive immune response system (e.g., activating therapeutic antitumor immunity) involves blockade of immune checkpoints. Immune checkpoints refer to the congestion of inhibitory pathways built into the immune system that are important for minimizing collateral tissue damage, maintaining self-tolerance, and regulating the duration and amplitude of physiological immune responses in peripheral tissues. Tumors incorporate specific immune checkpoint pathways as a primary mechanism of immune tolerance (especially against T cells specific for tumor antigens). Because many immune checkpoints are initiated by ligand-receptor interactions, they can be easily blocked by antibodies or modulated by recombinant forms of the ligand or receptor. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody was the first immunotherapeutic agent in this class to receive FDA approval (ipilimumab). Preclinical findings using blockade of additional immune checkpoint proteins, such as programmed cell death protein 1 (PD-1), indicate broad and diverse opportunities for enhancing antitumor immunity with the potential to produce durable clinical responses.

[0253] PD-1, which functions as an immune checkpoint, plays an important role in downregulating the immune system by preventing T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is achieved through a dual mechanism: promoting apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells). PD-1 inhibitors (e.g., anti-PD-1 antibodies), a new class of therapeutic agents that block PD-1, activate the immune system to attack tumors and thus are used to treat several types of cancer. In addition, antibodies against programmed death-ligand 1 (PD-L1) have similar effects on activating the adaptive immune response as antibodies targeting PD-1. Therefore, compositions and devices containing anti-PD-L1 antibodies are expected to provide similar therapeutic effects to those containing anti-PD-1 antibodies.

[0254] In some embodiments, the activator of the adaptive immune response is a small molecule. In some embodiments, the activator of the adaptive immune response is a biologic agent. In some embodiments, the biologic agent is a protein. In some embodiments, the biologic agent is an antibody or fragment thereof. In some embodiments, the biologic agent is a nucleic acid encoding a protein.

[0255] In certain embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM3 antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD 137 antibody, anti-CD3 antibody, anti-CD27 antibody, anti-CD28 antibody, anti-CD28H antibody, anti-CD30 antibody, anti-CD39 antibody, anti-CD40 antibody, anti-CD43 antibody, anti-CD47 antibody, anti-CD48 antibody, Anti-CD70 antibody, anti-CD73 antibody, anti-CD96 antibody, anti-CD123 antibody, anti-CD155 antibody, anti-CD160 antibody, anti-CD200 antibody, anti-CD244 antibody, anti-ICOS antibody, anti-TNFRSF25 Antibodies, anti-TMIGD2 antibody, anti-DNAM1 antibody, anti-BTLA antibody, anti-LIGHT antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-HVEM antibody, anti-Siglec antibody, anti-GAL1 antibody, anti-GAL 3 antibodies, anti-GAL9 antibody, anti-BTNL2 (butyrophilin) ​​antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H5 antibody, anti-B7-H6 antibody, anti-KIR antibody, anti-LIR antibody, anti-ILT antibody , anti-CEACAM1 antibody, anti-CEACAM5 antibody, anti-CEACAM6 antibody, anti-MICA antibody, anti-MICB antibody, anti-NKG2D antibody, anti-NKG2A antibody, anti-A2AR antibody, anti-C5aR antibody, anti-T GFβ antibody, anti-TGFβR antibody, anti-CXCR4 antibody, anti-CXCL12 antibody, anti-CCL2 antibody, anti-IL-10 antibody, anti-IL-13 antibody, anti-IL-23 antibody, anti-phosphatidylserine antibody, anti-nuclear -ropilin antibody, anti-GalCer antibody, anti-HER2 antibody, anti-VEGFA antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-Tie2 antibody, anti-CCR4 antibody, or anti-TRAIL-DR5 antibody.

[0256] In some embodiments, the activator of the adaptive immune response is a fragment of any of the antibodies listed above. In some embodiments, the activator of the adaptive immune response is a humanized form of any of the antibodies listed above. In some embodiments, the activator of the adaptive immune response is a single chain of any of the antibodies listed above. In some embodiments, the activator of the immune response is a multimeric form of the antibodies listed above (e.g., a dimeric IgA molecule, a pentavalent IgM molecule).

[0257] In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody, an agonistic anti-CD137 antibody, an agonistic anti-CD40 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3, or a combination thereof. In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody or an anti-CTLA-4 antibody. In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody. In some embodiments, the activator of the adaptive immune response is an anti-CTLA-4 antibody. In some embodiments, the activator of the adaptive immune response is an agonistic anti-CD137 antibody. In some embodiments, the activator of the adaptive immune response is an anti-LAG-3 antibody. In some embodiments, the activator of the adaptive immune response is an anti-TIM3 antibody.

[0258] In some embodiments, the activator of the adaptive immune response is selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-9365 59, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, IPH5401, IPH4102, IPH4301, IPH52, IPH53, varlilumab, ulocuplumab, monalizumab, MEDI0562, MEDI 0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T, CGEN15022, C GEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, lucatumumab, Dase Dacetuzumab, Chi Lob 7 / 4, RG6058, RG7686, R G7876, RG7888, TRX518, MK-4166, IMC-CS4, emactuzumab, trastuzumab, pertuzumab, obinutuzumab, cavilariz Cabiralizumab, margetuximab, enoblituzumab, mogamulizumab, panitumumab, carlumab, ramucirumab, bevacizumab, rituximab, cetuximab, fresolimumab, de Nosumab, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, teplizumab, FPA150, PF-04136309, PF-06747143, AZD5069, GSK3359609, FAZ053, TSR022, MBG453, REGN2810, REGN3767, MOXR0916, PF-04518600, RO7009789, BMS986156, GWN323, JTX-2011, NKTR-214, GSK3174998, DS-8273a, NIS793, or BGB-A317.

[0259] In some embodiments, the activator of the adaptive immune response is pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, REGN2810, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, or avelumab.

[0260] In some embodiments, the activator of the adaptive immune response is an antibody mimetic or an antibody fusion.

[0261] In some embodiments, the activator of the adaptive immune response is a bispecific antibody. In some embodiments, the bispecific antibody is selected from the group consisting of RG7802 (an antibody targeting carcinoembryonic antigen (CEA) and the CD3 receptor), RG7828 (a bispecific monoclonal antibody targeting CD20 on B cells and CD3 on T cells), RG7221 (a bispecific monoclonal antibody targeting VEGF and angiopoietin 2), RG7386 (a bispecific monoclonal antibody targeting FAP and DR5), ERY974 (a bispecific monoclonal antibody targeting CD3 and glypican-3), MGD012 (a bispecific monoclonal antibody targeting PD-1 and LAG-3), AMG211 (a bispecific T cell inducer (BiTE) targeting CD3 and CEA), MEDI573 (a bispecific monoclonal antibody targeting IGF1 and IGF2), MEDI565 (a bispecific monoclonal antibody targeting CD3 and CEA), bispecific monoclonal antibody), FS17 (undisclosed target), FS18 (bispecific monoclonal antibody targeting LAG3 and an undisclosed target), FS20 (undisclosed target), FS22 (undisclosed target), FS101 (bispecific monoclonal antibody targeting EGFR and HGF), FS117 (undisclosed target), FS118 (bispecific monoclonal antibody targeting LAG3 and PD-L1), RO6958688 (bispecific monoclonal antibody targeting CD3 and CEA), MCLA-128 (bispecific monoclonal antibody targeting HER2 and HER3), M7824 (bifunctional fusion protein targeting PD-L1 and TGFβ), MGD009 (humanized antibody recognizing both B7-H3 and CD3), or MGD013 (bispecific PD-1 and LAG-3 antibody).

[0262] In some embodiments, the activator of the adaptive immune response is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is trastuzumab emtansine, inotuzumab ozogamicin, PF-06647020, PF-06647263, PF-06650808, RG7596, RG7841, RG7882, RG7986, DS-8201, ABBV-399, glembatumumab vedotin, inotuzumab ozogamicin, isin, MEDI4276, or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the activator of adaptive immune response is a small molecule.In some embodiments, the small molecule is an IDO inhibitor, a TGFβR inhibitor, a BRAF inhibitor, a KIT inhibitor, an A2aR inhibitor, a Tie2 inhibitor, an arginase inhibitor, an iNOS inhibitor, a HIF1α inhibitor, a STAT3 inhibitor, a PGE2 inhibitor, a PDE5 inhibitor, a RON inhibitor, an mTOR inhibitor, a JAK2 inhibitor, an HSP90 inhibitor, a PI3K-AKT inhibitor, a β-catenin inhibitor, a GSK3β inhibitor, an IAP inhibitor, an HDAC inhibitor, a DNMT inhibitor, a BET inhibitor, a COX2 inhibitor, a PDGFR inhibitor, a VEGFR inhibitor, a BCR-ABL inhibitor, a proteasome inhibitor, an angiogenesis inhibitor, a MEK inhibitor, a BRAF+MEK inhibitor, a pan-RAF inhibitor, an EGFR inhibitor, a PARP inhibitor, a glutaminase inhibitor, a WNT inhibitor, a FAK inhibitor, an ALK inhibitor, a CDK4 / 6 inhibitor or an FGFR3 inhibitor.

[0264] In some embodiments, the small molecule is selected from the group consisting of celecoxib, sunitinib, imatinib, vemurafenib, dabrafenib, bortezomib, vorinostat, pomalidomide, thalidomide, lenalidomide, epacadostat, indoximid, GDC0919, BMS986205, AZD8055, AZD4635, CPI-444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, pexidartinib, galunisertib, birinapant, trametinib, cobimetinib, binimetinib , ensartinib, gefitinib, pazopanib, sorafenib, nintedanib, SYM004, veliparib, olaparib, BGB-290, everolimus, LXH254, azacitidine, decitabine, guadecitabine, RRX001, CC486, romidepsin, entinostat, panobinostat, tamoxifen, ibrutinib, Idelalisib, capmatinib, selumetinib, abemaciclib, palbociclib, glasdegib, enzalutamide, AZD9150, PF-06840003, SRF231, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, or a pharmaceutically acceptable salt thereof.

[0265] Further therapeutic agents The drug delivery compositions and devices may include additional therapeutic agents.

[0266] In some embodiments, drug delivery compositions and devices may contain modulators of macrophage effector function. Macrophages are immune cells derived from circulating monocytes, present in all tissues, and involved in many pathological conditions. Macrophages play a dual role in cancer, where they can promote tumor growth but also serve as important immune effectors of therapeutic antibodies. Macrophages express all classes of Fcγ receptors and have the potential to destroy tumors through the process of antibody-dependent cellular phagocytosis. Numerous studies have demonstrated that macrophage phagocytosis is the primary mechanism of action for many antibodies approved for cancer treatment. Consequently, many approaches are under investigation to enhance macrophage responses to therapeutic antibodies, including the discovery of new targets and the development of antibodies with enhanced function. Macrophage responses to antibody therapy can also be enhanced by engineered Fc variants, bispecific antibodies, or antibody-drug conjugates. Macrophages have demonstrated success as effectors of cancer immunotherapy.

[0267] In some embodiments, the macrophage effector function modulator is a modulator of suppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs). In some embodiments, the macrophage effector function modulator can kill, deplete, or enhance macrophages and / or MDSCs. In some embodiments, the macrophage effector function modulator is an anti-CD40 antibody, an anti-CD47 antibody, an anti-CSF1 antibody, or an anti-CSF1R antibody. In some embodiments, the macrophage effector function modulator is SRF231, Hu5F9-G4, CC-900002, or TTI-621 (anti-CD47 antibody). In some embodiments, the macrophage effector function modulator is MCS-110 (anti-CSF1 antibody). In some embodiments, the macrophage effector function modulator is FPA008, RG7155, IMC-CS4, AMG820, or UCB6352 (anti-CSF1R antibody). In some embodiments, the macrophage effector function modulator is a small molecule inhibitor of CSF1R. In some embodiments, the macrophage effector function modulator is BLZ945, GW2580, or PLX3397 (small molecule inhibitor of CSF1R). In some embodiments, the macrophage effector function modulator is a BTK inhibitor, an ITK inhibitor, a PI3Kγ inhibitor, or a PI3Kδ inhibitor. In some embodiments, the macrophage effector function modulator can replace one or more activators of the adaptive immune response in the composition or device.

[0268] In some embodiments, the drug delivery composition and device may further comprise an oncolytic virus. In some embodiments, the oncolytic virus includes, but is not limited to, herpes simplex virus (e.g., HSV1716, OncoVex GM-CSF); adenovirus (e.g., H101, Onyx-15); poliovirus (e.g., PV1 (RIPO)); reovirus (e.g., reolysin); Seneca virus (e.g., NTX-010, SVV-001); Rigvir virus; Maraba virus; measles; Newcastle disease virus; vaccinia; or ECHO virus.

[0269] In some embodiments, the drug delivery compositions and devices may further comprise a radioisotope (e.g., as part of the molecule or on the bead). In some embodiments, the radioisotope is yttrium-90, palladium-103, iodine-125, cesium-131, or iridium-192.

[0270] In some embodiments, the drug delivery compositions and devices may further comprise a chemotherapeutic agent, including, but not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), antiandrogens, and the like. Drugs (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine and temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, and oxaliplatin), vinca alkaloids (e.g., vincristine ... blastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents, such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoplexin), polyglutamic acid-bound paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-bound paclitaxel, such as 2'-paclitaxel methyl 2-glucopyranosyl;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, and mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, and edatrexate), IMP di Hydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, latitrexed, tegafur-uracil, and capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside; and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB1089, CB1093, and KH1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, and peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+ ATPase inhibitors (e.g., thapsigargin), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbidine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase , aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, hexamethylmelamine, and pharmaceutically acceptable salts thereof.

[0271] In some embodiments, the chemotherapeutic agent is an immunomodulatory chemotherapeutic agent. In some embodiments, the chemotherapeutic agent has a known immunomodulatory function (e.g., inducing immunogenic cell death or depleting immunosuppressive regulatory immune cells). In some embodiments, the chemotherapeutic agent is included in the drug delivery composition and device due to its immunotherapeutic properties, rather than its use as a traditional cancer cell-specific cytotoxic chemotherapy. In some embodiments, the drug delivery composition and device do not contain a chemotherapeutic agent. In some embodiments, the drug delivery composition and device do not contain a cytotoxic agent.

[0272] In some embodiments, the drug delivery composition and device may further comprise a targeting agent.In some embodiments, the targeting agent includes but is not limited to IDO inhibitor, TGFβR inhibitor, arginase inhibitor, iNOS inhibitor, HIF1α inhibitor, STAT3 inhibitor, CSF1R inhibitor, PGE2 inhibitor, PDE5 inhibitor, RON inhibitor, mTOR inhibitor, JAK2 inhibitor, HSP90 inhibitor, PI3K-AKT inhibitor, β-catenin inhibitor, GSK3β inhibitor, IAP inhibitor, HDAC inhibitor, DNMT inhibitor, BET inhibitor, A2AR inhibitor, BRAF+MEK inhibitor, pan-RAF inhibitor, PI3Kγ inhibitor, PI3Kδ inhibitor, EGFR inhibitor, VEGF inhibitor, PARP inhibitor, glutaminase inhibitor, BTK inhibitor, ITK inhibitor, WNT inhibitor, FAK inhibitor, ALK inhibitor, CDK4 / 6 inhibitor or FGFR3 inhibitor.

[0273] In some embodiments, the targeted agent includes, but is not limited to, imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, C), GP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), suni tinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), Gemtu Zumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®) )), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF -04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, Temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-46915 02 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI -027(OSI)), epacadostat, indoximide, GDC0919, BMS986205, AZD4635, CPI-444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, pexidartinib, galunisertib, virinapant, trametinib, dabrafenib, vemurafenib, cobimetinib, binimetinib, ensartinib, pazopanib, nintedanib, SYM004, veliparib, olaparib, BGB-290, LXH254, azacitidine, Examples of therapeutic agents include decitabine, guadecitabine, RRX001, CC486, romidepsin, entinostat, vorinostat, panobinostat, tamoxifen, ibrutinib, idelalisib, capmatinib, selumetinib, abemaciclib, palbociclib, glasdegib, enzalutamide, AZD9150, PF-06840003, SRF231, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, an anti-Tie2 antibody, or a pharmaceutically acceptable salt thereof.

[0274] Drug Delivery Composition and Device Embodiments In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an activator of the innate immune response.

[0275] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, and an additional activator of the innate immune response.

[0276] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, and a cytokine.

[0277] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a further activator of the innate immune response, and a cytokine.

[0278] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, and a chemokine.

[0279] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a further activator of the innate immune response, and a chemokine.

[0280] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a cytokine.

[0281] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a chemokine.

[0282] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an activator of the adaptive immune response.

[0283] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, and an activator of the adaptive immune response.

[0284] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a further activator of the innate immune response, and an activator of the adaptive immune response.

[0285] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0286] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the adaptive immune response, and two additional activators of the adaptive immune response.

[0287] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a cytokine, and an activator of the adaptive immune response.

[0288] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a further activator of the innate immune response, a cytokine, and an activator of the adaptive immune response.

[0289] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a cytokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0290] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, an additional activator of the innate immune response, a cytokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0291] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a chemokine, and an activator of the adaptive immune response.

[0292] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a further activator of the innate immune response, a chemokine, and an activator of the adaptive immune response.

[0293] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a chemokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0294] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, an additional activator of the innate immune response, a chemokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0295] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a cytokine, and an activator of the adaptive immune response.

[0296] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a cytokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0297] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a chemokine, and an activator of the adaptive immune response.

[0298] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a chemokine, an activator of the adaptive immune response, and an additional activator of the adaptive immune response.

[0299] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an NLR agonist.

[0300] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and M-TriDAP.

[0301] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, M-TriDAP, and an IL-15 superagonist.

[0302] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, M-TriDAP, and an anti-PD-1 antibody.

[0303] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, M-TriDAP, and an anti-CTLA-4 antibody.

[0304] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and M-TriDAP.

[0305] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), M-TriDAP, and an IL-15 superagonist.

[0306] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and M-TriDAP.

[0307] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, M-TriDAP, and an anti-PD-1 antibody.

[0308] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and IL-1β.

[0309] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an agonist of stimulator of interferon genes (STING).

[0310] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and 2'3'-cGAMP.

[0311] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0312] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an IL-15 superagonist.

[0313] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and interferon alpha (IFN-α).

[0314] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and interferon beta (IFN-β).

[0315] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and interferon gamma (IFN-γ).

[0316] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and an IL-15 superagonist.

[0317] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-cGAMP, and an IL-15 superagonist.

[0318] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist.

[0319] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and interferon alpha (IFN-α).

[0320] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and interferon beta (IFN-β).

[0321] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and interferon gamma (IFN-γ).

[0322] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and interferon alpha (IFN-α).

[0323] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and interferon-β (IFN-β).

[0324] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and interferon gamma (IFN-γ).

[0325] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a stimulator of interferon genes (STING) agonist, and an anti-PD-1 antibody.

[0326] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-PD-1 antibody.

[0327] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0328] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), an IL-15 superagonist, and an anti-PD-1 antibody.

[0329] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0330] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), and an anti-PD-1 antibody.

[0331] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), an IL-15 superagonist, and an anti-PD-1 antibody.

[0332] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, interferon beta (IFN-β), and an anti-PD-1 antibody.

[0333] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0334] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), an IL-15 superagonist, and an anti-PD-1 antibody.

[0335] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0336] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0337] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody.

[0338] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, c-di-GMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0339] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0340] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-cGAMP, an IL-15 superagonist, and an anti-CD137 antibody.

[0341] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-CD137 antibody.

[0342] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0343] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-PD-1 antibody.

[0344] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0345] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a TLR3 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0346] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, poly(I:C), an IL-15 superagonist, and an anti-PD-1 antibody.

[0347] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a TLR9 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0348] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a CpG oligonucleotide, an IL-15 superagonist, and an anti-PD-1 antibody.

[0349] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a stimulator of interferon genes (STING) agonist, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0350] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), and an anti-CTLA-4 antibody.

[0351] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a stimulator of interferon genes (STING) agonist, an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0352] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-LAG-3 antibody.

[0353] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), IL-15, and an agonist anti-CD40 antibody.

[0354] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an agonist of TLR7 and / or TLR8.

[0355] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a TLR7 agonist.

[0356] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a TLR8 agonist.

[0357] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and resiquimod.

[0358] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and an IL-15 superagonist.

[0359] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, resiquimod, and an IL-15 superagonist.

[0360] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and an anti-PD-1 antibody.

[0361] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0362] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0363] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0364] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, resiquimod, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0365] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, and an anti-CTLA-4 antibody.

[0366] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0367] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-LAG-3 antibody.

[0368] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, IL-15, and an agonist anti-CD40 antibody.

[0369] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0370] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0371] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0372] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0373] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an agonist anti-CD137 antibody.

[0374] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-CTLA-4 antibody.

[0375] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-PD-1 antibody.

[0376] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0377] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0378] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0379] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an agonist anti-CD137 antibody, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0380] In some embodiments, drug delivery compositions and devices comprise a hydrogel and an activator of the innate immune response, wherein the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), or resiquimod.

[0381] In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a chemokine, wherein the chemokine is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ.

[0382] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, and a chemokine; wherein the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), or resiquimod; and the chemokine is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ.

[0383] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an activator of the innate immune response, a chemokine, and an activator of the adaptive immune response; wherein the activator of the innate immune response is 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), or resiquimod; the chemokine is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ; and the activator of the adaptive immune response is an anti-PD-1 antibody, an anti-CTLA4 antibody, an anti-CD40 antibody, or an anti-CD137 antibody.

[0384] In some embodiments, the drug delivery composition is selected from the group consisting of: a composition comprising a hydrogel and 2'3'-cGAMP; A composition comprising a hydrogel and 2'3'-c-di-AM(PS)2(Rp,Rp); a composition comprising a hydrogel and resiquimod; a composition comprising a hydrogel and M-TriDAP; a composition comprising a hydrogel and an IL-15 superagonist; a composition comprising a hydrogel and interferon alpha (IFN-α); a composition comprising a hydrogel and interferon beta (IFN-β); a composition comprising a hydrogel and interferon gamma (IFN-γ); a composition comprising a hydrogel, 2'3'-cGAMP, and an IL-15 superagonist; A composition comprising a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist; a composition comprising a hydrogel, resiquimod, and an IL-15 superagonist; a composition comprising a hydrogel, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A composition comprising a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and A composition comprising a hydrogel, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0385] In some embodiments, the drug delivery device is selected from the group consisting of: a device comprising a hydrogel and 2'3'-cGAMP; a device comprising a hydrogel and 2'3'-c-di-AM(PS)2(Rp,Rp); a device comprising a hydrogel and resiquimod; a device comprising a hydrogel and M-TriDAP; a device comprising a hydrogel and an IL-15 superagonist; a device comprising a hydrogel and interferon alpha (IFN-α); a device comprising a hydrogel and interferon beta (IFN-β); a device comprising a hydrogel and interferon gamma (IFN-γ); a device comprising a hydrogel, 2'3'-cGAMP, and an IL-15 superagonist; a device comprising a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist; a device comprising a hydrogel, resiquimod, and an IL-15 superagonist; a device comprising a hydrogel, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A device comprising a hydrogel, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and The device includes a hydrogel, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0386] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an NLR agonist.

[0387] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and M-TriDAP.

[0388] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, M-TriDAP, and an IL-15 superagonist.

[0389] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, M-TriDAP, and an anti-PD-1 antibody.

[0390] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, M-TriDAP, and an anti-CTLA-4 antibody.

[0391] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and M-TriDAP.

[0392] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), M-TriDAP, and an IL-15 superagonist.

[0393] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and M-TriDAP.

[0394] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, M-TriDAP, and an anti-PD-1 antibody.

[0395] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and IL-1β.

[0396] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and IL-1β.

[0397] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and IL-1β.

[0398] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an agonist of stimulator of interferon genes (STING).

[0399] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and 2'3'-cGAMP.

[0400] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0401] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an IL-15 superagonist.

[0402] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and interferon alpha (IFN-α).

[0403] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and interferon beta (IFN-β).

[0404] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and interferon gamma (IFN-γ).

[0405] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and an IL-15 superagonist.

[0406] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-cGAMP, and an IL-15 superagonist.

[0407] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist.

[0408] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and interferon alpha (IFN-α).

[0409] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and interferon beta (IFN-β).

[0410] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and interferon gamma (IFN-γ).

[0411] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and interferon alpha (IFN-α).

[0412] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and interferon-beta (IFN-β).

[0413] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and interferon gamma (IFN-γ).

[0414] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and an anti-PD-1 antibody.

[0415] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-PD-1 antibody.

[0416] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0417] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), an IL-15 superagonist, and an anti-PD-1 antibody.

[0418] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0419] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), and an anti-PD-1 antibody.

[0420] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), an IL-15 superagonist, and an anti-PD-1 antibody.

[0421] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, interferon beta (IFN-β), and an anti-PD-1 antibody.

[0422] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0423] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), an IL-15 superagonist, and an anti-PD-1 antibody.

[0424] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0425] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0426] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody.

[0427] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, c-di-GMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0428] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0429] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-cGAMP, an IL-15 superagonist, and an anti-CD137 antibody.

[0430] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-CD137 antibody.

[0431] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0432] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-PD-1 antibody.

[0433] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0434] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a TLR3 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0435] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, poly(I:C), an IL-15 superagonist, and an anti-PD-1 antibody.

[0436] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a TLR9 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0437] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a CpG oligonucleotide, an IL-15 superagonist, and an anti-PD-1 antibody.

[0438] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0439] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), and an anti-CTLA-4 antibody.

[0440] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0441] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-LAG-3 antibody.

[0442] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), IL-15, and an agonist anti-CD40 antibody.

[0443] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an agonist of TLR7 and / or TLR8.

[0444] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a TLR7 agonist.

[0445] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a TLR8 agonist.

[0446] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and resiquimod.

[0447] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and an IL-15 superagonist.

[0448] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, resiquimod, and an IL-15 superagonist.

[0449] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and an anti-PD-1 antibody.

[0450] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0451] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0452] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0453] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, resiquimod, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0454] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, and an anti-CTLA-4 antibody.

[0455] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0456] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-LAG-3 antibody.

[0457] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, IL-15, and an agonist anti-CD40 antibody.

[0458] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0459] In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0460] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0461] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0462] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an agonist anti-CD137 antibody.

[0463] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-CTLA-4 antibody.

[0464] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-PD-1 antibody.

[0465] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0466] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0467] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0468] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an agonist anti-CD137 antibody, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0469] In some embodiments, the drug delivery composition is selected from the group consisting of: a composition comprising hyaluronic acid and 2'3'-cGAMP; A composition comprising hyaluronic acid and 2'3'-c-di-AM(PS)2(Rp,Rp); a composition comprising hyaluronic acid and resiquimod; a composition comprising hyaluronic acid and M-TriDAP; a composition comprising hyaluronic acid and an IL-15 superagonist; a composition comprising hyaluronic acid and interferon alpha (IFN-α); a composition comprising hyaluronic acid and interferon beta (IFN-β); a composition comprising hyaluronic acid and interferon gamma (IFN-γ); a composition comprising hyaluronic acid, 2'3'-cGAMP, and an IL-15 superagonist; A composition comprising hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist; a composition comprising hyaluronic acid, resiquimod, and an IL-15 superagonist; a composition comprising hyaluronic acid, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A composition comprising hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and A composition comprising hyaluronic acid, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0470] In some embodiments, the drug delivery device is selected from the group consisting of: a device comprising hyaluronic acid and 2'3'-cGAMP; a device comprising hyaluronic acid and 2'3'-c-di-AM(PS)2(Rp,Rp); a device containing hyaluronic acid and resiquimod; a device comprising hyaluronic acid and M-TriDAP; a device comprising hyaluronic acid and an IL-15 superagonist; a device comprising hyaluronic acid and interferon alpha (IFN-α); a device comprising hyaluronic acid and interferon beta (IFN-β); a device comprising hyaluronic acid and interferon gamma (IFN-γ); a device comprising hyaluronic acid, 2'3'-cGAMP, and an IL-15 superagonist; a device comprising hyaluronic acid, 2'3'-c-di-AM(PS)2 (Rp,Rp), and an IL-15 superagonist; a device containing hyaluronic acid, resiquimod, and an IL-15 superagonist; a device comprising hyaluronic acid, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A device comprising hyaluronic acid, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and The device includes hyaluronic acid, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0471] In some embodiments, the drug delivery compositions and devices comprise alginate and an NLR agonist.

[0472] In some embodiments, the drug delivery compositions and devices comprise alginate and M-TriDAP.

[0473] In some embodiments, the drug delivery compositions and devices comprise alginate, M-TriDAP, and an IL-15 superagonist.

[0474] In some embodiments, the drug delivery compositions and devices comprise alginate, M-TriDAP, and an anti-PD-1 antibody.

[0475] In some embodiments, the drug delivery compositions and devices comprise alginate, M-TriDAP, and an anti-CTLA-4 antibody.

[0476] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and M-TriDAP.

[0477] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), M-TriDAP, and an IL-15 superagonist.

[0478] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and M-TriDAP.

[0479] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, M-TriDAP, and an anti-PD-1 antibody.

[0480] In some embodiments, the drug delivery compositions and devices comprise alginate and IL-1β.

[0481] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and IL-1β.

[0482] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and IL-1β.

[0483] In some embodiments, drug delivery compositions and devices comprise alginate and an agonist of stimulator of interferon genes (STING).

[0484] In some embodiments, the drug delivery compositions and devices comprise alginate and 2'3'-cGAMP.

[0485] In some embodiments, the drug delivery compositions and devices comprise alginate and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0486] In some embodiments, the drug delivery compositions and devices comprise alginate and an IL-15 superagonist.

[0487] In some embodiments, the drug delivery compositions and devices comprise alginate and interferon alpha (IFN-α).

[0488] In some embodiments, the drug delivery compositions and devices comprise alginate and interferon beta (IFN-β).

[0489] In some embodiments, the drug delivery compositions and devices comprise alginate and interferon gamma (IFN-γ).

[0490] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and an IL-15 superagonist.

[0491] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-cGAMP, and an IL-15 superagonist.

[0492] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist.

[0493] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and interferon alpha (IFN-α).

[0494] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and interferon beta (IFN-β).

[0495] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and interferon gamma (IFN-γ).

[0496] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and interferon alpha (IFN-α).

[0497] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and interferon-beta (IFN-β).

[0498] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and interferon gamma (IFN-γ).

[0499] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and an anti-PD-1 antibody.

[0500] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-PD-1 antibody.

[0501] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0502] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon alpha (IFN-α), an IL-15 superagonist, and an anti-PD-1 antibody.

[0503] In some embodiments, the drug delivery compositions and devices comprise alginate, interferon alpha (IFN-α), and an anti-PD-1 antibody.

[0504] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), and an anti-PD-1 antibody.

[0505] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon beta (IFN-β), an IL-15 superagonist, and an anti-PD-1 antibody.

[0506] In some embodiments, the drug delivery compositions and devices comprise alginate, interferon beta (IFN-β), and an anti-PD-1 antibody.

[0507] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0508] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), interferon gamma (IFN-γ), an IL-15 superagonist, and an anti-PD-1 antibody.

[0509] In some embodiments, the drug delivery compositions and devices comprise alginate, interferon gamma (IFN-γ), and an anti-PD-1 antibody.

[0510] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0511] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody.

[0512] In some embodiments, the drug delivery compositions and devices comprise alginate, c-di-GMP, an IL-15 superagonist, and an anti-PD-1 antibody.

[0513] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0514] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-cGAMP, an IL-15 superagonist, and an anti-CD137 antibody.

[0515] In some embodiments, the drug delivery compositions and devices comprise alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-CD137 antibody.

[0516] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0517] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-PD-1 antibody.

[0518] In some embodiments, the drug delivery compositions and devices comprise alginate, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0519] In some embodiments, the drug delivery compositions and devices comprise alginate, a TLR3 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0520] In some embodiments, the drug delivery compositions and devices comprise alginate, poly(I:C), an IL-15 superagonist, and an anti-PD-1 antibody.

[0521] In some embodiments, the drug delivery compositions and devices comprise alginate, a TLR9 agonist, an IL-15 superagonist, and an anti-PD-1 antibody.

[0522] In some embodiments, the drug delivery compositions and devices comprise alginate, a CpG oligonucleotide, an IL-15 superagonist, and an anti-PD-1 antibody.

[0523] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0524] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), and an anti-CTLA-4 antibody.

[0525] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0526] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an IL-15 superagonist, and an anti-LAG-3 antibody.

[0527] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), IL-15, and an agonist anti-CD40 antibody.

[0528] In some embodiments, the drug delivery compositions and devices comprise alginate and an agonist of TLR7 and / or TLR8.

[0529] In some embodiments, the drug delivery compositions and devices comprise alginate and a TLR7 agonist.

[0530] In some embodiments, the drug delivery compositions and devices comprise alginate and a TLR8 agonist.

[0531] In some embodiments, the drug delivery compositions and devices comprise alginate and resiquimod.

[0532] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and an IL-15 superagonist.

[0533] In some embodiments, the drug delivery compositions and devices comprise alginate, resiquimod, and an IL-15 superagonist.

[0534] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and an anti-PD-1 antibody.

[0535] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD137 antibody.

[0536] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an agonist anti-CD40 antibody.

[0537] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0538] In some embodiments, the drug delivery compositions and devices comprise alginate, resiquimod, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.

[0539] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, and an anti-CTLA-4 antibody.

[0540] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an anti-LAG-3 antibody, and an anti-PD-1 antibody.

[0541] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an IL-15 superagonist, and an anti-LAG-3 antibody.

[0542] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, IL-15, and an agonist anti-CD40 antibody.

[0543] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0544] In certain embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0545] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of stimulator of interferon genes (STING), an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0546] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist of TLR7 and / or TLR8, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0547] In some embodiments, the drug delivery compositions and devices comprise alginate and an agonist anti-CD137 antibody.

[0548] In some embodiments, the drug delivery compositions and devices comprise alginate and an anti-CTLA-4 antibody.

[0549] In some embodiments, the drug delivery compositions and devices comprise alginate and an anti-PD-1 antibody.

[0550] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist anti-CD137 antibody, and an anti-PD-1 antibody.

[0551] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist anti-CD137 antibody, and an anti-CTLA-4 antibody.

[0552] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0553] In some embodiments, the drug delivery compositions and devices comprise alginate, an agonist anti-CD137 antibody, an anti-PD-1 antibody, and an anti-CTLA-4 antibody.

[0554] In some embodiments, the drug delivery composition is selected from the group consisting of: a composition comprising alginate and 2'3'-cGAMP; A composition comprising alginate and 2'3'-c-di-AM(PS)2(Rp,Rp); a composition comprising alginate and resiquimod; a composition comprising alginate and M-TriDAP; a composition comprising alginate and an IL-15 superagonist; a composition comprising alginate and interferon alpha (IFN-α); a composition comprising alginate and interferon beta (IFN-β); a composition comprising alginate and interferon gamma (IFN-γ); A composition comprising alginate, 2'3'-cGAMP, and an IL-15 superagonist; A composition comprising alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), and an IL-15 superagonist; a composition comprising alginate, resiquimod, and an IL-15 superagonist; a composition comprising alginate, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A composition comprising alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and A composition comprising alginate, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0555] In some embodiments, the drug delivery device is selected from the group consisting of: a device comprising alginate and 2'3'-cGAMP; a device comprising alginate and 2'3'-c-di-AM(PS)2(Rp,Rp); a device comprising alginate and resiquimod; a device comprising alginate and M-TriDAP; a device comprising alginate and an IL-15 superagonist; a device comprising alginate and interferon alpha (IFN-α); a device comprising alginate and interferon beta (IFN-β); a device comprising alginate and interferon gamma (IFN-γ); a device comprising alginate, 2'3'-cGAMP, and an IL-15 superagonist; a device comprising alginate, 2'3'-c-di-AM(PS)2 (Rp,Rp), and an IL-15 superagonist; a device containing alginate, resiquimod, and an IL-15 superagonist; a device comprising alginate, 2'3'-cGAMP, an IL-15 superagonist, and an anti-PD-1 antibody; A device comprising alginate, 2'3'-c-di-AM(PS)2(Rp,Rp), an IL-15 superagonist, and an anti-PD-1 antibody; and The device includes alginate, resiquimod, an IL-15 superagonist, and an anti-PD-1 antibody.

[0556] In some embodiments, the drug delivery compositions and devices do not include alginate, a COX-2 inhibitor (e.g., celecoxib), and an anti-PD-1 antibody.

[0557] In some embodiments, the drug delivery compositions and devices are free of 1,3,-bis(2-chloroethyl)-1-nitrosourea (BCNU) and ethylene vinyl acetate copolymer.

[0558] Drug Delivery Composition and Device Characteristics Biomaterials useful for the drug delivery compositions and devices described herein are biocompatible. Biomaterials (e.g., hydrogels) are biodegradable. Drug delivery compositions and devices can be chemically and / or biologically degraded in a physiological environment, e.g., within the body. Degradation of the compositions and devices can occur at various rates depending on the components and hydrogel used. For example, the half-life of the compositions and devices (the time it takes for 50% of the composition to degrade into monomers and / or other non-polymeric moieties) can be days, weeks, months, or years. The compositions and devices can be biologically degraded, for example, by enzymatic activity or cellular mechanisms in some cases, such as through exposure to lysozyme (e.g., having a relatively low pH) or by simple hydrolysis. In some cases, the compositions and devices can be degraded into monomers and / or other non-polymeric moieties that cells can reuse or dispose of without significant toxic effects to the cells. The drug delivery compositions and devices are stable in vivo so that they deliver the drug to the intended target within a suitable period of time.

[0559] In certain embodiments, 12 months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the device remains in vivo.

[0560] In some embodiments, 6 months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0561] In some embodiments, 5 months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0562] In certain embodiments, 4 months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0563] In certain embodiments, 3 months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0564] In some embodiments, two months after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0565] In some embodiments, one month after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0566] In some embodiments, one week after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0567] In some embodiments, one day after implantation of the drug delivery composition or device, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% of the composition remains in vivo.

[0568] The storage modulus of a viscoelastic material measures the stored energy in the elastic portion of the material. Storage modulus can be measured with a rheometer. The measurements provided herein were performed at room temperature using a TA Instruments AR-G2 magnetic bearing rheometer. The storage modulus of the drug delivery compositions and devices will vary depending on the components of the composition.

[0569] In general, the relationship between storage modulus and the concentration of thiol-modified hyaluronic acid (e.g., GLYCOSIL®) and thiol-reactive PEGDA crosslinker (e.g., EXTRALINK®) is linear (except at the limit of sensitivity). For example, a formulation of 0.8% GLYCOSIL® and 0.2% EXTRALINK® has a storage modulus of approximately 100 Pa. and a formulation of 1.3% GLYCOSIL® and 2% EXTRALINK® would have a storage modulus of about 1600 Pa.

[0570] In certain embodiments, the drug delivery composition or device has a storage modulus of at least 50 Pa, at least 100 Pa, at least 200 Pa, at least 300 Pa, at least 400 Pa, at least 500 Pa, at least 600 Pa, at least 700 Pa, at least 800 Pa, at least 900 Pa, at least 1000 Pa, at least 1100 Pa, at least 1200 Pa, at least 1300 Pa, at least 1400 Pa, at least 1500 Pa, at least 1600 Pa, at least 1700 Pa, at least 1800 Pa, at least 1900 Pa, at least 2000 Pa, at least 2100 Pa, at least 2200 Pa, at least 2300 Pa, at least 2400 Pa, at least 2500 Pa, at least 2600 Pa, at least 2700 Pa, at least 2800 Pa, at least 2900 Pa, or at least 3000 Pa.

[0571] In certain embodiments, the drug delivery composition or device has a storage modulus of about 50 Pa to about 100,000,000 Pa, about 50 Pa to about 100,000 Pa, about 50 Pa to about 10,000 Pa, about 50 Pa to about 3,000 Pa, about 100 Pa to about 3,000 Pa, about 100 Pa to about 2,000 Pa, about 500 Pa to about 3,000 Pa, about 500 Pa to about 2,000 Pa, about 1,000 Pa to about 2,000 Pa, about 1,200 Pa to about 1,800 Pa, about 1,300 Pa to about 1,700 Pa, or about 1,400 Pa to about 1,600 Pa.

[0572] In certain embodiments, the drug delivery composition or device has a storage modulus of about 600 Pa or less, about 700 Pa or less, about 800 Pa or less, about 900 Pa or less, about 1,000 Pa or less, about 1,100 Pa or less, about 1,200 Pa or less, about 1,300 Pa or less, about 1,400 Pa or less, about 1,500 Pa or less, about 1,600 Pa or less, about 1,700 Pa or less, about 1,800 Pa or less, about 1,900 Pa or less, about 2,000 Pa or less, about 2,500 Pa or less, about 3,000 Pa or less, about 5,000 Pa or less, about 10,000 Pa or less, about 100,000 Pa or less, about 1,000,000 Pa or less, about 10,000,000 Pa or less, or about 100,000,000 Pa or less.

[0573] Drug delivery compositions and devices release therapeutic agents under physiological conditions, such as in the body. The release of the therapeutic agent can occur at various rates, depending on the components of the composition or device (e.g., the identity and concentration of the hydrogel). For example, the release rate of the therapeutic agent (the time at which the therapeutic agent is no longer part of the composition or device) can be on the order of minutes, hours, days, weeks, months, or years. The therapeutic agent can be released by various mechanisms, such as diffusion, chemical activity, enzymatic activity, or cellular mechanisms. Drug delivery compositions and devices are stable in vivo so that they deliver the drug to the intended target for a suitable period of time.

[0574] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of the activator of the innate immune system is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0575] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of the activator of the innate immune system is released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0576] In certain embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of any additional activator of the innate immune system is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0577] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of any additional activators of the innate immune system are released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device. will be done.

[0578] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of the activator of the adaptive immune system is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0579] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of the activator of the adaptive immune system is released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0580] In certain embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of any additional activator of the adaptive immune system is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0581] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of any additional activators of the adaptive immune system are released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device. will be done.

[0582] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of the cytokine is released in vivo within 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0583] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1% or more of the cytokine is released in vivo within 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes after implantation of the composition or device.

[0584] Preparation and Administration of Drug Delivery Compositions and Devices The present disclosure provides a device comprising a drug delivery composition and a therapeutic agent as described herein. In some embodiments, the therapeutic agent is provided in the drug delivery composition and device in an effective amount for treating and / or preventing a disease (e.g., a proliferative disease such as cancer). In some embodiments, the effective amount is a therapeutically effective amount of a specific therapeutic agent. In some embodiments, the effective amount is a prophylactically effective amount of a specific therapeutic agent.

[0585] The drug delivery compositions and devices described herein can be prepared by any method known in the pharmaceutical field.In some embodiments, this preparation method comprises: adding thiol-modified hyaluronic acid to template; optionally adding the activator of adaptive immune response to template; optionally adding chemokine or cytokine to template; optionally adding the activator of innate immune response to template; adding crosslinker to template (for example, thiol-reactive PEGDA crosslinker); and leaving this mixture for at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 1 hour, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours or at least 6 hours to solidify.

[0586] In some embodiments, the concentration of thiol-modified hyaluronic acid (e.g., GLYCOSIL®) used for the preparation of the hydrogel is about 1% to about 10%, about 1% to about 5%, about 1% to about 3%, or about 1.5% to about 2.5% by weight / volume; and the concentration of thiol-reactive PEGDA crosslinker (e.g., EXTRALINK®) used for the preparation of the hydrogel is about 1% to about 10%, about 1% to about 5%, about 1% to about 3%, or about 1.5% to about 2.5% by weight / volume. The amount of thiol-modified hyaluronic acid (registered trademark) is about 1% to about 20%, about 10% to about 20%, about 5% to about 15%, or about 10% to about 15% by weight / volume. In a preferred embodiment, the concentration of thiol-modified hyaluronic acid is about 2% w / v and the concentration of thiol-reactive PEGDA crosslinker is about 12.5% ​​w / v. In one embodiment, a formulation of 2% thiol-modified hyaluronic acid and 12.5% ​​thiol-reactive PEGDA crosslinker provides a hydrogel with a storage modulus of about 1000 Pa to about 2000 Pa.

[0587] For preparation of standard tissue engineering applications known in the art, a typical concentration of thiol-modified hyaluronic acid (e.g., GLYCOSIL®) is about 1% w / v, and a typical concentration of thiol-reactive PEGDA crosslinker (e.g., EXTRALINK®) is about 1% w / v. is about 1% w / v. Thus, the use of 2% w / v thiol-modified hyaluronic acid (e.g., GLYCOSIL®) and 12.5% ​​w / v thiol-reactive PEGDA crosslinker (e.g., EXTRALINK®) provides the disclosed drug delivery compositions and This provides unexpectedly useful and advantageous biomaterials for devices.

[0588] In some embodiments, the concentration of alginate used to prepare the hydrogel is about 0.5% to about 2.5%, about 0.75% to about 2.0%, or about 1.0% to about 1.5% alginate by weight / volume. In some embodiments, the amount of 1 M calcium chloride crosslinker solution used in preparing the hydrogel is about 5 μL to 25 μL, about 10 μL to 20 μL, or about 15 μL. In some embodiments, the payload of interest can be loaded into about 10 μL to 70 μL of solvent (PBS or DMSO), 20 μL to 60 μL of solvent (PBS or DMSO), about 30 μL to 50 μL of solvent (PBS or DMSO), or about 40 μL of solvent (PBS or DMSO).

[0589] The drug delivery composition and device may further comprise at least one excipient. In some embodiments, the excipient is phosphate buffered saline, tris(hydroxymethyl)aminomethane, sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, sodium bicarbonate, sodium phosphate, potassium phosphate, calcium nitrate, glucose, lactose, trehalose, sucrose, or a combination thereof. In some embodiments, the excipient is phosphate buffered saline, tris(hydroxymethyl)aminomethane, sodium chloride, or a combination thereof. In some embodiments, the excipient is phosphate buffered saline.

[0590] In some embodiments, the drug delivery composition and device do not contain nanoparticles or microparticles. Nanoparticles include particles with a size of 1 to 100 nm. Microparticles include particles with a size of 0.1 to 100 μm. In some embodiments, the drug delivery composition and device do not contain silica microparticles, polyethylene microparticles, polystyrene microparticles, polyester microparticles, polyanhydride microparticles, polycaprolactone microparticles, polycarbonate microparticles, or polyhydroxybutyrate microparticles. In some embodiments, the drug delivery composition and device do not contain porous silica microparticles.

[0591] In some embodiments, the drug delivery compositions and devices include one or more organic solvents. In some embodiments, the drug delivery compositions and devices include dimethyl sulfoxide (DMSO).

[0592] In some embodiments, the drug delivery compositions and devices do not contain organic solvents. In some embodiments, organic solvents are not used in the preparation of the compositions or devices. In some embodiments, the drug delivery compositions and devices are organic solvent-free. In some embodiments, the drug delivery compositions and devices are substantially organic solvent-free. In some embodiments, the drug delivery compositions and devices contain less than 10% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.1% by weight, less than 0.01% by weight, less than 0.001% by weight, or less than 0.0001% by weight of organic solvent. In some embodiments, the drug delivery composition and device contain less than 1000 ppm by weight, less than 500 ppm by weight, less than 400 ppm by weight, less than 300 ppm by weight, less than 200 ppm by weight, less than 100 ppm by weight, less than 50 ppm by weight, less than 40 ppm by weight, less than 30 ppm by weight, less than 20 ppm by weight, less than 10 ppm by weight, less than 1 ppm by weight, less than 10 ppb by weight, or less than 1 ppb by weight of an organic solvent. In some embodiments, the drug delivery composition does not contain dimethyl sulfoxide (DMSO).

[0593] In some embodiments, the drug delivery composition comprises an organic solvent, hi some embodiments, the organic solvent is cyclodextrin, methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, or a combination thereof.

[0594] Drug delivery compositions and devices can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. A "unit dose" is a discrete amount of a composition or device containing a predetermined amount of a therapeutic agent. The amount of the therapeutic agent is generally equal to the dose of the therapeutic agent that would be administered to a subject, and / or a convenient fraction of such a dose, such as one-half, one-third, or one-quarter of such a dose.

[0595] The relative amounts of therapeutic agent, excipient, and / or any additional materials in a composition or device of the present disclosure will vary depending on the identity, size, and / or condition of the subject being treated. By way of example, a composition or device may contain 0.1%-99% (w / w), 0.1%-90% (w / w), 0.1%-80% (w / w), 0.1%-70% (w / w), 1%-50% (w / w), 10%-80% (w / w), 10%-90% (w / w), 10%-80% (w / w), 20%-80% (w / w), 30%-80% (w / w), 30%-70% (w / w), or 40%-60% (w / w) of therapeutic agent.

[0596] Additional pharmaceutically acceptable excipients may be used in the manufacture of the provided drug delivery compositions and devices. These include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or fats and oils. Excipients, colorants, and coating agents such as cocoa butter and suppository waxes may also be present in the compositions or devices.

[0597] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0598] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicic acid, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), micronized starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0599] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and monostearic acid). propylene glycol phosphate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monolaurate (Tween® 80), Sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (MYRJ 45), polyoxyethylene esters (e.g., polyoxyethylene esters (MYRJ 45), ... Ethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid ester, polyethylene glycol fatty acid ester ( For example, Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene Poly(vinylpyrrolidone), Diethylene Glycol, Polyethylene Glycol, Ethylenediamine Distearate, Polyethylene Glycol These may include but are not limited to: ethanol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLURONIC F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0600] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol shell mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM), and larch arabinogalactan), alginates, polysaccharides, and the like. Examples of suitable additives include polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or mixtures thereof.

[0601] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0602] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0603] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0604] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0605] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoic acid, and phenylethyl alcohol.

[0606] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0607] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butyric acid, butylated hydroxytoluene (BHT), ethylenediamine, Sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium disulfite, potassium sulfate, GLYDANT PLUS, PHENONIP, methylparaben, GERMALL 115, GERMABEN II, NEOLONE, KATHON, and EUXYL.

[0608] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium phosphate hydroxide, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0609] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0610] Exemplary natural oils and fats include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, and the like. Examples of suitable oils include laurel oil, laurel oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0611] Although the description of drug delivery compositions provided herein is primarily directed to compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications to drug delivery compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacist of ordinary skill can design and / or implement such modifications with routine experimentation.

[0612] The drug delivery compositions and devices provided herein are typically formulated in suitable size (e.g., volume) and weight for intended use (e.g., surgical implantation) for ease of administration.However, it will be understood that the total amount of the compositions or devices of the present disclosure (e.g., the number of devices to be implanted) will be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will depend on a variety of factors, including the disease and severity of the disorder being treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and excretion rate of the specific active ingredient used; the duration of treatment; the drugs used in combination with the specific active ingredient used; and similar factors well known in the medical field.

[0613] The drug delivery compositions and devices provided herein can be administered by surgical implantation. For example, the drug delivery composition or device can be administered by surgical implantation in the void volume of a resected tumor.

[0614] The exact amount of therapeutic agent required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, general condition, severity of side effects or disorders, the identity of the particular agent, etc.

[0615] In certain embodiments, an effective amount of a composition or device for administration to a 70 kg adult human may comprise from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg.

[0616] In certain embodiments, the composition or device may be at a dosage level sufficient to deliver about 0.001 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.1 mg to about 40 mg, about 0.5 mg to about 30 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, or about 1 mg to about 25 mg of any of the therapeutic agents present in the composition per kg of subject body weight per day to achieve the desired therapeutic effect.

[0617] It will be understood that the dosage ranges as described herein provide guidance for administration of the provided drug delivery compositions and devices to adults. For example, the amount to be administered to a child or infant can be determined by a physician or person skilled in the art and may be lower than or the same as that administered to an adult.

[0618] It will also be understood that the compositions and devices described herein can be administered in combination with one or more additional medicinal agents.For example, compositions and devices can be administered in combination with additional medicinal agents that reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution in the body.It will also be understood that the additional treatments used can achieve the desired effect for the same disorder and / or achieve different effects.

[0619] The compositions and devices can be administered simultaneously with, prior to, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. The pharmaceutical agents include therapeutically active agents. The pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent can be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents will be administered separately at different doses and / or by different routes of administration. The specific combination to be used in the regimen will take into account the compatibility of the drug delivery composition with the additional pharmaceutical agent and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the additional pharmaceutical agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels at which they are used individually.

[0620] Exemplary additional pharmaceutical agents include, but are not limited to, growth inhibitors, anti-cancer agents, anti-inflammatory agents, immunosuppressants and pain relievers.Pharmaceutical agents include small molecule therapeutic agents, such as drug compounds (for example, compounds that are approved by the US Food and Drug Administration as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules that are linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0621] In some embodiments, the drug delivery compositions and devices do not contain cells. In some embodiments, the drug delivery compositions and devices do not contain adoptively transferred cells. In some embodiments, the drug delivery compositions and devices do not contain T cells. In some embodiments, the additional pharmaceutical agent is not an adoptively transferred cell. In some embodiments, the additional pharmaceutical agent is not a T cell. In some embodiments, the drug delivery compositions and devices do not contain a tumor antigen. In some embodiments, the drug delivery compositions and devices contain ex vivo loaded tumor antigens. Does not include Hara.

[0622] In some embodiments, the term "drug delivery composition" refers to a composition in liquid form. In some embodiments, the term "drug delivery device" refers to a composition in solid form. In some embodiments, the transition from composition to device may occur by sufficient crosslinking such that the resulting material has a storage modulus consistent with the solid form, allowing it to be physically manipulated and implanted in a surgical procedure. Thus, a drug delivery device in its solid form may be particularly acceptable for the intended uses (e.g., surgical implantation) of the present disclosure.

[0623] In some embodiments, the drug delivery composition and / or drug delivery device is The drug delivery composition and / or drug delivery device are prepared immediately prior to implantation (e.g., in or near the operating room). In some embodiments, the drug delivery composition and / or drug delivery device are administered within 24 hours, 18 hours, or 24 hours of in vivo implantation. Prepared within hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0624] In some embodiments, the drug delivery composition and / or drug delivery device is In some embodiments, the drug delivery composition and / or drug delivery device is prepared 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, Prepared within 4, 3, 2, or 1 day.

[0625] In some embodiments, the drug delivery composition is prepared within 1 year, 10 months, 8 months, 6 months, 4 months, 3 months, 2 months, 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day of its use in a therapeutic setting. In some embodiments, the prepared drug delivery composition is then administered within 31 days, 28 days, 21 days, or 1 day of in vivo implantation. Within 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute, use to prepare the corresponding drug delivery device by addition of a crosslinker as described herein.

[0626] Also included in the present disclosure is kit.Provided kit may comprise the composition and / or device described herein and a container (for example, vial, ampoule, bottle, syringe and / or dispenser package, or other suitable container).In some embodiments, provided kit may further comprise a second container, which optionally comprises pharmaceutical excipients for diluting or suspending the pharmaceutical composition or compound described herein.In some embodiments, kit comprises precursor components (for example, hyaluronic acid and crosslinker; or alginate and crosslinker) to drug delivery composition and / or drug delivery device.

[0627] In some embodiments, the kit comprises a hydrogel and an activator of the innate immune response. In some embodiments, the kit comprises a hydrogel and a cytokine. In some embodiments, the kit comprises a hydrogel and an activator of the adaptive immune response. In some embodiments, the kit further comprises an activator of innate immune function. In some embodiments, the kit further comprises a cytokine. In some embodiments, the kit further comprises an activator of the adaptive immune response. In some embodiments, the kit further comprises a modulator of macrophage effector function. In some embodiments, the kit further comprises a further activator of the adaptive immune response. In some embodiments, the kit further comprises an oncolytic virus, a radioisotope, an immunomodulatory chemotherapeutic agent, a targeted agent, or a combination thereof. In some embodiments, the kit comprises any drug delivery composition described herein. In some embodiments, the kit comprises any drug delivery device described herein.

[0628] In some embodiments, the kit does not include a chemotherapeutic agent. In some embodiments, the kit does not include a cytotoxic agent.

[0629] In some embodiments, the kits described herein further comprise instructions for using the kit.The kits described herein may also comprise information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA).In some embodiments, the information included in the kit is prescription information.In some embodiments, the kit and instructions provide for treating cancer.The kits described herein may also comprise one or more additional pharmaceutical agents described herein as separate compositions.

[0630] Treatment Methods and Uses The present disclosure provides methods of using the drug delivery compositions and devices described herein for the treatment and / or prevention of proliferative diseases, such as cancers (e.g., sarcomas, carcinomas, lymphomas, germ cell tumors, blastomas) in a subject.

[0631] In some embodiments, the drug delivery compositions and devices described herein are useful in treating cancer. In some embodiments, the drug delivery compositions and devices described herein are useful for delaying the onset of cancer symptoms, slowing its progression, or ameliorating it. In some embodiments, the drug delivery compositions and devices described herein are useful for preventing cancer. In some embodiments, the drug delivery compositions and devices described herein are useful for preventing the regrowth of primary tumors. In some embodiments, the drug delivery compositions and devices described herein are useful for preventing tumor metastasis. In some embodiments, the drug delivery compositions and devices described herein are administered in combination with other compounds, drugs, or therapeutic agents to treat cancer.

[0632] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a sarcoma, carcinoma, lymphoma, germ cell tumor, blastoma, or a combination thereof. In some embodiments, the tumor is a sarcoma, carcinoma, lymphoma, germ cell tumor, blastoma, or a combination thereof.

[0633] In some embodiments, the drug delivery compositions and devices described herein are useful for treating cancers including, but not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bile duct cancer; bladder cancer; bone cancer; breast cancer (e.g., Adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast; brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ductal carcinoma in situ; ependymoma; endothelial sarcoma (e.g., cystic leukemia, thyroid carcinoma ... Pozi's sarcoma, multiple idiopathic hemorrhagic sarcoma; endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma)), throat cancer (e.g., Hematopoietic cancers (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Barton's lymphoma, Kitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's hypergammaglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, and leukemia. follicular lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; mixed leukemia / lymphoma of one or more of the above; multiple myeloma; heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); smooth muscle Myosinoma (LMS); mastocytosis (e.g., systemic mastocytosis); melanoma; midline carcinoma; multiple endocrine neoplasia syndrome; muscle carcinoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); nasopharyngeal carcinoma; neuroblastoma; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannoma);Neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet tumors); parathyroid carcinoma; papillary adenocarcinoma; penile cancer (e.g., Paget's disease of the penis and scrotum); pharyngeal cancer; pinealoma; pituitary carcinoma; pleuropulmonary blastoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasms; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., adenocarcinoma of the prostate); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancers (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine vowel) cancer (e.g., appendix cancer); soft tissue; Sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; gastric cancer; small intestine cancer ; sweat gland carcinoma; synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thymic carcinoma; thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; vulvar cancer (e.g., Paget's disease of the vulva), or any combination thereof.

[0634] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is thyroid cancer.

[0635] In some embodiments, the drug delivery compositions and devices described herein are useful for treating adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, carcinoid tumor, cardiac tumor, cervical cancer, choriocarcinoma, chordoma, colorectal cancer, connective tissue cancer, craniopharyngioma, ductal carcinoma in situ, endothelial sarcoma, endometrial cancer, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's sarcoma, eye cancer, familial hypereosinophilia, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hemangioblastoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal carcinoma, inflammatory myofibroblastic tumor, Intraepithelial neoplasia, immune cell amyloidosis, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), mastocytosis, melanoma, midline lining carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma, muscle carcinoma, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD), nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroendocrine carcinoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, paraneoplastic syndromes, parathyroid carcinoma, papillary adenocarcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pinealoma, pituitary carcinoma, pleuropulmonary blastoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasms, prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sebaceous gland cancer, skin cancer, small vowel cancer , small intestine cancer, soft tissue sarcoma, gastric cancer, sweat gland cancer, synovial cancer, testicular cancer, thymic cancer , thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer, or a combination thereof.

[0636] In some embodiments, the drug delivery compositions and devices described herein are useful for treating and / or preventing solid tumors and metastases.

[0637] In some embodiments, the methods described herein include implanting an effective amount of a drug delivery composition or device described herein in a subject. In some embodiments, the methods described herein include surgically implanting an effective amount of a drug delivery composition or device described herein in a subject. In some embodiments, the methods described herein further include implanting a drug delivery composition or device after surgical resection of a tumor. In some embodiments, the methods described herein further include implanting a drug delivery composition or device at the site of tumor resection. In some embodiments, the methods described herein further include implanting a drug delivery composition or device in the void volume of the resected tumor. In some embodiments, the methods described herein further include implanting a drug delivery composition or device at the site of tumor reaction during tumor resection surgery.

[0638] In some embodiments, the methods described herein comprise implanting a drug delivery composition or device after removal of 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more by volume of the resected tumor. In some embodiments, the methods described herein comprise implanting a drug delivery composition or device after removal of 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more by volume of the resected tumor.

[0639] In some embodiments, the methods described herein do not involve implanting a drug delivery composition or device near a tumor. In some embodiments, the methods described herein do not involve implanting a drug delivery composition or device near a tumor without resecting the tumor.

[0640] In some embodiments, the drug delivery compositions and devices described herein are administered in combination with one or more additional therapeutic agents described herein. In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0641] In some embodiments, the subject being treated is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent, pig, dog, or non-human primate. In some embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or transgenic pig.

[0642] example In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

[0643] Materials and methods for the preparation of hydrogels: GLYCOSIL® hyaluronic acid (thiol-modified hyaluronic acid and a component of the native extracellular matrix) and EXTRALINK® polyethylene glycol diacrylate (thiol-reactive crosslinker) (-) was purchased from ESI BIO. Hydrogels were prepared using the Hystem Hydrogel Kit (ESI Bio). Teflon molds (9 mm diameter) were first filled with 120 μl of Glycosil, followed by the addition of 200 μg of R848 (Sigma, SML0196) or 100 μg of c-di-AM(PS)2 (Rp, Rp) (Invivogen, tlrl-nacda2r). For comparative studies, 300 μg of rat anti-mouse PD-1 (anti-PD-1) (BioXCell, clone 29F.1A12), 300 μg of hamster anti-mouse CTLA-4 (anti-CTLA-4) (BioXCell, clone 9H10), 3 μg of mouse IL-15 / IL-15R complex recombinant protein carrier-free (IL-15sa) (eBioscience, 34-8152-82), 100 μg of 2'3'-cGAM P (Invivogen, tlrl-nacga23), 200 μg of lenalidomide (Sigma, CDS022536), 1 500 μg of celecoxib (Selleckchem, S1261), 10 μg of Ccl4 (R&D Systems , 451-MB / CF), 10 μg Ccl5 (R&D Systems, 478-MR / CF), 10 μg Cxcl 10 (R&D Systems, 466-CR / CF), 100 μg paclitaxel (Selleckchem, S1150), or 100 μg doxorubicin (Selleckchem, S1208) was added. Next, 30 μl of Extralink was added to the mold, and the hydrogel was allowed to crosslink for at least 1 hour. For in vitro release studies and confocal imaging, anti-PD-1 and IL-15sa were added. Alexa Fluor 405 NHS ester (Thermo Fisher Scientific, A30000) and and VivoTag 680XL Protein Labeling Kit (Perkin Elmer, NEV11118) according to the manufacturer's guidelines. Fluorescently tagged 2'3'-cGAMP (BIOLOG Life Science Institute, C195) was transfected with 2'3'-c-di-PS(2)(Rp,Rp) according to the guidelines. For in vivo imaging, anti-PD-1 and Both IL-15 and IL-15sa were fluorescently labeled with VivoTag 800 (Perkin Elmer, NEV11107). Sulfo-Cy7-labeled 2'3'-cGAMP (BIOLOG Life Science Institute, custom To assess the degradation of the hydrogel in vivo, 1.2 μl of Alexa Fluor 750 C5-maleimide (Molecular Probes, A30459) was directly conjugated to the hydrogel. Alginate hydrogels were prepared by filling Teflon molds with 200 μl of sodium alginate solution (amsbio, AMS.CSR-ABC-AL) and then adding 200 μg of R848 followed by 15 μl of 1 M calcium chloride (bioWORLD, 40320005). The hydrogels were allowed to stand for at least 30 minutes. Protein conjugation and hydrogel preparation were performed under sterile conditions. Anti-CD40 (clone FGK45) and anti-CD137 (clone 3H3) antibodies were also purchased from BioxCell. c-di-GMP, resiquimod (TLR7 / 8 agonist) (for Figures 68 and 69, where resiquimod was dissolved in water instead of DMSO), poly(I:C) (TLR3 agonist), and CpG (TLR9 ​​agonist) were purchased from Invivogen. ALEXA FLUOR® 750 dye was purchased from Thermo Fisher Scientific.

[0644] Confocal microscopy: Fluorescently tagged 2'3'-cGAMP, IL-15sa, and anti-PD-1 as described herein were imaged under a confocal laser scanning microscope (Leica TCS SP8 STED CW; Leica Microsystems). Processing was carried out using LAS AF software (Leica Microsystems).

[0645] Cell lines: Luc2-expressing metastatic mouse 4T1 breast cancer cells (Perkin Elmer) were cultured in complete RPMI 1640 medium containing 10% FBS, 1% penicillin-streptomycin, and 1% L-glutamine. Metastatic mouse 4T1 breast cancer (ATCC, CRL2539) and B16-BL6 melanoma (kindly provided by Dr. Glenn Merlino at the NIH) were cultured in complete RPMI 1640 medium containing 10% FBS, 1% penicillin-streptomycin, and 1% L-glutamine. The mouse LLC lung carcinoma cell line (kindly provided by Dr. Harvey Cantor at DFCI) was cultured in complete RPMI 1640 medium containing 10% FBS, 1% penicillin-streptomycin, and 1% L-glutamine. The cells were cultured in complete DMEM containing phospho-streptomycin and 1% sodium pyruvate. Cells were tested for mycoplasma contamination and found to be negative.

[0646] Mice: All animal experiments were performed in accordance with protocols approved by the Dana-Farber Cancer Institute (DFCI) Institutional Animal Care and Use Committee (IACUC). For the metastatic breast cancer model, female BALB / cJ mice (6–8 weeks old) were purchased from Jackson Laboratories (stock #000651). For the metastatic melanoma model, B6(Cg)-Tyrc-2J / J mice (7 weeks old) were purchased from Jackson Laboratories (stock #000058). For the lung cancer model, female C57BL / 6J mice (6–8 weeks old) were purchased from Jackson Laboratories (stock #000664). Mice were housed in the DFCI animal facility.

[0647] General Surgical Procedure: Seven-week-old Balb / c mice were orthotopically inoculated (into the fourth mammary fat pad) with 100,000 4T1-Luc2 syngeneic breast cancer cells. After 10 days, the mice were anesthetized, the tumors were surgically excised, and the composition was placed at the reaction site. For in vivo degradation studies, For most mice, tumors were not inoculated or removed for these studies because the majority of mice succumbed to recurrence when immunotherapeutic agents were not included in the composition, although one mouse survived through surgery alone. The order of surgery was determined by group allocation to avoid systematic errors. Standard post-treatment care (wound clips, analgesia) was provided.

[0648] In vitro release studies: To determine the release kinetics of each payload from the hydrogels, hydrogels loaded with fluorescently tagged anti-PD-1, fluorescently tagged IL-15sa, lenalidomide, celecoxib, fluorescently tagged 2'3'-cGAMP, or R848 were immersed in 3 mL of pH 7.4 phosphate-buffered saline (PBS). At each time point, 1 mL of medium was removed and replaced with the same amount of fresh buffer. The amount of released payload was then measured using a fluorescent plate reader or via HPLC.

[0649] Assessment of in vivo hydrogel degradation: After implantation of the hydrogel into mice, the degradation of fluorophore-labeled hydrogels in vivo was monitored using an IVIS Spectrum In Vivo Imaging System (Perkin Elmer). Fluorescent images were acquired weekly and analyzed using Living Imaging software (Perkin Elmer). Both tumor-bearing and tumor-free mice were examined for in vivo hydrogel degradation assessment, but the tumor-bearing mice were not included in the analysis. Only one tumor-bearing mouse survived longer than a few weeks in the absence of treatment, as tumors recurred in nearly all treated animals.

[0650] In vivo release studies: Cy7 carboxylic acid (model compound for R848), anti-PD In vivo release profiles of IL-1, IL-15sa, and 2'3'-cGAMP To evaluate the efficacy of fluorophores or hydrogels containing one of the fluorescently labeled payloads, we surgically implanted them into tumor-free mice, and monitored fluorescence imaging using an IVIS Spectrum In Vivo Imaging System (Perkin Elmer).

[0651] In vivo tumor model and treatment: For metastatic breast cancer model, 10 5 4T1-Lu c2 or 4T1 cells (in 30 μl of DPBS) were orthotopically seeded into the fourth mammary fat pad of mice to generate local tumor masses. Cells were injected without any incision to expose the mammary fat pad. Mice were randomly assigned to treatment groups and operated on 10 days after tumor seeding. For metastatic melanoma and lung cancer models, 10 6 B16-BL6 or 5 x 10 5LLC cells (in 100 μl of DPBS) were inoculated subcutaneously in mice to produce local tumor masses. Mice were randomly assigned to treatment groups and tumors were grown until tumor volume reached approximately 600 mm. 3 When the tumor reached 100%, surgery was performed. While the mice were kept under anesthesia with 2% isoflurane, the tumor was excised and hydrogel was placed at the site of the resulting cavity at the time of surgery. The wound was closed with medical clips. Control experiments were performed in which therapeutic agents were administered in solution either intraperitoneally or intravenously at the site of surgery. For tumor re-challenge experiments, 10 4 4T1-Luc2 cells were seeded in the contralateral fourth mammary fat pad. Surgeries were performed at least three times independently, and surgeons were often blinded.

[0652] In vivo bioluminescence and imaging: After surgery, mice were monitored weekly for tumor recurrence and Distal metastases were examined by bioluminescence imaging (BLI). For this purpose, mice were anesthetized with 2% isoflurane 10 minutes after intraperitoneal injection of D-luciferin (150 mg / kg), a substrate for Luc2, and imaged using an IVIS Spectrum In Vivo Imaging System (Perkin Elmer).

[0653] Depletion of NK cells, CD8+ T cells, or CD4+ T cells, and neutralization of IFNAR-1: Specific cell subsets (NK cells, CD8+ T cells, or CD4+ T cells) were depleted by intraperitoneal administration of depleting antibodies every 3 days, starting 1 day before treatment. The antibodies used for depletion were anti-Asialo GM1 (polyclonal antibody), ... lonal, Wako Chemical, 30 μl), anti-mouse CD8a (clone 2.43), and The antibodies were anti-IFN alpha / beta receptor subunit 1 (anti-IFNAR-1, clone MAR1-5A3) and anti-mouse CD4 (clone GK1). To test the role of type I IFN signaling, mice were administered a blocking anti-IFN alpha / beta receptor subunit 1 (anti-IFNAR-1, clone MAR1-5A3). All antibodies were purchased from BioXCell, and 200 μg of antibody was used unless otherwise specified. Cell depletion of NK cells, CD8+ T cells, and CD4+ T cells was confirmed by flow cytometry of leukocytes isolated from the blood of mice treated with antibody or PBS.

[0654] In vivo cytokine analysis: tumor excision and scaffold (empty or triple combination) Blood was collected from mice 14 days after placement of the R848-loaded hydrogel (or combination). Blood was collected from mice 1.5 hours, 6 hours, 3 days, and 14 days after tumor resection and treatment with R848-loaded hydrogel or no hydrogel. STING-RR-loaded hydrogel was used in other experiments. Plasma was sent to Eve Technologies to measure the levels of circulating cytokines produced in response to treatment. IFN-α and IFN-β were assessed to complement the MD-31 panel.

[0655] Flow cytometry: Flow cytometry was performed on a BD LSRFortessa X-20 (BD Biosciences). All antibodies were purchased from BioLegend, eBioscience, or BD Biosciences. Splenocytes were stimulated using a leukocyte activation cocktail containing BD GolgiPlug (BD Biosciences). GWEPDDNPI (purity >95%), an immunodominant peptide of survivin (amino acids 66-74), was purchased from New England Peptide. SPSYVYH QF (purity >95%), an immunodominant peptide (amino acids 423-431) of murine leukemia virus envelope glycoprotein gp70, was purchased from New England Peptide. GolgiPlug (BD Biosciences) for testing intracellular cytokines and cytolytic molecules was used.

[0656] Blood counts and liver enzyme assessment: Blood was collected from mice 15 days after tumor resection and treatment administration, or 3 and 14 days after tumor resection and treatment administration. Blood counts (hemoglobin, hematocrit, creatine phosphate, thrombus ... White blood cells, platelets, differentials, and red blood cells Serum was isolated from the blood and liver enzymes (AS) were measured by IDEXX BioResearch. T, ALT and BUN were quantified.

[0657] Statistical methods: No statistical methods were used to predetermine the required sample size. The sample size was selected based on the results of pilot experiments so that appropriate statistical tests could reveal significant differences between experimental groups. Statistical analysis was performed using GraphPad Prism software, version 7.01. Data are expressed as mean ± SEM, as indicated in the figure legends. For statistical significance comparing two groups, a two-tailed unpaired t-test was used. For analysis of survival rates, the log-rank (Mantel-Cox) test was used. *p≦0.05 , **p≦0.01, ***p≦0.001, ****p≦0.0001

[0658] Example 1. Preparation of drug delivery compositions A series of hydrogels were prepared to determine useful preparation methods and the amounts of reagents required to construct a hydrogel system. Generally, GLYCOSIL® hyaluronic acid and EXTRALINK® polyethylene glycol diacrylate crosslinker were combined in a TEFLON® mold. The combined reagents were allowed to stand for at least 1 hour. Upon standing, a hydrogel was formed. The storage modulus of the hydrogel was measured using a rheometer. These are summarized in Table 1. [Table 1] Hydrogels were also prepared from alginate. To prepare hydrogel 5, 200 μL of sodium alginate solution (approximately 0.5–2.5% solution purchased from amsbio; product code: AMS.CSR-ABC-AL) was mixed with 15 μL of 1 M calcium chloride solution and the compound of interest (e.g., 100 μg of STING-RR dissolved in 40 μL of PBS). In a similar manner, alginate hydrogels containing resiquimod were prepared. A Teflon mold was filled with 200 μL of sodium alginate solution (approximately 0.5–2.5% solution purchased from amsbio; product code: AMS.CSR-ABC-AL), followed by the addition of 200 μg of resiquimod (dissolved in 20 μL of DMSO), followed by the addition of 15 μL of 1 M calcium chloride (bioWORLD, product code: 40320005). The hydrogel was allowed to rest for at least 30 minutes before use.

[0659] General procedure for preparation of drug delivery compositions: 120 μL of GLYCOSIL® hyaluronic acid (2.0%) was poured into a TEFLON® mold (diameter: 9 mm; height: 3.2 mm). Optionally, an activator of the adaptive immune response was dissolved in PBS (30 μL) and added to the mold. Optionally, a cytokine was dissolved in PBS (10 μL) and added to the mold. Optionally, an activator of the innate immune response was dissolved in water (10 μL) and added to the mold. 30 μL of EXTRALINK® polyethylene glycol diacrylate (12.5%) was added to the mold. The mixture was allowed to stand for at least 1 hour to solidify.

[0660] Compositions were prepared according to the general procedure above and are summarized in Table 2. In Table 2, S = STING agonist (2'3'-cGAMP); STING-RR = 2'3'-c-di-AM(PS)2 (Rp,Rp); I = IL-15 superagonist; P = anti-PD-1 antibody; R848 = resiquimod. The respective doses were 25 μg for S, 1.5 μg for I, and 150 μg for P, unless otherwise indicated. A fluorescent dye (e.g., ALEXA FLUOR® 750 dye) was sometimes added to the composition to allow imaging of the device (e.g., Device F was Device 8 + 1.2 μL of ALEXA FLUOR® 750 C5-maleimide, which was directly conjugated to the hydrogel). (FIG. 1). The devices in this table (as well as Device F) were prepared according to the method described for Hydrogel 4 in Table 1. [Table 2-1] [Table 2-2]

[0661] Example 2. Biodegradation research Seven-week-old Balb / c mice were orthotopically inoculated (into the fourth mammary fat pad) with 100,000 4T1-Luc2 syngeneic breast cancer cells. Ten days later, the mice were anesthetized, the tumors were surgically removed, and Device F was placed at the site of the reaction. Due to tumor recurrence, the majority of mice were euthanized. The presence of the composition in surviving mice was monitored over a 13-week period via imaging (Figure 2). The composition was stable and completely biodegraded after 13 weeks (Figure 3).

[0662] Untreated mice bearing 4T1 tumors died from their primary tumors within 7 weeks of tumor dissemination (median survival 40 days), and surgical resection of the tumor did not provide much survival benefit in this model, as mice succumbed to tumor recurrence and metastasis (median survival 44 days) (Figure 4).

[0663] In further studies, Device F was placed near the mammary fat pads of five mice that had not been inoculated with tumors or had tumors removed. The presence of the hydrogel in the mice was monitored via imaging over a 20-week period (Figure 5). The hydrogel was stable in the mice, with less than 5% remaining after 20 weeks (Figure 6). The implantation sites were also subjected to histopathological analysis. A certified pathologist detected no abnormalities, confirming the hydrogel's high biocompatibility. For comparison, a fluorescent dye solution was administered topically, revealing that free dye diffused very rapidly when not conjugated to the scaffold (Figures 7 and 8). These data confirm that crosslinked hyaluronic acid can serve as a stable, biodegradable depot.

[0664] Example 3. Imaging of compositions containing hydrogel therapeutic agents Device 1 was prepared with FITC conjugated to 2'3'-cGAMP, ALEXA FLUOR® 405 dye conjugated to an anti-PD-1 antibody, and VIVOTAG® 680 dye conjugated to IL-15sa. Confocal images were obtained and showed that all three were distributed throughout the device (Figure 9).

[0665] Device 2 was prepared with ALEXA FLUOR® 555 dye conjugated to an anti-PD-1 antibody and VIVOTAG® 680 dye conjugated to IL-15sa. Confocal images were obtained and showed that the anti-PD-1 antibody and IL-15sa were distributed throughout the device (FIG. 10).

[0666] Example 4. In vitro release of therapeutic agents from hydrogel compositions Hydrogels were prepared according to the general procedure in Example 1. They contained one or all of the payloads shown. Fluorescent dyes were conjugated to the proteins to facilitate measurement of protein release kinetics. The hydrogels were then dissolved in 3 mL of buffer (PBS only, PBS plus Tween 80 (0.2% v / v), or RPMI plus 10% F. The plates were immersed in either PBS or PBS containing 100% EDTA and incubated at 37°C with stirring.

[0667] At the indicated sampling time points, 1 mL of buffer was withdrawn for measurement and replaced with an equal volume of fresh buffer. Aliquots were measured using a fluorescent plate reader to detect protein concentration. Aliquots were also evaluated by HPLC to detect small molecule concentration.

[0668] Several compositions were prepared by varying the therapeutic agent and excipients incorporated into the composition. Device 3 was prepared according to the general procedure in Example 1. Drug release from this device was measured in PBS, PBS + Tween 80 (0.2% v / v), or RPMI + 10 % FBS. The release of celecoxib was delayed the longest in PBS buffer (Figure 11).

[0669] Device 4 was prepared according to the general procedure in Example 1. Drug release from this device was measured using PBS, PBS + Tween 80 (0.2% v / v), or RPMI + 10% FBS. The release rate of anti-PD-1 was similar in all three buffers (Figure 11).

[0670] Device 5 was prepared according to the general procedure in Example 1. Drug release from this device was studied in PBS + Tween 80 (0.2% v / v) or RPMI + 10% FBS. The release rate of IL-15sa was similar in both of these buffers (Figure 11).

[0671] Device 6 [c-di-GMP+I+P] was prepared according to the general procedure in Example 1. Device 1 [2'3'-cGAMP+I+P] and Device 7 [2'3'-cGAMP only] were prepared according to the general procedure in Example 1. Drug release from these devices Release was studied in PBS or RPMI + 10% FBS. The release rates of c-di-GMP and 2'3'-cGAMP were similar in both of these buffers. The release rate of 2'3'-cGAMP is similar whether the small molecule is formulated alone or together with the protein (Figure 12).

[0672] Further comparison of the release rates of 2'3'-cGAMP, IL-15sa, and anti-PD-1 antibody from devices 1, 4, 5, and 7 is shown in Figure 13. Release kinetics were nearly identical in PBS and media, ranging from several hours for small molecules to several days for biologics under in vitro sink conditions. The inclusion of multiple payloads did not affect the release kinetics of any individual molecule, as results were indistinguishable whether the compound was loaded alone or in combination with two other compounds.

[0673] In addition, devices 4, 5, 7, and 22 were prepared by varying the amount of drug loaded into each device. The release rates of 2'3'-cGAMP (25 μg, 50 μg, 100 μg) from drug delivery device 7 in PBS (pH 7.4), resiquimod (R848; 100 μg, 200 μg) from drug delivery device 22 in PBS (pH 7.4), anti-PD-1 antibody (150 μg, 300 μg) from drug delivery device 4 in PBS (pH 7.4), and IL-15sa from drug delivery device 5 in PBS (pH 7.4) were determined. In each experiment, there was little dependence of the release rate on drug concentration (Figure 65).

[0674] The loading and release properties of the hydrogels were tested in further experiments. Under sink conditions in phosphate-buffered saline (PBS), the release kinetics of devices 3 (1500 μg celecoxib), 7 (100 μg S), 18, 19, 22, and 30 ranged from several hours for small molecules to several hours for biological agents (Figures 38A-38F). The hydrogels then extended the release of small molecules and biological agents in vivo. We confirmed this. Cy7 carboxylic acid (Cy7-CA) was used as a model small molecule payload because its physical properties closely resemble those of resiquimod (R848). Cy7-CA was administered to tumor-free mice in solution or loaded into a scaffold placed near the fourth mammary fat pad. Mice were evaluated by fluorescent IVIS imaging (Figure 37B), and data were quantified (Figure 37C). Within 2 hours of administration of the fluorophore in solution, a loss of approximately 60% of the signal was detected, whereas this amount of signal decay required 24 hours for the fluorophore loaded into the hydrogel. Over this time course, there was an average of approximately a three-fold increase in signal for the latter group.

[0675] Example 5. In vivo implantation and evaluation of exemplary drug delivery compositions Hydrogels confirmed to sustain the release of small molecules and biological agents in vivo To determine the specificity of the 2'3'-cGAMP, IL-15sa, or anti-PD-1 antibodies, fluorescently labeled versions were administered to tumor-free mice in solution or in devices (fluorescently labeled devices 4, 5, and 7) after placement near the fourth mammary fat pad. Mice were then fluorescently imaged using an IVIS Spectrum In Vivo Imaging System (Perkin Elmer). The release rates were assessed by optical IVIS imaging (Figures 14-16), and data were analyzed and quantified by Living Imaging software (Perkin Elmer) (Figure 17). As expected for a more physiologically relevant environment than sink conditions, the release rates in vivo were significantly higher than those in vitro. The hydrogel-mediated delivery of 2'3'-cGAMP showed prolonged kinetics compared to the free compound. For 2'3'-cGAMP, the percentage remaining locally after hydrogel-mediated delivery was, on average, nearly twice that of the free compound at each time point tested over the first 24 hours. ...

Claims

1. 1. A composition for use in treating cancer, comprising a biomaterial and a cytokine, the treatment comprises intraoperative administration of the composition at a tumor resection site in a subject suffering from cancer; the biomaterial is or comprises a hydrogel, said hydrogel being or comprising hyaluronic acid and / or cross-linked hyaluronic acid; The cytokine is or comprises at least one selected from the group consisting of IL-15, IL-15 superagonist, IL-2, IL-2 superkine, IL-21, IL-21 superagonist, and denenicoquinone; The composition.

2. The composition for use according to claim 1, wherein the cytokine is or comprises an IL-15 superagonist.

3. The composition for use according to claim 1 , wherein the cytokine regulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells.

4. 10. The composition for use according to claim 1, wherein the biomaterial is characterized by a storage modulus of about 500 Pa to about 3000 Pa.

5. The composition for use of claim 1, wherein the step of administering does not include (i) adoptive transfer of T cells to the subject; (ii) administration of a tumor antigen to the subject; and / or (iii) administration of microparticles to the subject.

6. 2. The composition for use according to claim 1, wherein the crosslinked hyaluronic acid is crosslinked with a polyethylene glycol crosslinker.

7. The composition for use according to claim 1, wherein the biomaterial forms a matrix or depot and the cytokine is within the biomaterial.

8. The composition for use according to claim 7, wherein the cytokine is released by diffusion through the biomaterial.

9. The composition for use according to claim 1 , wherein the biomaterial is biodegradable in vivo.

10. 2. The composition for use according to claim 1, wherein the biomaterial is characterized in that, when tested in vivo by placing the composition in PBS (pH 7.4), less than 100% of the cytokine is released from the biomaterial within 3 hours.

11. 2. The composition for use according to claim 1, wherein the biomaterial is characterized in that when tested in vivo by implanting the composition into the mammary fat pad of a mouse subject, 50% or less of the cytokines are released in vivo 8 hours after implantation.

12. 2. The composition for use according to claim 1, wherein the biomaterial is characterized in that it prolongs the release of the cytokine, such that when assessed 24 hours after administration, more cytokine is present at the tumor resection site than is observed when the cytokine is administered in solution.

13. 2. The composition for use of claim 1, wherein the biomaterial is characterized in that when tested in vivo by administering the composition at the site of tumor resection in a group of mouse subjects, more mouse subjects in the group survive than observed when the cytokine is administered in solution and / or than observed when the composition is administered peri- or intratumorally.

14. 10. The composition for use according to claim 1, formulated for administration by implantation.

15. 10. The composition for use according to claim 1, formulated for administration by injection.

16. 16. The composition for use of claim 15, wherein administering comprises injecting one or more precursor components of the biomaterial and allowing the biomaterial to form at the tumor resection site.

17. The composition for use according to claim 1, wherein the tumor resection site is characterized by the total absence of residual tumor antigens.

18. 2. The composition for use of claim 1, wherein the cancer is a metastatic cancer or comprises micrometastases.

19. 10. The composition for use of claim 1, wherein the treatment further comprises monitoring at least one metastatic site in the subject after administration.

20. The composition for use according to claim 1 , wherein the cytokine is provided in the composition as a monotherapy.

21. 2. The composition for use according to claim 1, further comprising an activator of innate immunity, an activator of adaptive immunity, and / or a cytokine that regulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells.

22. 10. The composition for use according to claim 1, further comprising a cyclooxygenase-2 (COX2) inhibitor.

23. 23. The composition for use according to claim 22, wherein the COX2 inhibitor is or comprises celecoxib.

24. The composition for use according to claim 1, further comprising an agonist of NOD1 and / or NOD2.

25. 10. The composition for use according to claim 1, further comprising a chemotherapeutic agent with immunomodulatory capabilities.

26. The composition for use according to claim 1, further comprising an anti-PD-1 antibody and / or an anti-CD137 antibody.

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