Compositions and methods for cancer treatment

Abstract

To provide localized delivery of immunotherapeutic agents to avoid certain adverse events that can be associated with systemic administration of immunotherapeutic agents.SOLUTION: The present invention provides a method comprising the step of: intraoperative administration, at a tumor resection site of a subject suffering from cancer, of a composition comprising a biomaterial and an inhibitor of a proinflammatory immune response mediated by a p38 mitogen-activated protein kinase (MAPK) pathway.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a joint venture of U.S. Provisional Patent Application No. 62 / 645,613, filed March 20, 2018, and U.S. Provisional Patent Application No. 62 / 645,613, filed January 11, 2019. Priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 791,481, filed on No. 6,393,636, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] background Systemic administration of pharmaceutical, nutrient, or other substances into the circulatory system affects the entire body. Routes of systemic administration include enteral (e.g., oral, which results in absorption of the drug through the gastrointestinal tract) Administration by intravenous, intramuscular, and subcutaneous injections. Administration of therapeutic agents typically relies on these systemic routes of administration, which can result in undesirable side effects. In some cases, certain promising therapeutic agents may be more effective than currently administered The methods and systems are very difficult to develop due to their associated toxicities and limitations. .

[0003] Surgery is often the first choice of treatment for solid cancers and is generally used as a treatment for cancer. However, surgically induced immunosuppression is , which ultimately leads to the death of many patients due to a variety of altered metabolic and endocrine responses. , has been associated with the development of postoperative septic complications and tumor metastasis (Smyth, MJ et al. ., Nature Reviews Clinical Oncology, 2016, 13, 143-158). Summary of the Invention

[0004] Abstract Systemic administration of immunotherapeutic agents can have adverse side effects, such as the loss of non-cancerous targets, such as non-tumor-specific immune cells. Induction of undesirable toxicity to cells and / or tissues of interest and / or therapeutic The requirement for high doses to achieve sufficient concentrations at the target site to produce a response. and surgical removal of the tumor can result in immunosuppression. Surgery can also result in the Stress can be induced, which can induce one or more physiological events that promote wound healing, for example, following injury. Such responses may involve activation of, for example, neurological, inflammatory, and / or Activation of angiogenic signaling pathways, which also contribute to cancer growth and / or Inflammation that may occur at the surgical site following tumor resection The changes in function include, for example, recruitment of immune and / or inflammatory cell types and / or activation of the immune system. The local inflammatory wound response and the systemic inflammatory process include the release of humoral factors. Together, they activate dormant micrometastases or induce the proliferation of residual cancer cells. This can increase the risk of cancer recurrence.

[0005] The present disclosure relates, inter alia, to certain conventional approaches to the treatment of cancer, including, for example, The present disclosure provides insights including identification of the sources of problems with the prior art. Certain adverse events that may be associated with systemic administration of inflammation, hypophysitis, thyroiditis, and adrenal insufficiency) may be immune-related or at least partially This can be attributed to the exposure of non-tumor-specific immune cells to systemically administered immunotherapeutic agents. In particular, the present disclosure recognizes that the expression of a marker sufficient for inducing a desired response in a tumor is To achieve such desirable concentrations, the high doses typically required for systemic administration are required. We recognize that the above-mentioned factors may contribute to or be the cause of the undesirable effects of the present invention. The present invention solves such problems by, among other things, providing localized delivery of immunotherapeutic agents. The present invention provides a system for concentrating the action of a drug in, among other things, the location where the drug is needed. By shrinking the formulation, efficacy can be improved.

[0006] Additionally, the present disclosure provides specific immunosuppressants that are classically used to treat autoimmune conditions. When the modulating agent is administered as described herein, it is possible that the modulating agent may be an off-label agent that would not be otherwise administered. Contrary to expectations for anti-cancer immunomodulatory compounds, on-target toxicity is predicted to exist. This provides insight into how these compounds may be useful in the treatment of cancer, despite their potential to cause cancer in the first place. Thus, the present disclosure provides the discovery of agents not previously believed to be useful for the treatment of cancer. and further teaches the usefulness of the compounds of the present invention as being particularly effective and / or effective for these and other agents. Desired delivery and administration strategies are taught.

[0007] The present disclosure relates, inter alia, to a method for the detection of one or more p38 mitogen activating proteins at a tumor resection site. Induction of inflammation mediated by the proteinase kinase (MAPK) pathway (e.g., by administration of p38 MAPK inhibitors) By inhibiting the immune response, it reduces the risk of cancer recurrence, thereby improving survival. It is recognized that the present disclosure provides a method for the delivery of one or more immunomodulatory agents to a target site ( For example, a tumor has been removed, for example by chemotherapy or radiation, and / or to the site where the cancer cells are treated or killed, thereby To provide a drug delivery system that can concentrate the action at the target site where it is needed. Such a drug delivery system may be particularly useful for the treatment of cancer. For example, following tumor resection, in some embodiments, adverse side effects and / or systemic exposure may be reduced. For example, to prevent tumor recurrence and / or metastasis (e.g., to prevent the onset of one or more inflammatory processes for the treatment of cancer, such as by slowing or reducing the severity of the onset of inflammation Induced pathways (e.g., proinflammatory immune responses mediated by the p38 MAPK pathway; e.g., Figures 4-6 In one embodiment, the present invention delivers one or more therapeutic agents that act on (e.g., inhibit) the inflammatory bowel disease (see, e.g., inflammatory bowel disease).

[0008] In some aspects, provided is a method for administering a therapeutically effective amount of ... target site (e.g., a cellular targeting agent) to a subject suffering from cancer. For example, at the site of tumor resection, biomaterials and p38 mitogen-activated protein kinase The present invention relates to a method for treating inflammatory bowel disease by administering a composition comprising an inhibitor of the proinflammatory immune response mediated by the MAPK pathway during surgery. and

[0009] In one embodiment, the biomaterial has a storage modulus of about 500 Pa to about 50,000 Pa. In some embodiments, the biomaterial is or comprises a hydrogel. In one embodiment, the biomaterial is or comprises hyaluronic acid. is or comprises cross-linked hyaluronic acid. is or contains hyaluronic acid crosslinked with a polyethylene glycol crosslinker. nothing.

[0010] In some embodiments, the method does not include adoptive transfer of T cells into a subject. In some embodiments, the method does not include administering a tumor antigen to the subject. It does not involve administering particles to a subject.

[0011] In some embodiments, the inhibitor inhibits the ATP and / or allosteric binding sites of P38 MAPK. In one embodiment, the p38α / β MAPK inhibitor is a p38α / β MAPK inhibitor that binds to the locus. It's called losmapimod.

[0012] In some embodiments, the composition further comprises an activator of innate immunity. The activator of natural immunity is the stimulator of interferon genes. In one embodiment, the innate immune activator is a Toll In one embodiment, the antibody is a TLR7 / 8 agonist. The composition modulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells In one embodiment, the composition further comprises an activator of adaptive immunity and / or a cytokine. The composition may further comprise a cytokine that regulates T cells, NK cells, monocytes, and / or dendritic cells. Examples of such cytokines include, but are not limited to, IL-15 superagonists. In one embodiment, the immunosuppressants include IFN-α, IFN-β, IFN-γ, and combinations thereof. In some embodiments, the composition further comprises an inhibitor of cyclooxygenase (COX), including, for example, a COX-2 inhibitor. include.

[0013] Those skilled in the art will recognize that certain COX inhibitors and / or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory agents) may be effective in treating Anti-inflammatory drugs (NSAIDs and / or anti-inflammatory analgesics) may upregulate the p38 MAPK pathway or its components. It will be appreciated that the present invention may act as a modulator (e.g., an inhibitor) (see, for example, See Esposito et al., "Non-steroidal anti-inflammatory drugs in arkinson's disease" Experimental Neurology 205: 295-312 (2007); Desai et al., "Mecha Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation R "elated to Cancer" Nutrition and Cancer, 70: 350-375 (2018); Huang et al., "MAPK / ERK s ignal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human "Endometriosis stomal cells in vitro" Int J Clin Exp Pathol, 6: 2129-2136 (2013); and Di Mari et al., “HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts” Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101(2007)). Thus, in some embodiments, COX- 2 inhibitors or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and / or The anti-inflammatory analgesic agent may be a p38 MAPK inhibitor as described herein (and and / or may be used as such); alternatively or in addition, in some embodiments Such COX-2 inhibitors or other anti-inflammatory agents (e.g., anti-inflammatory analgesics) are referred to herein as It may be utilized in combination with another p38 MAPK inhibitor as described.

[0014] In some embodiments, the biomaterial forms a matrix or depot and the inhibitor is In some embodiments, the inhibitor is released by diffusion through the biomaterial. In some embodiments, the biomaterial is biodegradable in vivo. The material was tested in vivo by implanting the biomaterial in the mammary fat pad of mouse subjects. In particular, when implanted, less than 10% of the biomaterial remains in vivo 4 months after implantation. In one embodiment, the biomaterial is a composition comprising a biomaterial and losmapimod. When tested in vitro by placing the material in PBS (pH 7.4), Less than 100% is characterized as being released from the biomaterial within 3 hours. In one embodiment, the biomaterial is administered to the mammary gland of a mouse subject using a composition comprising the biomaterial and losmapimod. Five of the losmapimod drugs, when tested in vivo by implantation in fat pads, 0% or less is characterized by release after 8 hours of implantation in vivo. In this manner, the biomaterial is evaluated 24 hours after administration to determine whether the inhibitor is in solution. More inhibitors were observed at the tumor resection site compared to that observed when the is characterized by extending the release of the inhibitor such that

[0015] In some embodiments, administration is by implantation. In some embodiments, administration is by injection. In some embodiments, the administering comprises administering one or more precursor structures of the biomaterial. Allows the injection of components and the formation of a biomaterial at the tumor resection site In some embodiments where the target site is a tumor resection site, the tumor resection site is a In some embodiments, the cancer is characterized by the absence of residual tumor antigens in the eye. In some embodiments, the method comprises administering the composition to a subject, the subject receiving the composition, and then administering at least The method further includes monitoring another metastatic site.

[0016] Details of certain aspects of the invention are set forth herein. Other features, objects and advantages of the invention are set forth herein. Further advantages will be apparent from the detailed description, examples, and claims.

[0017] definition As used herein, the term "salt" refers to any and all salts of a drug. This includes physiologically acceptable salts.

[0018] The term "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is not undue toxicological or toxic. with, for example, human and / or animal tissues without causing irritation, allergic responses, etc. Salts suitable for contact use commensurate with a reasonable benefit / risk ratio Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. In J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts are described in detail below for use in accordance with certain aspects of the present disclosure. As pharma- ceutically acceptable salts which can be derived from suitable inorganic and organic acids and bases, Examples of pharma- ceutically acceptable, non-toxic acid addition salts include those of hydrochloric acid, hydrobromic acid, and the like. by inorganic acids such as acetic acid, oxalic acid, maleic acid, by organic acids such as acetic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by ionic Salts of amino groups formed using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipates, alginates, ascorbates, Aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate , camphorate, camphorsulfonate, citrate, cyclopentanepropionate Onate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate , glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, Hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, la Citrobionate, lactate, laurate, lauryl sulfate, malate, maleate, Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate , oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropionate, phosphate, picrate, pivalate, propionate, sulphate Thearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfones Salts derived from appropriate bases include ethyl acetate, undecanoate, valerate, etc. , alkali metals, alkaline earth metals, ammonium, and N + (C1-C4 alkyl)4 - Salt is rising Representative alkali or alkaline earth metal salts include sodium, lithium, Potassium, calcium, magnesium, etc. Further Pharmacologically Acceptable Salts As appropriate, non-toxic ammonium, quaternary ammonium and halides are used. ides, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitric acids, lower alkyl sulfonic acids and aryl acids. Examples of suitable counter ions include amine cations formed with counter ions such as arylsulfonic acid.

[0019] The term "polymer" is given its ordinary meaning in the art, i.e., It is a molecular structure that contains one or more repeating units (monomers) linked by bonds. The repeating units are: They may all be identical, or in some cases, there may be more than one type of repeat. The units may be present in a polymer. In some embodiments, the polymer is a naturally occurring In some embodiments, the polymer is synthetic (i.e., not naturally occurring). In some embodiments, a polymer for use in accordance with the present disclosure is a polypeptide. In some embodiments, the polymers for use in accordance with the present disclosure are not nucleic acids.

[0020] The term "bioadhesive" refers to a material capable of adhering to a target surface, such as a tissue surface. In some embodiments, the bioadhesive refers to a biocompatible agent that can adhere to a target surface, e.g. For example, the nucleosomes can be attached to a tissue surface and retained on the target surface, for example, for a period of time. In some embodiments, the bioadhesive may be biodegradable. In this regard, the bioadhesive may be a natural agent, which may be obtained by isolation or by synthesis. In some embodiments, the bioadhesive may be prepared or obtained by The agent may be non-naturally occurring, e.g., produced by the hand of man (e.g., as will be understood by those of skill in the art). (e.g., by processing, synthesis, and / or recombinant production, depending on the agent) In some particular embodiments, the The adhesive may be or include a polymeric material. The saccharide may consist of or include a monomer (such as a sugar). Examples of suitable bioadhesives include cyanoacrylates (Dermabond, 2-octyl cyanoacrylate). Indermil, n-butyl-2-cyanoacrylate, Histoacryl and Histoacryl Blue , n-butyl-2-cyanoacrylate), albumin and glutaraldehyde (BioGlue (commercially available) (Tisseel™), bovine serum albumin and 10% glutaraldehyde), fibrin glue (Tisseel™ , human pooled plasma fibrinogen and thrombin; Evicel™, human pooled plasma fibrinogen and thrombin; autologous plasma fibrinogen and thrombin; Vitagel™, autologous plasma fibrinogen and thrombin; Fibrinogen and thrombin; Cryoseal™ system, autologous plasma fibrinogen and and thrombin), cross-linked with formaldehyde and / or glutaraldehyde Gelatin and / or resorcinol, polysaccharide-based adhesives (gelatin, collagen, de xytran, chitosan, alginate), PEG, acrylate, polyamine, or urethane A variety of FDA approved agents, including isocyanate-terminated prepolymers, and / or combinations thereof. ies and Applications of Tissue Bioadhesives” Macromol Biosci 13:271-288 (2013). Other examples of bioadhesives known in the art, such as those described in In some embodiments, the method can be used for the purpose of the method described above. The adhesive may be a biodegradable bioadhesive. Examples of such biodegradable bioadhesives include: These include, but are not limited to, fibrin glue, gelatin-resorcinol-formaldehyde / Glutaraldehyde glue, poly(ethylene glycol) (PEG)-based hydrogel adhesive, Polysaccharide adhesives, polypeptide adhesives, polymeric adhesives, biomimetic bioadhesives, as well as , Bhagat and Becker, "Degradable Adhesives for Surgery and Tissue Engineering," B Examples of such macromolecules include those described in iomacromolecules 18: 3009-3039 (2017).

[0021] The term "crosslinker" refers to a compound that crosslinks one entity (e.g., one polymer chain) to another entity (e.g., another polymer chain). In some embodiments, the link between two entities (i.e. In some embodiments, the cross-linking of two real bodies is or includes a covalent bond. The linkage between the bodies is or includes a non-covalent association. For example, some In embodiments, the link between the two entities is an ionic bond or an ionic interaction; In some embodiments, the cross-linking agent is a cross-linker between an aldehyde and an amino group. A small molecule (e.g., a dialdehyde or genipin) to induce the formation of a covalent bond. In some embodiments, the crosslinker comprises a photosensitive functional group. In some embodiments, the crosslinker comprises a pH-sensitive functional group. Contains functional groups.

[0022] The term "solvate" as used herein is understood in the art. and means a compound (which may, for example, be in the form of a salt of the compound) and one or more solvents. In some embodiments, a solvate is a liquid. In some embodiments, the solvate is in a solid form (e.g., a crystalline form). In embodiments, the solid form solvate can be isolated. In some cases, the association between the solvent atoms and the compound in a solvate is a non-covalent association. In some embodiments, such associations may be by hydrogen bonds, van der Waals interactions, or the like. In some embodiments, the atom is a solvent. The solvents contained in the solvates were water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and ethyl acetate. Suitable solvates may be or include one or more of: It may be a pharma- ceutically acceptable solvate; in some particular embodiments, the solvate is , hydrate, ethanolate or methanolate. In some embodiments, the solvate may be a stoichiometric or non-stoichiometric solvate.

[0023] The term "hydrate" as used herein is understood in the art. means a compound (which may be, for example, in the form of a salt of the compound) and one or more water molecules. Typically, the number of water molecules in a hydrate of a compound is The number of molecules is in a definite ratio. Thus, a hydrate of a compound may have the general formula It can be represented as R x H2O, where R is the compound and x is a number greater than 0. A given compound may exist as, for example, a monohydrate (where x is 1), a lower hydrate (where x is greater than 0 and less than 1), hemihydrate (R 0.5 H2O)) and polyhydrate (x > 1 more than one, including, for example, the dihydrate (R 2 H2O) and the hexahydrate (R 6 H2O). Hydrates of the type can be formed.

[0024] The term "tautomer" or "tautomeric" refers to at least one formal substitution of a hydrogen atom. and at least one change of valency (e.g., from a single bond to a double bond, from a triple bond to a Refers to two or more interconvertible compounds resulting from a single bond or vice versa. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Conversion (i.e., the reaction to give the tautomeric pair) can be catalyzed by acids or bases. Exemplary tautomerizations include keto to enol, amide to imide, lactam to cyclopentadiene, etc. to lactim, enamine to imine, and enamine to different enamine Examples include isomerization.

[0025] Also, compounds that have the same molecular formula but differ in the nature or arrangement of bonds of their atoms It is understood that compounds that differ in structure or in the arrangement of their atoms in space can be referred to as "isomers". "Isomers" that differ in the arrangement of their atoms in space are called "stereoisomers." It is called the "body."

[0026] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof). Many compounds can exist in a variety of different crystalline forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, etc. and / or melting point, density, hardness, crystal shape, optical properties, electrical properties, stability They may differ in some or all of their properties, such as their affinity, solubility, and bioavailability. The recrystallization solvent, rate of crystallization, storage temperature, and other factors may result in one crystal form being the only one that exists. Polymorphic forms of a compound can typically be obtained by varying the conditions of the compound. It can be prepared by crystallization under reduced pressure.

[0027] The term "co-crystal" refers to a crystal structure consisting of at least two components. In the above, the co-crystal comprises a compound of interest (e.g., as disclosed herein), and one or more other components, such as one or more atoms, ions, or molecules (e.g., solvent molecules) In certain embodiments, the co-crystal comprises the compound of interest and one or more solvent molecules. In certain embodiments, a co-crystal comprises a compound of interest and one or more acids or bases.

[0028] The term "prodrug" refers to a form of an active compound that is decomposable by solvolysis or biodegradation. one or more compounds that are removed under physiological conditions, resulting in the release of the active compound Exemplary prodrug forms include, but are not limited to, those that contain a cleavable group such as However, choline ester derivatives and N-alkylmorpholine esters are also included. In some embodiments, the prodrug can be prepared by, for example, reacting a parent acid with a suitable alcohol. esters prepared by reaction of the parent acid compound with a substituted or unsubstituted amine; The amides, anhydrides, or mixed anhydrides prepared by the methods known in the art are also known. Such an acid derivative may be a simple acid derivative derived from a pendant acid group on the compound of interest. Pure aliphatic or aromatic esters, amides, and anhydrides are specific candidates for the prodrug form. In some cases, (acyloxy)alkyl esters or ((alkoxy)alkyl esters are

[0033] To prepare double ester type prodrugs such as (oxycarbonyl)oxy)alkyl esters, It may be desirable to use C1-C8 alkyl, C2-C8 alkenyl, C2-C8 Alkynyl, aryl, C7-C 12 Substituted aryl, and C7-C 12 Aryl alkyl esters .

[0029] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., any Age groups, male or female, e.g., pediatric subjects (e.g., infants, children, adolescents) or adults Elephants (e.g., young adults, middle-aged adults, or older adults), and / or non-human animals. , e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); bovine, porcine , domestic animals such as horses, sheep, goats, cats and / or dogs; and / or birds (e.g. For example, chickens, ducks, geese and / or turkeys. In the present specification, the animal is a mammal (e.g., at any stage of development). In some embodiments, the animal (e.g., a non-human animal) is transgenic or genetically engineered. In some embodiments, the subject is a tumor resection subject, e.g., a recently In some embodiments, a tumor resection subject is a subject having undergone tumor resection. Less than 72 hours (e.g., 48 hours) prior to receiving the drug delivery composition or device described herein. (including less than 10 minutes, less than 24 hours, less than 12 hours, less than 6 hours, or less than one hour) In some embodiments, a tumor resection subject is a subject having undergone tumor resection. The patient was administered a drug delivery composition or device as described herein for less than 48 hours prior to tumor resection. In some embodiments, the tumor resection subject is a subject who has undergone tumor resection. 1. Have undergone tumor resection within 24 hours prior to receiving the drug delivery composition or device to be administered In some embodiments, the tumor resection subject is a subject who has undergone tumor resection. Subjects who underwent tumor resection within 12 hours prior to receiving the drug delivery composition or device It is an elephant.

[0030] The term "biological sample" includes tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (e.g. For example, cytological smears (such as Pap smears or blood smears) or samples obtained by microdissection a sample of cells; a sample of a whole organism (e.g., a yeast or bacterial sample); or a fraction of a cell, fraction Fragments or organelles (cells lysed and their components separated by centrifugation or other methods) The term refers to any sample, including samples obtained by isolating a biological sample from another source. Examples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucous membranes, tears, Sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate fluid, milk, vaginal fluid, saliva, swab (e.g., oral swab), or a biological sample derived from a first biological specimen. The material may be any material that contains biological molecules.

[0031] The terms "administer," "administering," or "administration" are used herein to refer to Such drug delivery compositions can be implanted, absorbed, digested, injected, etc. " refers to inhaling or otherwise introducing the same."

[0032] The terms "treatment," "treat," and "treating" are used herein to refer to A "pathological condition" (e.g., a disease, disorder or condition, including one or more signs or symptoms thereof) that is To reverse, alleviate, delay the onset of, or slow the progression of a condition In some embodiments, treatment refers to inhibiting one or more signs or symptoms of Treatment may be administered after symptoms have developed or been observed. After the initial treatment, continued This may continue.

[0033] The terms "condition," "disease," and "disorder" are used interchangeably.

[0034] An "effective amount" is an amount that induces a desired biological response, e.g., reduces the likelihood that a subject will be afflicted. As will be understood by those skilled in the art, In addition, an effective amount of a drug delivery composition is determined based on the desired biological endpoint, the therapeutic agent in the composition, and the amount of the therapeutic agent in the composition. The pharmacokinetics of the drug, the condition being treated, and the age and health of the subject will vary depending on factors such as The effective amount includes therapeutic and prophylactic treatments. For example, treating cancer. In the method, an effective amount is an amount that prevents tumor regrowth, reduces tumor burden, or reduces tumor Those skilled in the art will appreciate that an effective amount may be contained in a single dosage form. It will be understood that administration of an effective amount need not necessarily be a single dose. Rather, administration of an effective amount may potentially be over time (e.g., For example, according to a dosing regimen), which may include administration of multiple doses.

[0035] A "therapeutically effective amount" is an amount sufficient to provide a therapeutic benefit in the treatment of a condition. Thus, the therapeutic benefit can be, for example, the reduction or amelioration of one or more characteristics or symptoms associated with the condition. even if the frequency and / or severity is reduced and / or the onset is delayed, or A therapeutically effective amount is an amount that, alone or in combination with other therapeutic agents, The term "therapeutically effective amount" refers to the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a condition. improves the overall treatment, reduces or avoids the symptoms or causes of a condition, or Those skilled in the art will appreciate that a therapeutically effective amount includes an amount that enhances the therapeutic efficacy of a single dosage form. It will be understood that administration of an effective amount need not necessarily be included in the This may involve administration of multiple doses over time (e.g., according to a dosing regimen).

[0036] A "prophylactically effective amount" refers to an amount that prevents a condition (e.g., reduces one or more symptoms or alleviates one or more of the symptoms of a condition). The onset or recurrence of the characteristic is predicted, e.g., it / they are predicted to be absent by administration of the amount. (enough to delay the detection significantly so that it is not detected by the time it would be detected) A prophylactically effective amount of a composition is an amount that, alone or in combination with other therapeutic agents, is effective to prevent or prevent a condition. The term "therapeutically effective amount" refers to the amount of a therapeutic agent that provides a prophylactic benefit in the prevention of It may include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. It will be appreciated that a prophylactically effective amount need not be contained in a single dosage form. Rather, administration of an effective amount may be in multiple doses, potentially over time (e.g., according to a dosing regimen). The method may include administration of

[0037] "Proliferative disease" means any abnormal growth or spread of cells due to multiplication. (Walker, Cambridge Dictionary of Biology ;Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal locations. 3) protein synthesis (e.g., metastasis of neoplastic cells); Pathological expression of protein-degrading enzymes (e.g., collagenase, gelatinase, and elastase) or 4) pathological angiogenesis, such as that in proliferative retinopathies and tumor metastasis. Representative proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, and These include angiogenesis-related diseases, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases. can be.

[0038] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue. where the growth of the mass inhibits or does not cooperate with the growth of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: The degree of cell differentiation (including morphology and function), rate of proliferation, local invasion and metastasis. "Tissues" are generally well differentiated, have characteristically slower growth than malignant tumors, and are localized to the site of origin. In addition, benign neoplasms may infiltrate, invade, or Exemplary benign neoplasms include, but are not limited to, those that are cancerous or have no ability to metastasize to distant sites. However, lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, lentigines, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors may develop after may give rise to malignant neoplasms, which may result in further genetic alterations in a subpopulation of neoplastic cells in the tumor. These tumors may arise from secondary changes and are referred to as "premalignant neoplasms." An example of a tumor is a teratoma. In contrast, a "malignant neoplasm" is generally a tumor that is poorly differentiated (degenerate). formation), characteristically rapid growth with progressive infiltration, invasion, and destruction of surrounding tissue In addition, malignant neoplasms generally have the ability to metastasize to distant sites.

[0039] The terms "metastasis," "metastatic," or "metastasizing" refer to the process of growing a tumor away from the primary or original tumor. It refers to the spread or migration of cancerous cells to other organs or tissues, typically from the primary or extant organ. The presence of "secondary tumors" or "secondary cell masses" of the tumor histology, and secondary (metastatic) The absence of a "secondary tumor" or "secondary cell mass" in the organ or tissue in which the tumor is located For example, prostate cancer that has spread to the bone is called metastatic prostate cancer and can be detected in bone tissue. These include cancerous prostate cancer cells that grow in the prostate gland.

[0040] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hens (Ed., Williams & Wilkins: Philadelphia, 1990). In the context of some embodiments of this disclosure, Of particular interest in this regard are cell killing and / or ablation therapies (e.g., surgical resection, and / or certain chemotherapeutic agents, such as cytotoxic drug treatments. In some embodiments, the cancer treated by the present disclosure is a cancer that has been surgically removed. (i.e., for which at least one tumor has been surgically removed) In some embodiments, the cancers treated by the present disclosure are those for which resection is the standard of care. In some embodiments, the cancer treated by the present disclosure is one that has metastasized. In some embodiments, exemplary cancers include one or more of the following: : Acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma) , lymphangioendotheliosarcoma, hemangiosarcoma); benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); cholangiocarcinoma; bladder cancer Bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., For example, meningiomas, glioblastomas, gliomas (e.g., astrocytomas, oligodendrogliomas), medulloblastomas) ;bronchial cancer;carcinoid tumors;cardiac tumors;cervical cancer (e.g., adenocarcinoma of the cervix);choriocarcinoma ;chordoma;craniopharyngioma;colorectal cancer (e.g., colon cancer, rectal carcinoma, colorectal adenocarcinoma);connective tissue Cancer; epithelial carcinoma; ductal carcinoma in situ; ependymoma; epithelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma; Endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); -ing sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; biliary gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., , head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal hematopoietic cancer (e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell carcinoma)); leukemias such as 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 (CL L) (e.g., B-cell CLL, T-cell CLL)); lymphoma, e.g., 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., mucosal intralymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma) lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoma Plasma cell lymphoma (i.e., Waldenström macroglobulinemia), hairy lymphoma 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 Blood disorders, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides) , Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma leukemia; mixture of one or more of the above leukemia / lymphomas; multiple myeloma; heavy chain disease (e.g. , alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammation myofibroblastic tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as pulmonary mucosal tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., , bronchogenic lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (L MS; mastocytosis (e.g., systemic mastocytosis); melanoma; midline tract carcinoma a); multiple endocrine neoplasia syndrome; muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder ( MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (agno Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic osteogenic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic osteoporosis myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); nasopharyngeal carcinoma; neuro blastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., Pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor; parathyroid carcinoma; papillary adenocarcinoma; negative Pediculomas (e.g., Paget's disease of the penis and scrotum); pharyngeal cancer; pinealoma; pituitary carcinoma; pleuropulmonary tumours Cell tumor;Primitive neuroectodermal tumor (PNT);Plasma cell neoplasia;Paraneoplastic syndrome;Intraepithelial neoplasia ;Prostate cancer (e.g., adenocarcinoma of the prostate);Rectal cancer;Rhabdomyosarcoma;Retinoblastoma;Salivary gland cancer;Skin Skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); Cancer (e.g. appendix cancer); soft tissue sarcomas (e.g. malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral sarcoma) peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; gastric cancer; small intestine cancer; sweat gland synovial tumors; testicular cancer (e.g., seminoma, embryonal carcinoma of the testis); thymic cancer; thyroid cancer (e.g., , papillary thyroid cancer, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; and Vulvar cancer (e.g., Paget's disease of the vulva).

[0041] The term "immunotherapy" refers to the induction, enhancement, or suppression of an immune response. It refers to a therapeutic agent that promotes the treatment of a disease by inducing or amplifying an immune response. Immunotherapies designed to suppress the immune response are classified as activating immunotherapies, whereas immunotherapies designed to suppress the immune response are classified as suppressing immune responses. Immunotherapies that stimulate or suppress the immune system are classified as suppressive immunotherapies. Although not a cancer treatment, they are typically biotherapeutics. Many immunotherapies are These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, and These include cytokines, chemokines, vaccines, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapies include, but are not limited to, type I interferon Inducers, interferons, stimulator of interferon genes (STING) agonists, TLRs 7 / 8 agonist, IL-15 superagonist, anti-PD-1 antibody, anti-CD137 antibody, and anti-CTLA-4 Examples include antibodies.

[0042] The terms "biologic," "biologic drug," and "biopharmaceutical product" are used interchangeably. "Biological products" means vaccines, blood and blood components, allergens, etc. nics), somatic cells, gene therapy agents, tissues, nucleic acids and proteins. Biologics are drugs that contain sugars, proteins, or nucleic acids, or complex combinations of these substances. It may contain living entities such as cells and tissues. The agents may be isolated from a variety of natural sources (e.g., human, animal, microbial), and and / or may be produced by biotechnological methods and / or other techniques.

[0043] The term "antibody" refers to a functional component of serum and is often used to refer to a collection of molecules (also called antibodies). or immunoglobulin) or as a single molecule (antibody molecule or immunoglobulin molecule). Antibodies bind to a specific antigenic determinant (an antigen or an epitope of an antigen). can bind or react with the IL-1 domain, which then activates the immunological effector mechanisms Individual antibodies are generally considered to be monospecific, and compositions of antibodies may be They can be monoclonal (i.e., made up of identical antibody molecules) or polyclonal (i.e. That is, to the same or different epitopes on the same antigen or on distinct different antigens. Each antibody may be composed of two or more different antibodies that react with each other. It has a unique structure that allows it to specifically bind to the corresponding antigen and is unique to all natural antigens. All antibodies have the same overall basic structure: two identical light chains and two identical heavy chains. are also known collectively as immunoglobulins. Antibodies may be human or non-human (e.g., Whether derived from rodents (e.g. mice, dogs, camels, etc.) or from humans or non-human having a sequence that originally occurred in a human cell or organism), or, e.g. Based on a human or non-human antibody (or, in some embodiments, an antigen-binding portion thereof) and chimeric, humanized, reshaped, or reformatted antibodies. It may also include this.

[0044] In some embodiments, as will be clear from the context, the term "antibody" refers to As used herein, the term encompasses formats that include an epitope binding sequence of an antibody, Such formats include, for example, chimeric and / or single chain antibodies (e.g., nanobodies or Fcab), as well as Fab, Fv fragments or single chain Fv (scFv) fragments of antibodies. binding fragments, as well as multimeric forms such as dimeric IgA molecules or pentavalent IgM molecules. Also included are bispecific antibodies, bispecific T cell-engaging antibodies (BiTEs), and immune mobilizing antibodies. Cancer monoclonal T cell receptor (ImmTAC), dual-affinity retargeting re-targeting (DART); alternative scaffolds or antibody mimics (e.g., antibodies Chikarin, FN3 Monobody, DARPins, Affibodies, Affilins, Affimers, Affitins, Al phabodies, Avimers, Fynomers, Im7, VLR, VNAR, Trimb, CrossMab, Trident); nanobodies D, binanobody, F(ab')2, Fab', di-sdFv, single domain antibody , trifunctional antibodies, diabodies, and minibodies

[0045] The term "small molecule" or "small molecule therapeutic agent" refers to a small molecule therapeutic agent, whether naturally occurring or artificially created. It refers to a molecule having a relatively low molecular weight, whether synthesized (eg, via chemical synthesis). Typically, a small molecule is an organic compound (i.e., it contains carbon). A number of carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carboxyls, etc.) In some embodiments, the molecular weight of the small molecule may include aryl, phenyl ... 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 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 less, or about 10 In some embodiments, the molecular weight of a small molecule is at least about 100 g / mol, 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 ol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or less at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g. For example, at least about 200 g / mol and no 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., as defined in the Code of Federal Regulations (CFR)). A small molecule may also be one or more In this example, the small molecule Also referred to as "small organic molecules." Preferred small molecules are biologically active agents. and which produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging In some embodiments, the small molecule is a drug. However, drugs must be approved for use in humans or animals by the appropriate governmental or regulatory agency. are already considered safe and effective for human use. Drugs approved by the FDA in accordance with 21 C.FR §§ 3, which is incorporated herein by reference. Drugs for veterinary medicine are listed under 30.5, 331-361, and 440-460. All listed items are listed in 21 C.FR §§ 500-589, which are incorporated by reference in this document. Medicaments such as these are considered acceptable for use in accordance with the present invention.

[0046] The term "therapeutic agent" refers to an agent that has one or more therapeutic properties and is intended to provide a desired, usually effective For example, a therapeutic agent may treat or ameliorate a disease, and / or may prevent this. In some embodiments, the therapeutic agent is a biologic, It may be or include a molecule, or a combination thereof.

[0047] The term "chemotherapeutic agent" refers to any agent known to be useful in chemotherapy for cancer. This refers to a therapeutic agent.

[0048] The term "targeted agent" refers to a specific agent involved in the growth, progression, and spread of cancer. Anticancer drugs that block the growth and spread of cancer by interfering with molecules ("molecular targets") Targeted agents are sometimes called "targeted cancer treatment agents," "molecularly targeted drugs," or "molecularly targeted therapeutic agents." Targeted drugs act against specific molecular targets associated with cancer. whereas many chemotherapeutic agents act against all rapidly dividing cells (e.g. It differs from standard chemotherapy in that it treats all types of cancer (whether the cells are cancerous or not). Targeting agents are deliberately selected or designed to interact with their targets, whereas Many standard chemotherapeutics are identified by the cells they kill.

[0049] The term "biomaterial" means any material that is not capable of eliciting an unacceptable response (according to sound medical judgment). and can be administered to a subject for medical (e.g., therapeutic, diagnostic) purposes without Biomaterials refer to materials that are biocompatible and characterized by their ability to be biocompatible. Biomaterials may be derived from natural sources or The biomaterial may be derived or synthetic. In some embodiments, the biomaterial is in the form of a gel. In some embodiments, the biomaterial may be in an injectable form. For example, the biomaterial may be in situ (e.g., in a subject). It may also contain precursor components of a gel to be formed (after administration).

[0050] The term "hydrogel" refers to a material formed from a network of hydrophilic polymer chains. It is sometimes found as a colloidal gel in which the aqueous phase is the dispersion medium. In this regard, hydrogels are highly absorbent (e.g., they absorb more than 90% water). and / or retain the polymeric network, which may be natural or synthetic. In some embodiments, hydrogels, for example due to their significant water content, It has a degree of flexibility similar to natural tissue.

[0051] The terms "implantable," "implant," "to transplant," and "to transplant" typically refer to The drug delivery composition is delivered to a specific location (sentinel site) in a subject by standard surgical procedures. This refers to the placement of a tumor in a lymph node (e.g., within the tumor resection site).

[0052] The term "biocompatible" means substantially non-biological in the in vivo environment of its intended use. toxic and not substantially rejected by the patient's physiological system (i.e., non-antigenic This refers to materials that meet the International Organization for Standardization (ISO) standard numbers 10993 and / or 10994. or United States Pharmacopeia (USP) 23 and / or US Food and Drug Administration (FDA) Blue Book Memorandum Program number G95-1, title "Use of International Standard ISO-10993, Biological Evaluation Biocompatibility as described in the "IEC 61111: Evaluation and Testing of Medical Devices Part-1" The ability of a person to pass certain tests of sexual maturity can be measured. Typically, these tests include: The toxicity, infectivity, pyrogenicity, irritant potential, reactivity, hemolytic activity, carcinogenicity, and / or A biocompatible structure or material is one that, when introduced to the majority of patients, In this case, it is a mild, transient inflammation that typically accompanies surgery or the implantation of a foreign object into the body. Distinguished, unnecessarily harmful, long-lasting, or gradually increasing biological reaction It does not induce any reaction or response.

[0053] The term "antagonist" refers to an agent that (i) reduces or inhibits one or more of the effects of another agent. and / or (ii) reduce or inhibit one or more biological events. In some embodiments, an antagonist refers to an agent that inhibits one or more of the receptors that it targets. In various embodiments, the level and / or activity of the above agents can be reduced. Antagonists include, for example, small molecules, polypeptides, nucleic acids, carbohydrates, etc., that exhibit suitable antagonistic activity. agents of various chemical classes, including lipids, metals, and / or other entities; or This may include. An antagonist may be a direct (in which case it has an antagonistic effect on its target) It exerts its effect directly, or indirectly, in which case it has a direct effect on its target. By other than binding to the target, e.g., by modulation of the target, such that the level or activity of the target is altered. In some embodiments, the effect is exerted by interacting with a factor. In the present invention, the antagonist is a receptor antagonist, e.g., an agonist that inhibits the receptor. By binding to and blocking receptors rather than activating the body's biological response The inhibitor may be a receptor ligand or a drug that blocks or attenuates the activity of the receptor.

[0054] The term "agonist" refers to an agent that (i) enhances or induces one or more of the effects of another agent. and / or (ii) augment or induce one or more biological events. In some embodiments, an agonist refers to an agent that inhibits the activity of one or more agents that it targets. In various embodiments, an agonist may increase the level and / or activity of, for example, Small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or suitable agonists It may be or may include agents from a variety of chemical classes that include other entities that exhibit activity. An agonist can be direct (in this case, it acts directly on its target). It may be that the effect is direct (i.e., it exerts a direct effect by binding to its target) or indirect (i.e., it exerts a direct effect by binding to its target). and / or by; e.g., by regulation of a target, e.g., such that the level or activity of the target is altered. A partial agonist is an antagonist that exerts its effect by interacting with a factor. In the presence of a full agonist, it interacts with its target and / or its regulator. It competes with the interacting full agonist, thereby suppressing the effects observed with only the full agonist. (i) a decrease in one or more effects of another agent, and / or (ii) a decrease in one or more effects of another agent, compared to the Acting as a competitive antagonist by resulting in a reduction in biological events can be done.

[0055] The terms "inhibit" or "inhibition" refer to an inhibition of the levels (e.g., expression and function) of a target (e.g., p38 MAPK). The regulation of the function (function and / or activity) is not limited to total inhibition. In some embodiments, partial inhibition or relative reduction falls within the scope of the term "inhibition." In some embodiments, the term refers to the level ( An initial or other suitable reference level (e.g., expression and / or activity) of reproducibly and / or statistically significantly above the baseline level of the target In some embodiments, the term refers to a reduction in the level of a target ( Initial levels (which may be, for example, baseline levels of the target) of less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10% of Full, Less than 9%, Less than 8%, Less than 7%, Less than 6%, Less than 5%, Less than 4%, Less than 3%, Less than 2%, 1% to levels of less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% This refers to a decline in.

[0056] As used herein, the term "inhibitor" refers to an agent whose presence or level is inappropriate for regulation. It refers to an agent that correlates with a decrease in the level or activity of a target to be inhibited. In this case, the inhibitor may act directly (in which case it acts against its target). directly, e.g., by binding to a target); in some embodiments In this case, the inhibitor may act indirectly (in which case it acts at the level of the target). interact with and / or modify target regulators to reduce their level and / or activity (The effect is exerted by modifying or otherwise altering the In this case, an inhibitor is an inhibitor whose presence or level is relative to a particular reference level or activity (e.g., a known or the absence of an inhibitor as disclosed herein. Correlates with decreased target levels or activity compared to that observed below It is.

[0057] The term "inhibitor of a proinflammatory pathway" as used herein refers to an inhibitor of a proinflammatory pathway in several embodiments. In such cases, agents that prevent the recruitment of immunosuppressive cells or prevent acute inflammation are used. Such acute inflammation and / or recruitment of immunosuppressive cells may occur following local trauma (such as surgery) In some embodiments, inflammation may be induced by Inhibitors of pathways include, for example, inhibitors of proinflammatory cytokines (e.g., TNF-alpha, IL- production of IL-1β and IL-6, increased activity and / or proliferation of Th1 cells, and mobilization of myeloid cells. The present invention can inhibit immune responses that induce inflammation, including

[0058] The term "proinflammatory immune response" as used herein refers to, e.g., an inflammatory response. production of proinflammatory cytokines (e.g., TNF-alpha, IL-1β, and IL-6), activation of Th1 cells Refers to an immune response that induces inflammation, including the expansion and / or proliferation, recruitment of myeloid cells, etc. In some embodiments, the proinflammatory immune response is one of acute inflammation and chronic inflammation. It may be or include one or both of the above.

[0059] The term "activator of the innate immune response" refers to an agent that activates the innate immune system. Activation helps initiate inflammatory responses and / or induce adaptive immune responses. They stimulate the expression of molecules that mediate antigen-specific adaptive immunity. Activation of the immune system involves cytokine production, proliferation, and survival, as well as antigen presentation and anti-inflammatory. Improved T cell priming by enhancing expression of costimulatory molecules by T cell presenting cells This can result in

[0060] The term "activator of the adaptive immune response" refers to an agent that activates the adaptive immune system. Activation can occur by neutralizing inhibitory immune checkpoints or by inducing costimulatory receptors. This ultimately results in helper and / or immunogenic antigens expressed by cancer cells. Generate effector T cell responses and generate populations of memory B and / or T cells In some embodiments, activation of the adaptive immune response can restore anti-tumor function. Factors include modulation of the adaptive immune response and / or leukocyte trafficking.

[0061] The term "modifier of macrophage effector function" refers to a modulator of macrophage effector function. activates receptor function or inhibits immune-suppressive macrophages or macrophage-derived This refers to agents that deplete suppressor cells of the macrophage and myeloid lineages. and destroying tumors and their stroma, including tumor vasculature. Macrophages secrete antitumor cytokines and / or mediate phagocytosis (antibody-dependent The endothelial cells can be induced to undergo various metabolic processes, including phagocytosis of essential cells.

[0062] As used herein, the terms "sustained release" and "long-term "Extended release" is an equivalent term. The compositions and devices of the present disclosure The therapeutic agent can be released over a period of time. and "extended" refers to the administration of one or more therapeutic agents over a timescale ranging from 5 minutes to several months. In some embodiments, one or more of the therapeutic agent is 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 for 4 weeks, 3 weeks, 2 weeks, 10 days, or 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 5 minutes duration In some embodiments, 99% or more of the therapeutic agent is released from the biomaterial over a period of 10 minutes or less. % 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 for 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 5 minutes In some embodiments, the biomaterial is released over a period of time. The extent of long-term release can be characterized in vitro or in vivo. In some embodiments, the release kinetics include a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor). The composition can be prepared in vitro by placing the composition in an aqueous buffered solution (e.g., PBS at pH 7.4). In some embodiments, biomaterials and therapeutic agents (e.g., p38 A composition containing a MAPK inhibitor is placed in an aqueous buffered solution (e.g., PBS at pH 7.4). If the therapeutic agent is used, it should be 100% or less (e.g., 90% or less, 80% or less, 70% or less, 50% or less, or less than that). (including lower) are released from the biomaterial within 3 hours. The release kinetics may be determined by administering a composition comprising a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) to an animal. In vivo by transplantation into a target site (e.g., mammary fat pad) in an elephant (e.g., mouse) In some embodiments, biomaterials and therapeutic agents (e.g., p38 M A composition comprising an APK inhibitor is administered to an animal subject (e.g., a murine subject) at a target site (e.g., a mammary adipose tissue). When implanted into the body, it should contain no more than 70% or less of the therapeutic agent (e.g., no more than 60% or is lower, 50% or less or lower, 40% or less or lower, 30% or less or lower) is released in vivo 8 hours after implantation. [Brief description of the drawings]

[0063] [Figure 1] FIG. 1 is a Kaplan-Meier curve of female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, the tumors of which were surgically removed and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid hydrogel) without a p38 MAPK inhibitor or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and a p38 MAP kinase inhibitor (e.g., losmapimod).

[0064] [Diagram 2] FIG. 2 is a Kaplan-Meier curve of female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, the tumors of which were surgically removed and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid hydrogel) without an anti-IL-1β antibody or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-1β antibody (e.g., clone B122).

[0065] [Diagram 3] FIG. 3 is a Kaplan-Meier curve of female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, the tumors of which were surgically removed and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid hydrogel) without anti-IL-6 antibody or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-6 antibody (e.g., clone MP5-20F3).

[0066] [Figure 4]Figure 4 is a schematic diagram showing the interrelationship of certain pro-inflammatory pathways, including p38 mitogen-activated protein kinase (MAPK) and COX-2. See Desai et al., "Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer," Nutrition and Cancer, 70: 350-375 (2018). Those skilled in the art familiar with such pathways will recognize that pro-inflammatory signals, such as, for example, the cytokines TNF-α, IL-6 and / or IL-1β, can stimulate transcription of COX-2, for example, via activation of the MAPK pathway. For example, it has been established that IL-1β upregulates COX-2 expression through activation of the p38 MAPK pathway (Huang et al., “MAPK / ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stomal cells in vitro,” Int J Clin Exp Pathol, 6: 2129-2136 (2013) and Di Mari et al., “HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts,” Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101 (2007)).

[0067] [Diagram 5]5 is a schematic diagram showing that certain nonsteroidal anti-inflammatory drugs (NSAIDs) can act as inhibitors of cyclooxygenase (COX), including, for example, inhibitors of COX-1 and / or inhibitors of COX-2, and / or as inhibitors of p38 MAPK. See Esposito et al., "Non-steroidal anti-inflammatory drugs in Parkinson's disease," Experimental Neurology 205: 295-312 (2007). For example, in some embodiments, NSAIDs can inhibit or reduce the activity and / or levels of COX-1 and / or COX-2. In some embodiments, NSAIDs can inhibit or reduce the activation of the p38 MAPK pathway or its components, thereby reducing or inhibiting the activation of AP-1.

[0068] [Figure 6] FIG. 6 is a schematic diagram showing the interrelationship of certain proinflammatory pathways involving p38 mitogen-activated protein kinase (MAPK) and Wnt-β-catenin. See Bikkavilli et al., “p38 mitogen-activated protein kinase regulates canonical Wnt-β-catenin signaling by inactivation of GSK3β,” Journal of Cell Science, 121: 3598-3607 (2008). Those skilled in the art familiar with such pathways will recognize that p38 MAPK can be activated by stimulation of Wnt3a, which can be dependent on both G protein and dishevelled. A p38 MAPK-specific inhibitor can reduce the expression of β-catenin induced by Wnt3a. Thus, p38 MAPK plays a role in Wnt-β-catenin signaling, for example, by inactivating GSK3β and / or by operating downstream of dishevelled. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Provided herein are methods for targeting one or more immunomodulatory agents at a target site (e.g., a tumor) and / or a tumor-associated The cancer cells are removed and / or treated, for example, with chemotherapy or radiation. and limiting the delivery of the immunomodulator to the site of injury or death, thereby limiting the effect of the immunomodulator to the site of injury or death. and a drug delivery device that can be concentrated at a target site in need thereof. Such a drug delivery system may be particularly useful for treating cancer. The device may include a biomaterial and an inhibitor of a pro-inflammatory pathway. In the present invention, the drug delivery composition and device are Inhibitors of proinflammatory immune responses mediated by the proteinase kinase (MAPK) pathway (e.g., p38 MAPK The drug delivery compositions and devices may include a biomaterial, a p38 mitogen inhibitor, Inhibitors of proinflammatory immune responses mediated by the activated protein kinase (MAPK) pathway and and activators of the innate immune response. Materials, Induction of Inflammation Mediated by the p38 Mitogen-Activated Protein Kinase (MAPK) Pathway These may include inhibitors of the innate immune response, activators of the innate immune response, and cytokines. The drug delivery compositions and devices include biomaterials, p38 mitogen-activated protein kinase Inhibitor of proinflammatory immune responses mediated by the MAPK pathway; activator of innate immune responses The drug delivery compositions and devices may comprise one or more of the following: The drug delivery compositions and devices may further comprise an activator of the immune response. Therapeutic agents that can inhibit the immune system (e.g., inhibitors of proinflammatory pathways, modifiers of macrophage effector functions) The composition may further comprise a therapeutic agent (such as a chemotherapeutic agent).

[0070] In some embodiments, the therapeutic agent (e.g., For example, immunomodulators) may be used to treat inflammation induced by surgery, such as surgical tumor resection (e.g., chronic A unique tool for the treatment of cancer, especially solid tumors, by mediating anti-inflammatory In some embodiments, the drug delivery compositions and devices can provide The therapeutic agents provided (e.g., immunomodulatory agents) are directed to tumors induced by surgery, e.g., surgical tumor resection. In some embodiments, the drug can inhibit induced inflammation (e.g., chronic inflammation). The therapeutic agents (e.g., immunomodulatory agents) provided in the drug delivery compositions and devices are derived from myeloid lineage-derived cells. The activity of MDSCs can be reduced or inhibited. In some embodiments, the therapeutic agents (e.g., immunomodulatory agents) provided in the drug delivery compositions and devices are Immunosuppressant agents can reduce or inhibit the recruitment of immunosuppressive cells. In some embodiments, the therapeutic agent (e.g., Immunomodulators (immunomodulators) can reduce or inhibit acute inflammation. In some embodiments, the drug delivery compositions and devices are directed to the innate immune response system and / or The composition may further include one or more therapeutic agents that activate the immune response system (e.g., immunomodulatory agents). The compositions, devices, methods, systems, and kits provided herein also include methods for administering cells. administration (e.g., adoptive cell transfer) or by the addition of additional structures such as microparticles, peptides or tumor antigens. It has the advantage over existing methods in that it does not require the incorporation or presence of any components.

[0071] The drug delivery compositions and devices described herein are useful in the perioperative setting. In some embodiments, the compounds are useful for treating cancer (e.g., solid tumors) in The compositions and devices are provided for administering to a subject in need thereof at a site in need of treatment. Immunotherapeutic agents can be delivered by implantation of the device described herein. In some embodiments, the drug delivery compositions and devices include immunomodulatory agents. The drug (e.g., p38 MAPK inhibitor) can be delivered directly to the site of tumor resection, avoiding systemic administration. This is particularly advantageous over existing immunotherapies, as it allows the prevention of inflammatory bowel disease. The drug delivery compositions and devices described in are suitable for systemic administration of classical immunotherapies. To provide a vehicle for drug delivery at the site of tumor resection that avoids potential toxicity that may be associated with Concentrating immunotherapeutic agents at the site of tumor resection also improves efficacy. In some embodiments, the drug delivery compositions and devices can slow tumor growth. and / or inhibiting the recurrence of cancer, preventing tumor metastasis, and In some embodiments, the present invention is useful for treating or preventing regrowth of a primary tumor.

[0072] Notably, in some embodiments, the present disclosure provides a method for treating atopic dermatitis that may itself be used to treat atopic dermatitis. The present invention provides a technique for suppressing immune responses by cultivating DSC activity.

[0073] While not wishing to be bound by any particular theory, the present disclosure provides In this manner, the techniques provided herein address the issues commonly observed with chronic inflammation. (e.g., often associated with autoimmune diseases), as described herein: Reducing the types of inflammation that may be activated in acute settings (i.e., post-surgery) The present disclosure describes a method for targeting p38 as described herein. This provides insight that the treatment may have unique utility in the post-tumor resection context. For example, p38 has been described in association with certain autoimmune conditions and is being used to treat such conditions. Those skilled in the art will recognize that there are numerous therapeutic targets designed to treat autoimmune diseases. Many therapeutic strategies that are successful and / or useful are based on the fact that they suppress the progression of tumor phenotypes. Understanding that this would be disastrous in the setting of tumor resection The present disclosure will not be limited to this general principle, but will be incorporated herein by reference. This study shows that targeting p38 to inhibit cancer cell proliferation is extremely useful for cancer treatment. .

[0074] In some embodiments described, therapies targeting p38 include, for example, natural Immune system activation / receptor activation (e.g., STING agonists or TLR agonists) The therapeutic approaches may also be combined with treatments involving other immunomodulatory strategies, such as those involving administration of immunosuppressive agents.

[0075] Drug delivery compositions and devices Biomaterials (e.g. hydrogels) The drug delivery compositions and devices include a biomaterial. In some embodiments, the biomaterial is A scaffold or depot. A scaffold or depot is a drug-containing scaffold as described herein. The delivery compositions and devices include any therapeutic agent for sustained or prolonged release. This includes any synthetic or naturally occurring material suitable for promoting Biomaterials provide advantageous properties of the compositions and devices described herein, such as The polymer has properties that provide the desired properties (storage modulus, biodegradation, and therapeutic agent release profile).

[0076] In some embodiments, the biomaterial may regulate the release of a therapeutic agent at the tumor resection site by administering the same therapeutic agent to a subject. In some embodiments, the biomaterial is administered at the tumor resection site. The release of the therapeutic agent in the solution is compared to the administration of the same therapeutic agent in solution for 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 hour, 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.

[0077] In some embodiments, the biomaterial, when evaluated at a particular time point after administration, The therapeutic agent is administered in solution so that more of the therapeutic agent is present at the tumor resection site than if the therapeutic agent were administered in solution. Thus, the release of a therapeutic agent (e.g., a p38 MAPK inhibitor) is extended. For example, in some embodiments, and released and present at the tumor resection site when evaluated 24 hours after administration. The amount of therapeutic agent administered is at least 30% more (e.g., at least 40%, at least 50%, at least 60%, at least 70% , including at least 80%, at least 90%, or more. and released to and present at the tumor resection site when evaluated 48 hours after administration. The amount of therapeutic agent absorbed is less than that observed when the therapeutic agent is administered in solution. 30% more (e.g., at least 40%, at least 50%, at least 60%, at least 70%) %, at least 80%, at least 90%, or more). In the present study, the 5'-aminobutyric acid was released and present at the tumor resection site when evaluated 3 days after administration. The amount of therapeutic agent absorbed is less than that observed when the therapeutic agent is administered in solution. 30% more (e.g., at least 40%, at least 50%, at least 60%, at least 70%) %, at least 80%, at least 90%, or more). In the present study, the 5-day post-administration evaluation revealed that the 5-day post-administration 5-aminopropyl 1-methyl-2-propanediol (5-methyl-2-propanediol) was released and present at the tumor resection site. The amount of therapeutic agent absorbed is less than that observed when the therapeutic agent is administered in solution. 30% more (e.g., at least 40%, at least 50%, at least 60%, at least 70%) %, at least 80%, at least 90%, or more).

[0078] In some embodiments, the biomaterial has a resistance of at least 500 Pa, at least 1000 Pa, At least 1500 Pa, at least 2000 Pa, at least 2500 Pa, at least 3000 Pa, at least 4000 Pa, at least 5000 Pa, at least 10 kPa, at least 15 kPa, or higher stored In some embodiments, the biomaterial is characterized by a thermal stability of 50 kPa or less, 40 kPa or less. Lower, 30kPa or less, 20kPa or less, 10kPa or less, 5000kPa or less, 4000Pa or less, 3000Pa or less, 2000Pa The elastic modulus is characterized by a storage modulus of less than or equal to 0.05 mm. For example, in some embodiments, the biomaterial can be subjected to a pressure of 500 Pa to 50,000 Pa, or 1000Pa~20kPa, or 1000Pa~10kPa, or 1000Pa~5000Pa, or 1000Pa~30 It is characterized by a storage modulus of 0.00 Pa.

[0079] In some embodiments, the biomaterial is hyaluronic acid, alginate, chitosan, chitin, sulfur. Chondroitin acid, dextran, gelatin, collagen, starch, cellulose, polysaccharides , fibrin, ethylene-vinyl acetate (EVA), poly(lactic-co-glycolic) acid (PLGA), polylactide Acid (PLA), Polyglycolic Acid (PGA), Polyethylene Glycol (PEG), PEG Diacrylate (P EGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), polydioxane Non (PDO), polyhydroxybutyrate (PHB), poly(2-hydroxyethyl methacrylate) (pHEMA ), polycaprolactone (PCL), poly(beta-amino ester) (PBAE), poly(ester amine) 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 carbonate) (PDTE), poly[bis( (trifluoroethoxy)phosphazene], polyoxymethylene, single-walled carbon nanotubes, Polyphosphazene, polyanhydride, poly(N-vinyl-2-pyrrolidone) (PVP), poly(vinylalcohol) Poly(acrylic acid) (PVA), Poly(methacrylic acid) (PMA), Polyacetal, Poly(alpha ester), poly(ortho ester), polyphosphoester, polyurethane, poly Polycarbonates, polyamides, polyhydroxyalkanoates, polyglycerols, poly glucuronic acid, derivatives thereof, and / or combinations thereof.

[0080] In some embodiments, the biomaterial is or comprises a non-crosslinked biomaterial. In some embodiments, the biomaterial is or comprises a crosslinked biomaterial. For example, in some embodiments, such crosslinked biomaterials are hydrogels or The hydrogel may be crosslinked by any method known in the art. Those skilled in the art will appreciate that in some cases, hydrogels can be crosslinked, e.g. crosslinking methods (e.g., whether derived from natural sources or synthetic by using good small molecule crosslinkers), polyelectrolyte crosslinking (e.g., by crosslinking a polymer with (mixing with a second polymer containing a charge), thermally induced crosslinking, photoinduced crosslinking (e.g., vinyl with sulfones, methacrylates, acrylic acids), pH-induced crosslinking, and / or enzyme catalysis It will be appreciated that cross-linking may be used. In some embodiments, In forming hydrogels, Parhi, Adv Pharm Bull., Review 7(4): 515-530 (2017) may be used. In the present invention, the hydrogel is a thiol (e.g., EXTRACEL®, HYSTEM®), Methacrylate, hexadecylamide (e.g., HYMOVIS®), and / or thylamine Crosslinking can be achieved by attaching a tertiary amine (e.g., CORGEL®). In some embodiments, the hydrogel is a hydrogel containing formaldehyde (e.g., HYLAN-A®). , divinyl sulfone (DVS) (e.g., HYLAN-B®), 1,4-butanediol diglycidyl diethyl ether (BDDE) (e.g., RESTYLANE®), glutaraldehyde, and / or It can be directly crosslinked with genipin (see, e.g., Khunmanee et al., "Crosslinking method of "Hyaluronic-based hydrogel for biomedical applications" J Tissue Eng. 8: 1-16(20 In some embodiments, the hydrogel is made of divinyl sulfone (DVS) (e.g., , HYLAN-B (registered trademark).

[0081] In some embodiments, the hydrogel biomaterial has a resistance of at least 500 Pa, at least 100 0 Pa, at least 1500 Pa, at least 2000 Pa, at least 2500 Pa, at least 3000 Pa, At least 4000 Pa, at least 5000 Pa, at least 10 kPa, at least 15 kPa, at least 20 kPa, at least 25 kPa, at least 30 kPa, at least 35 kPa, at least 40 kPa, or In some embodiments, the hydrogel is characterized by a higher storage modulus. Biomaterials are 50kPa or less, 40kPa or less, 30kPa or less, 20kPa or less, 10kPa or less, 5000Pa or less , characterized by a storage modulus of 4000 Pa or less, 3000 Pa or less, 2000 Pa or less, or less than that. Combinations of the above ranges are also possible. For example, in some embodiments , hydrogel biomaterials are 500 Pa to 50 kPa, or 1000 Pa to 50 kPa, or 1000 Pa to 20 kPa or 1000 Pa to 10 kPa, or 500 Pa to 5000 Pa, or 500 Pa to 3000 Pa storage modulus In some embodiments, the storage modulus of the hydrogel biomaterial is characterized as: It can be determined when it is fully saturated with an aqueous solution (eg, water).

[0082] In some embodiments, the biomaterial (e.g., a hydrogel biomaterial) is at least 5 mm thick. Pa / s, at least 10mPa / s, at least 20mPa / s, at least 30mPa / s, at least 40mPa / s , at least 50 mPa / s, or higher (e.g., 1000 s at 10°C) -1 At a shear rate of In some embodiments, the hydrogel biocompatible material is characterized by a viscoelasticity (measured by a viscoelasticity test). Materials are 50mPa / s or less, 45mPa / s or less, 40mPa / s or less, 35mPa / s or less, 30mPa / s or less, 25mPa / s Viscosity of less than 20 mPa / s, less than 15 mPa / s, less than 10 mPa / s, or lower (e.g., at 10°C, 1000s -1 Combinations of the above ranges are also possible. It is also possible. For example, in some embodiments, the hydrogel biomaterial has a viscosity of 5 to 50 mPa / s, or 10-40 mPa / s, or 20-30 mPa / s viscosity (for example, 1000 s at 10°C) -1 Shear rate of In some embodiments, the hydrogel is characterized by a hydrogel viscosity (measured by 100 μm). The viscosity of the filler material can be measured using a rheometer.

[0083] In some embodiments, the biomaterial (e.g., hydrogel biomaterial) may be made of hyaluronic acid, aldehydes, glycerol ... ginate, chitosan, chondroitin sulfate, dextran, gelatin, collagen, den Pus, 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 polyvinyl alcohol (PVA), polyacetal, polyglycerol, polyglucuronic acid, or In some embodiments, the biomaterial is a hydrophilic biomaterial. If a gel, the therapeutic agent of the composition or device is a hydrophilic molecule. In the case where the biomaterial is a hydrogel, the therapeutic agent of the composition or device may be a hydrophobic molecule. In some embodiments, when the biomaterial is a hydrogel, the composition or device The therapeutic agent may be a hydrophobic or hydrophilic molecule. In some embodiments, the biomaterial is a hydrogel. In the case of a hydrophilic, hydrophobic, and / or hydrophilic, therapeutic agent of the composition or device is a hydrophobic and / or hydrophilic molecule.

[0084] In some embodiments, the biomaterial is hyaluronic acid or alginate. In this case, the biomaterial is cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the biomaterial comprises hyaluronic acid or alginate. In one embodiment, the biomaterial comprises cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the hydrogel is hyaluronic acid or alginate. The hydrogel is cross-linked hyaluronic acid or cross-linked alginate. In some embodiments, the hydrogel comprises hyaluronic acid or alginate. In the present invention, the hydrogel comprises cross-linked hyaluronic acid or cross-linked alginate. .

[0085] In some embodiments, the biomaterial comprises hyaluronic acid. , cross-linked hyaluronic acid. In one embodiment, the biomaterial is hyaluronic acid. In one embodiment, the biomaterial is cross-linked hyaluronic acid. The hydrogel comprises hyaluronic acid. In some embodiments, the hydrogel is a crosslinked In one embodiment, the hydrogel is hyaluronic acid. In one embodiment, the hydrogel is cross-linked hyaluronic acid.

[0086] Hyaluronic acid, also known as hyaluronan, is found throughout connective, epithelial and neural tissues. It is a widely distributed, anionic, non-sulfated glycosaminoglycan. They are not necessarily ubiquitous, they form in the plasma membrane instead of the Golgi, and they can become very large and They are unique among glycosaminoglycans in that their molecular weights often reach one million. do.

[0087] Hyaluronic acid, one of the major components of the extracellular matrix, is involved in cell proliferation and It plays an important role in cancer metastasis because it significantly contributes to migration. In tumors, the level of hyaluronic acid correlates with malignancy and poor prognosis. Often used as tumor markers for certain cancers (e.g., prostate and breast cancer) and can be used to monitor the progression of the disease in an individual. Thus, hyaluronan as a biomaterial in the disclosed drug delivery compositions and devices. The use of ronic acid provides an unexpectedly useful and effective cancer treatment.

[0088] In some embodiments, the hyaluronic acid is a thiol (e.g., EXTRACEL®, HYSTEM®). methacrylates, hexadecylamides (e.g., HYMOVIS®), and and tyramine (e.g., CORGEL®) Hyaluronic acid can also be used in combination with formaldehyde (e.g., HYLAN-A®), divinyl sulfate, DVS (e.g., HYLAN-B®), 1,4-butanediol diglycidyl ether (BDD E) directly with (e.g., RESTYLANE®), glutaraldehyde, or genipin Crosslinking of hyaluronan can be carried out by using a crosslinking method (see, for example, Khunmanee et al., "Crosslinking method of hyaluronan"). c-based hydrogel for biomedical applications” J Tissue Eng. 8: 1-16 (2017) In some embodiments, the hyaluronic acid is divinyl sulfone (DVS) (e.g., HYLAN-B (registered trademark).

[0089] In one embodiment, 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., G LYCOSIL®), and thiol-reactive PEGDA crosslinkers (e.g., EXTRALINK® In one embodiment, the thiol-modified hyaluronic acid and the thiol-reactive PEGD A crosslinker is a compound that, when combined, crosslinks the drug delivery composition and the deba The resulting crosslinked hydrogel is useful in implants.

[0090] In some embodiments, thiol-modified hyaluronic acid, thiol-reactive hyaluronic acid The amount and concentration of the crosslinking agent are adjusted to achieve the desired physical properties (storage elasticity of about 500 Pa to about 3000 Pa). In order to provide drug delivery compositions and devices having It is possible.

[0091] In some embodiments, the biomaterial comprises alginate. , cross-linked alginate. In some embodiments, the biomaterial is an alginate. In some embodiments, the biomaterial is a cross-linked alginate. The hydrogel comprises an alginate. In some embodiments, the hydrogel is a cross-linked In some embodiments, the hydrogel is an alginate. In one embodiment, the hydrogel is a cross-linked alginate. The material does not include alginate. In some embodiments, the biomaterial is not an alginate. In some embodiments, the hydrogel is not an alginate. Hydrogel does not contain alginate.

[0092] In some embodiments, the alginate may be modified with the addition of a salt (e.g., calcium chloride) to promote crosslinking. This allows ionically crosslinking.

[0093] In some embodiments, the alginate is a mixture of alginate and a crosslinking agent (e.g., calcium chloride). In some embodiments, the hydrogel comprises an alginate and a crosslinker (e.g., a chloride). In some embodiments, alginate and calcium chloride (e.g., iodine) are used. The crosslinking agent is preferably a carboxylic acid or a carboxylic acid. The resulting crosslinked hydrogels are useful in pharmaceutical applications.

[0094] In some embodiments, the amounts and concentrations of alginate and calcium chloride are as desired. A drug delivery composition having physical properties (such as a storage modulus of about 500 Pa to about 3000 Pa). The present invention can be adapted to provide objects and devices.

[0095] In some embodiments, the biomaterial is a hydrophobic polymer. The polymers are ethylene-vinyl acetate (EVA), poly(lactic-co-glycolic) acid (PLGA), polylactic acid (P LA), polyglycolic acid (PGA), polydioxanone (PDO), polyhydroxybutyric acid (PHB), poly Caprolactone (PCL), poly(ester amide), poly(propylene fumarate) (PPF), poly( Sebacic anhydride (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl tyrosyl) trialkyl carbonate ester (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 ester), poly(ortho ester), polyphosphoester, polyurethane, poly The hydrophobic polycarbonate is a polyamide or a polyhydroxyalkanoate. The use of the mer as a biomaterial is advantageous when the therapeutic agent in the composition or device is hydrophilic. Hydrophobic therapeutic agents may be particularly useful in the treatment of cancer. Released over a longer period (e.g. days / weeks) rather than on a microscale (e.g. hours) It would be expected that the biomaterial would be hydrophobic. When the therapeutic agent of the composition or device is a polymer, it is a hydrophilic molecule.

[0096] In some embodiments, the biomaterial comprises a crosslinked biologic. The iodine formulation is a self-immolating crosslinker, dithio-bis(ethyl 1H-imidazo[3,4-dithiocarbamate]-1H-imidazo[3,4-dithiocarbamate]). In some embodiments, the resulting crosslinked polymer is crosslinked with diol-1-carboxylate (DIC). The hydrogels are loaded with small molecules.

[0097] Inhibitors of proinflammatory pathways The drug delivery compositions and devices may include inhibitors of pro-inflammatory pathways. The compositions and devices may include inhibitors of more than one pro-inflammatory pathway. In some embodiments, inhibitors of proinflammatory pathways may prevent the recruitment of immunosuppressive cells. In some embodiments, inhibitors of proinflammatory pathways can prevent acute inflammation. In such a manner, an inhibitor of a proinflammatory pathway can be, for example, one or more proinflammatory cytokines. production of cytokines (e.g., TNF-alpha, IL-1β, and / or IL-6), increased activity of Th1 cells, and may inhibit inflammatory immune responses, including proliferation and / or recruitment of myeloid cells. For example, in some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor of IL-1β. In some embodiments, the inhibitor of a pro-inflammatory pathway may be an inhibitor of IL-6.

[0098] In some embodiments, the inhibitor of a proinflammatory pathway is p38 as described herein. Proinflammatory immune responses mediated by the mitogen-activated protein kinase (MAPK) pathway is an inhibitor of.

[0099] In some embodiments, inhibitors of proinflammatory pathways prevent the recruitment of immunosuppressive cells. In some embodiments, the inhibitor of a proinflammatory pathway is CCR2, CCR5, CXCR2, CXCR4, CXCL12 or CCCR5. In one embodiment, the inhibitor is an inhibitor, antagonist, or partial agonist of L2. Pathway inhibitors include inhibitors, antagonists or partial inhibitors of CCR5, CXCR2, CXCL12 or CCL2. It is an agonist.

[0100] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or receptor of CCR2. In some embodiments, CCR2 is associated with the p38 MAPK pathway (e.g., Mon Tague et al., J. Inflammation 2018, 15:101; and Xu et al., Am. J. Transl. Res. 2017, 9, 2878-2890). In one embodiment, an inhibitor of CCR2, The antagonists or partial agonists are PF-04136309, CCX872-B or prosalizumab (pl In some embodiments, the inhibitor of the proinflammatory pathway is PF-04136309, CCX872 In one embodiment, the inhibitor of the proinflammatory pathway is an inhibitor of CCR2. In some embodiments, the inhibitor is not a toxic agent, antagonist, or partial agonist of a proinflammatory pathway. The inhibitor is not PF-04136309.

[0101] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or receptor of CCR5. In some embodiments, CCR5 is associated with the p38 MAPK pathway (e.g., Lei , et al., Biochem. Biophys. Res. Commun. 2005, 329, 610-615; and Manes, et al. , J. Exp. Med. 2003, 198, 1381-1389). CCR5 inhibitors, antagonists or partial agonists include maraviroc, DAPTA, and GSK706769. , INCB009471, GW873140, Vicriviroc or PRO 140. In some embodiments, inflammation Inhibitors of the induction pathway include maraviroc, DAPTA, GSK706769, INCB009471, GW873140, and vicribin. Roku or PRO 140.

[0102] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor or antagonist of CCR2 and CCR5. In some embodiments, the inhibitors, antagonists, or partial agonists of CCR2 and CCR5 are The agonists or partial agonists are PF-04634817, cenicriviroc, or BMS-813160. In some embodiments, the inhibitor of the proinflammatory pathway is PF-04634817, cenicriviroc, or is BMS-813160.

[0103] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or inhibitor of CXCR2. In some embodiments, the inhibitor, antagonist or partial agonist of CXCR2 is The agonist is danilixin, QBM076, SX-682 or SB225002. , inhibitors of proinflammatory pathways are danilixin, QBM076, SX-682 or SB225002.

[0104] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or inhibitor of CXCR4. In some embodiments, CXCR4 is associated with the p38 MAPK pathway (e.g., Lei, et al., Biochem. Biophys. Res. Commun. 2005, 329, 610-615; and Trushin, e. (as described in U.S. Pat. No. 6,311,623, 2007, 178, 4846-4853). CXCR4 inhibitors, antagonists or partial agonists include plerixafor, AMD070, , AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL31 1 or SP01A. In some embodiments, the inhibitor of the proinflammatory pathway is plerixafor, AM D070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, U In one embodiment, the inhibitor of the proinflammatory pathway is an inhibitor of CXCR4. , but not antagonists or partial agonists.

[0105] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or inhibitor of CXCL12. In some embodiments, CXCL12 is associated with the p38 MAPK pathway (e.g., , Gao, et al., Int. J. Clin. Exp. Pathol. 2018, 11, 3119-3125 As shown.

[0106] In some embodiments, the inhibitor of a proinflammatory pathway is an inhibitor, antagonist or receptor of CCL2. In some embodiments, CCL2 is a partial agonist. , et al., J. Neuroimmunol. 2008, 199, 94-103; and Marra, et al., Am. J. Physio l. Gastrointest. Liver Physiol. 2004, 287, G18-26). In embodiments, the inhibitor, antagonist or partial agonist of CCL2 is bindarit (b indarit).

[0107] In some embodiments, the inhibitor of the proinflammatory pathway is PF-04136309, CCX872-B, prosalicylic acid Bu, Maraviroc, DAPTA, GSK706769, INCB009471, GW873140, Vicriviroc, PRO 140, P F-04634817, Cenicriviroc, BMS-813160, Danilixin, QBM076, SX-682, SB225002, Plerixafor, AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X 4P-001, BL-8040, USL311 or SP01A.

[0108] In some embodiments, the inhibitor of the proinflammatory pathway is CCX872-B, prosalizumab, maraviroc , DAPTA, GSK706769, INCB009471, GW873140, Vicriviroc, PRO 140, PF-04634817, Se Nikriviroc, BMS-813160, Danilixin, QBM076, SX-682, SB225002, Plerixafor , AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-804 0, USL311 or SP01A.

[0109] In some embodiments, inhibitors of proinflammatory pathways prevent acute inflammation. Inhibitors of proinflammatory pathways include anti-IL-1α antibodies, anti-IL-1β antibodies, anti-IL-1R antibodies, IL-1 inhibitors, and anti-I L-6 antibody, anti-IL-6R antibody, anti-IL17 antibody, anti-IL-17A antibody, anti-IL-17RA antibody, anti-IL-23 / IL-12 antibody , or an anti-IL-23 antibody.

[0110] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-1α antibody. In one embodiment, the anti-IL-1α antibody is MABp1. In one embodiment, the inhibitor of the proinflammatory pathway is MABp1. be.

[0111] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-1β antibody. IL-1β is associated with the p38 MAPK pathway (e.g., Kulawik, et al., J. Biol. Chem. 2017, 292, 6291-6302;Rovin, et al., Cytokine 1999, 11, 118-126;Laporte, et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 279, L932-L941;Baldassare, et al., J Immunol. 1999, 162, 5367-5373; and Weber, et al. Sci. Signal. 2010, 3, cm1 In some embodiments, the anti-IL-1β antibody is canakinumab. In some embodiments, the inhibitor of the pro-inflammatory pathway is canakinumab.

[0112] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-1R antibody. IL-1R is involved in the p38 MAPK pathway (see, e.g., Weber, et al., Sci. Signal. 2010, 3, c m1; and as described in Jain, et al., Nat. Commun. 2018, 9:3185). In one embodiment, the anti-IL-1R antibody is anakinra. It's anakinra.

[0113] In some embodiments, the inhibitor of a pro-inflammatory pathway is an IL-1 inhibitor. The IL-1 inhibitor is rilonacept. In some embodiments, the inhibitor of the proinflammatory pathway is rilonacept. It is Nacept.

[0114] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-6 antibody. IL-6 is involved in the p38 MAPK pathway (see, e.g., Sinfield, et al., Biochem. Biophys. Res. Commun. 2013, 430, 419-424; Suzuki, et al., FEBS Lett. 2000, 465, 23-27; and N As described in Ishikai-Yan Shen, et al., PLoS One 2017, 12, 1-17). In embodiments, the anti-IL-6 antibody is selected from the group consisting of olokizumab, clazakizumab, OPR-003, sirukumab, A In one embodiment, the inhibitor of the proinflammatory pathway is orofumab. Kizumab, clazakizumab, OPR-003, sirukumab, ARGX-109, FE301, or FM101 .

[0115] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-6R antibody. In one embodiment, the anti-IL-6R antibody is tocilizumab, sarilumab, or bovalilizumab. In this study, the inhibitors of the proinflammatory pathway were tocilizumab, sarilumab, or bovalilizumab. do.

[0116] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-17 antibody. IL-17 is involved in the p38 MAPK pathway (e.g., Noubade, et al., Blood 2011, 118, 3290 -3300;Roussel, et al., J. Immunol. 2010, 184, 4531-4537; and Mai, et al., J. As described in Biol. Chem. 2016, 291, 4939-4954). In one embodiment, anti-I The L-17 antibody is a combination of ixekizumab, bimekizumab, ALX-0761, CJM112, and CNTO 67. 85, LY3074828, SCH-900117, or MSB0010841. In some embodiments, the pro-inflammatory pathway Inhibitors include ixekizumab, bimekizumab, ALX-0761, CJM112, CNTO 6785, and LY3074828. , SCH-900117 or MSB0010841.

[0117] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-17A antibody. In one embodiment, the anti-IL17A antibody is secukinumab. Secukinumab.

[0118] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-17RA antibody. In one embodiment, the anti-IL17RA antibody is brodalumab. , brodalumab.

[0119] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-23 / IL-12 antibody. In one embodiment, the anti-IL-23 / IL-12 antibody is ustekinumab or briakinumab. In the present case, the inhibitor of the proinflammatory pathway is ustekinumab or briakinumab.

[0120] In some embodiments, the inhibitor of a proinflammatory pathway is an anti-IL-23 antibody. IL-23 is involved in the p38 MAPK pathway (see, e.g., Tang, et al., Immunology 2012, 135, 11 2-124; and Canavese, et al., J. Clin. Exp. Dermatol. Res. 2011, S2:002. doi:10 In some embodiments, the anti-IL-23 antibody is In some embodiments, the pro-inflammatory pathway is The inhibitors are tildrakizumab, BI 655066 or guselkumab.

[0121] In some embodiments, the inhibitor of the proinflammatory pathway is MABp1, canakinumab, anakinra, rifapril, or the like. Lonacept, Olokizumab, Clazakizumab, OPR-003, Sirukumab, ARGX-109, FE301, FM101, tocilizumab, sarilumab, bovalilizumab, ixekizumab, bimekizumab, A LX-0761, CJM112, CNTO 6785, LY3074828, SCH-900117, MSB0010841, Secukinumab, Lodalumab, ustekinumab briakinumab, tildrakizumab, BI 655066 or Guse It is lucumab.

[0122] In some embodiments, the inhibitor of a pro-inflammatory pathway is a TGFβR inhibitor. , TGFβR is related to the p38 MAPK pathway (e.g., Yu et al., EMBO J. 2002, 21, 3749-375 9;Sato, et al., J. Invest. Dermatol. 2002, 118, 704-711; and Hanafusa, et al. (as described in J. Biol. Chem. 1999, 274, 27161-27167). In one embodiment, the TGFβR inhibitor is galunisertib. is galunisertib.

[0123] In some embodiments, the inhibitor of a proinflammatory pathway is a specialized mediator. SPMs are or contain pro-resolving mediators (SPMs) derived from long-chain fatty acids. Lipid mediators that prevent excessive inflammation and / or reduce acute inflammatory responses Examples of such SPMs include Araki These include lipoxins derived from docosahexaenoic acid (AA) and resolvins derived from docosahexaenoic acid (DHA). Convergence is a mechanism by which inflammation is suppressed through specific cell surface receptors without compromising host defenses. It also acts to relieve inflammation, enhance efferocytosis, and transmit signals that repair tissue damage. For example, Cai et al., "MerTK cleavage limits "Proresolving mediator biosynthesis and worsens tissue inflammation" PNAS, 1 13: 6526-6531 (2016); and Serhan et al., "Novel anti-inflammatory - Pro-resolving "Mediators and their receptors" Curr Top Med Chem 11: 629-647 (2011). Oxygenase enzymes (eg, COX-2) may be involved in the production of certain SPMs.

[0124] In some embodiments, SPMs that may be useful as inhibitors of proinflammatory pathways include resolving Resolvins are or contain resolvins that mediate tumor cell proliferation via macrophage phagocytosis. Enhances the clearance of cellular debris, e.g., TNFα, IL-6, IL-8, CCL4 and / or CCL5. It has been shown to counterregulate the release of cytokines / chemokines including IL-1, IL-2, and IL-1. For example, Sulciner et al., "Resolvins suppress tumor growth and enhance cancer therapy" " J Exp Med 215: 115-140 (2018). Resolvins (Rv) are divided into several classes. Resolvin Ds (RvDs) derived from docosahexaenoic acid (DHA); Resolvin Es (RvEs) derived from diphenyl ether (DPA) isomers, osbonic acid Resolvin D induced by n-6DPA (RvD n-6DPA ); DPA isomer, derived from clupanodonic acid Resolvin D n-3DPA (RvD n-3DPA ); Resolvin Ts (RvTs) derived from clupanodonic acid (R vD n-3DPA (having a 17S-hydroxyl residue) ). Those skilled in the art will recognize that in some cases, resolvins are RvD1, RvD2, RvD3, RvD4, RvD5, , RvD6, 17R-RvD1, 17R-RvD2, 17R-RvD3, 17R-RvD4, 17R-RvD5, 17R-RvD6, RvE1, 18S-Rv E1, RvE2, RvE3, RvT1, RvT2, RvT3, RvT4, RvD1 n-3 , RvD2 n-3 , RvD5 n-3 , or them It will be understood that the present invention may be, or may include, a combination of:

[0125] In some embodiments, SPMs that may be useful as inhibitors of pro-inflammatory pathways include lipokines, Syn (e.g., including LxA4, LxB4, 15-epi-LxA4, and / or 15-epi-LxB4), Neuroprotectins / neuroprotectins (e.g., DHA-derived neuroprotectins / neuroprotectins and and / or n-3 DPA-derived protectins / neuroprotectins), maresins (e.g., DHA-derived maresins derived from n-3 DPA and / or maresins derived from n-3 DPA), as well as other DPA metabolites, Or includes this.

[0126] Proinflammatory immunity mediated by the p38 mitogen-activated protein kinase (MAPK) pathway Inhibitors of response The present disclosure relates, inter alia, to methods for inhibiting p38 mitogenic activity at a target site (e.g., a tumor resection site). Inhibiting proinflammatory immune responses mediated by the activating protein kinase (MAPK) pathway ( For example, a p38 MAPK-mediated proinflammatory pathway or a component thereof may be regulated (e.g., inhibited) by a p3 8 The administration of MAPK inhibitors (see, for example, Figures 4-6) reduces the risk of cancer recurrence. Recognize that MAPK-targeted therapy can enhance survival by promoting cell death and thereby prolonging survival. For example, inhibition of the BRAF / MEK / ERK module) provides a response to anti-PD-1 immune checkpoint blockade therapy. This induces a transcriptional signature associated with resistance to anti-PD-1 / L1 cancer therapy. It has been reported that serotonin-dependent agonists may negatively affect the response to serotonin-dependent agonists (e.g., Hugo et al., Cell 2016, 165, 35-44), and inhibition of MAPK can promote antitumor immunity. That was unexpected.

[0127] Thus, in some embodiments, provided herein are p38 mitogens. Inhibition of proinflammatory immune responses mediated by the agonist-activated protein kinase (MAPK) pathway In some embodiments, the present invention provides a drug delivery composition and device comprising the agent. The drug delivery compositions and devices provided herein are capable of delivering one or more p38 mitogen activators. Inhibitors of proinflammatory immune responses mediated by protein kinase (MAPK) pathways good.

[0128] The p38 family of MAPKs includes the p38α, p38β, p38γ and p38δ isoforms. MAPKs are activated by a number of immune receptors, thereby acting either upstream or downstream of p38. Inhibition of signaling modules or regulatory targets functioning in the This could provide an effective and selective method for inhibiting molecular pathways and proinflammatory immune responses. .

[0129] For example, p38 MAPK is a mitogen-activated protein kinase kinase 3 (MAP2K3), Mitogen-activated protein kinase kinase 6 (MAP2K6), mitogen-activated protein Protein kinase kinase kinase 1 (MAP3K1), and / or mitogen-activated protein kinase It can be activated by MAP3K4, thus acting upstream of p38 MAPK. Inhibiting this target may be effective in inhibiting the p38 MAPK pathway.

[0130] Inhibition of downstream targets of p38 MAPK may also be an effective means of inhibiting the p38 MAPK pathway. Downstream of p38 MAPK, e.g., mitogen-activated protein kinase-interacting protein kinase Mitochondrial kinase (MNK1) interacting protein kinase 1 and 2 MNK kinases (MNK1 and MNK2) are activated by the p38 MAPK pathway. MNK kinases regulate the translation of mRNA. It plays an important role in the regulation of cancer progression, drug resistance, and proinflammatory cytokines. It is a key mediator of cytokine production and cytokine signaling. Mitogen- and stress-activated kinase 1 and 2 (M SK1 and MSK2) are also downstream targets of p38 MAPK and influence inflammatory responses. Kinase-activated protein kinases 2, 3, and 5 (MK2, MK3, MK5) are activated by p38 MAPK and is involved in cellular stress and inflammatory responses.

[0131] Considering the above, inhibition of the p38 MAPK pathway offers a therapeutic strategy for the treatment of cancer. In particular, the local inflammatory wound response and the systemic inflammatory process together , activate dormant micrometastases or induce proliferation of residual cancer cells, thereby Therefore, the p38 MAPK pathway may be involved in the resection of tumors, which may increase the risk of recurrence of cancer. By inhibiting the proinflammatory immune response mediated by IL-1, the risk of cancer recurrence is reduced and It can extend the survival of elephants.

[0132] In one embodiment, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is p3 In one embodiment, the p38 MAP kinase inhibitor is p38α, p38 In one embodiment, the p38 MAPK inhibitor is an inhibitor of p38 MAPK. P kinase inhibitors include semapimod, pexmetinib, BMS-582949, and rosmapimod. Modo, pamapimod, ralimetinib, dorampimod, VX-702, VX-745, TAK-715 , SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, ARRY-797, ARRY-614 , AVE-9940, LY3007113, Skepinon-L, UM-164, SCIO 323, SX-011, SK-F860002, SB706 504, SB681323, CHF-6297, RWJ-67657, Org48762-0, ML3403, JX-401, EO-1428, DBM 128 5, AMG-548, AL-8697, PD-169316, PF-03715455, PH-797804, Selonsertib, Sorafe In one embodiment, the p38 MAP kinase inhibitor is The agents are quinazolinones, pyrimido-pyrimidones, pyrido-pyrimidones, pyrazoles, quinolinones, In some embodiments, the p38 MAP kinase inhibitor comprises a p38 MAP kinase inhibitor. The inhibitor is losmapimod.

[0133] In one embodiment, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is p3 In one embodiment, the compound is an inhibitor of p38α, p38β, p38γ, and / or p38δ MAP kinase. Inhibitors of the proinflammatory immune response mediated by the p38 MAPK pathway include semapimod and pexme. Tinib, BMS-582949, Rosmapimod, Pamapimod, Ralimetinib, Dramapimod, VX-702 , VX-745, TAK-715, SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, A RRY-797, ARRY-614, AVE-9940, LY3007113, Skepinon-L, UM-164, SCIO 323, SX-011, SK-F860002, SB706504, SB681323, CHF-6297, RWJ-67657, Org48762-0, ML3403, JX-401 , EO-1428, DBM 1285, AMG-548, AL-8697, PD-169316, PF-03715455, PH-797804, Theron In one embodiment, the inhibitor is selected from the group consisting of sertib, sorafenib, and dilmapimod. Inhibitors of the proinflammatory immune response mediated by quinazolinones, pyrimido-pyrimidones, Contains pyrido-pyrimidone, pyrazole, quinolinone and / or naphthyridinone core structures In one embodiment, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is This is Rosmapimod.

[0134] In certain embodiments, the p38 MAP kinase inhibitor inhibits at least one p38 MAP kinase, e.g. For example, it binds to the ATP binding site of p38α, p38β, p38γ and / or p38δ MAP kinase. In some embodiments, the p38 MAP kinase inhibitor inhibits at least one p38 MAP kinase, e.g. For example, allosteric inhibitors of p38α, p38β, p38γ and / or p38δ MAP kinases. do.

[0135] In one embodiment, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is p3 In one embodiment, the inhibitor is an upstream effector of p38 MAPK mediated by the p38 MAPK pathway. Inhibitors of the proinflammatory immune response mediated by RIPK1, RIPK2, RIPK3, RIPK4, RAC1, CDC42, and M TK1, TAK1, MEKK1, MEKK2, MEKK3, MEKK4, DLK, MLK2, TAO1, TAO2, TLP2, TPL2, ASK1, In one embodiment, the inhibitor is an inhibitor of MKK3, MKK4 and / or MKK6. Inhibitors of the proinflammatory immune response mediated by p38 MAPK are inhibitors of downstream effectors In one embodiment, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is Inhibitors of MK2, MK3, MNK1, MNK2, MSK1, MSK2, MSK3, RSK, PP2A and / or cPLA2 do.

[0136] In some embodiments, one skilled in the art can identify a proinflammatory immune response mediated by the p38 MAPK pathway. Inhibitors of the enzyme cyclooxygenase (COX)-1 and / or COX- It will be appreciated that the activity and / or expression of the 2 can be modulated (e.g., inhibited). For example, Matsui et al., "Release of prostaglandin E2 and nitric oxide from sp inal microglia is dependent on activation of p38 mitogen-activated protein kinas e,” Anesthesia & Analgesia, 111(2): 554-560 (2010).

[0137] In some embodiments, one of skill in the art may be familiar with the use of certain COX inhibitors (e.g., COX-1 and / or CO X-2 inhibitors) and / or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and / or or anti-inflammatory analgesics) are modulators (e.g., inhibitors) of the p38 MAPK pathway or its components. It will be appreciated that the present invention can act as a "Roidal anti-inflammatory drugs in Parkinson's disease" Experimental Neurology 2 05: 295-312 (2007); Desai et al., “Mechanisms of Phytonutrient Modulation of Cycloox ygenase-2 (COX-2) and Inflammation Related to Cancer” Nutrition and Cancer, 70: 350-375 (2018); Huang et al., “MAPK / ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stomal cells in vitro” Int J Clin Exp Pathol, 6: 2129-2136 (2013); and Di Mari et al., “HETEs enhance IL-1-med iated COX-2 expression via augmentation of message stability in human colonic my Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101 (2007) Thus, in some embodiments, a COX-2 inhibitor or Other anti-inflammatory agents may be p38 MAPK inhibitors as described herein (and and / or may be used as a In this regard, such COX inhibitors or other anti-inflammatory agents may be used in combination with other p 38 It may also be used in combination with a MAPK inhibitor.

[0138] In some embodiments, the COX inhibitor is a non-selective COX-1 and / or COX-2 inhibitor. In some embodiments, the COX inhibitor is a selective COX-1 and / or COX The inhibitor may be a -2 inhibitor.

[0139] In some embodiments, a p38 MAPK pathway inhibitor (i.e., an inhibitor of the p38 MAPK pathway or a component thereof) is Specific COX inhibitors useful as inhibitors of COX-releasing compounds include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), such as steroid inhibitors, steroid agonists ... In some embodiments, the NSAID is, for example, a typical Cyclooxygenase (COX-1) is involved in the production of prostaglandins, which are involved in inflammation. and / or COX-2) enzyme activity, thereby reducing inflammation.

[0140] In some embodiments, the NSAIDs for use as p38 MAPK pathway inhibitors are typically The drug is or includes celecoxib, which is known as a selective COX-2 inhibitor. Chen et al., “Celexocib inhibits the lytic activation of Kaposi's sarcoma-assoc iated herpesvirus through down-regulation of RTA expression by inhibiting the ac tivation of p38 MAPK,” Viruses 7:2268-2287 (2015); and Fan et al., “Celecoxib attenuation uates systemic lipopolysaccharide-induced brain inflammation and white matter in Jury in the neonatal rats,” Neuroscience 240: 27-38 (2013).

[0141] In some embodiments, the NSAID for use as a p38 MAPK pathway inhibitor is ketoconazole. Ketorolac is or contains ketorolac, e.g., by competitive blockade of the COX enzyme. It is known to inhibit prostaglandin synthesis. Lorac can reduce the expression of IL-6. See, for example, Singh et al., "A prospective study tudy to assess the levels of interleukin-6 following administration of diclofena c, ketorolac and tramadol after surgical removal of lower third molars” J. Maxil lofac Oral Surg. 14: 219-225 (2015). Those skilled in the art will also recognize that ketorolac is a known It will be appreciated that it may act as a non-selective COX inhibitor with inflammatory properties. Without wishing to be bound by any particular theory, in some embodiments, ketorolac may be considered to have greater selectivity for inhibiting COX-1 over COX-2. (See Hersh and Dionne, "Nonopioid analgesics" in Pharmacology and Therapeutics f See Oral Dentisty (7th ed.), Dowd et al., Elsevier Inc. 2017. Ketorolac is used for short-term pain relief. Traditionally used for pain management and therefore typically for longer than 5 days In some embodiments, ketoconazole for use in the present disclosure is not prescribed. RAK inhibits or reduces the immunosuppressive inflammation induced by tumor resection surgery. For example, at least 5 days or longer, e.g., at least 6 days, 7 days, at least 8 days, at least 9 days, at least 10 days, or longer Over time, the biomaterial is released (e.g., as described herein). Trolac may be administered as a racemic mixture or as individual enantiomers, e.g., S- It may also be administered as an enantiomer.

[0142] Other examples of NSAIDs that are useful according to the present disclosure include, but are not limited to, the following: (i) Salicylates (e.g., acetylsalicylic acid, diflunisal, salicyl acids and other salicylates, and / or salsalates; (ii) propionic acid derivatives (e.g. For example, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprazine, lorphen, dexketoprofen, flurbiprofen, oxaprozin, and / or (iii) acetic acid derivatives (e.g., indomethacin, tolmetin, sulinda , etodolac, ketorolac, diclofenac, aceclofenac, and / or nab (iv) enolic acid (oxicam) derivatives (e.g., piroxicam, metron); Roxicam, tenoxicam, droxicam, lornoxicam, isoxicam, and / or or phenylbutazone; (v) anthranilic acid derivatives or fenamates (e.g., mefenamide, (vi) selective COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, and / or firocoxib; (vii) sulfonamides. (viii) others (e.g., clonixin, licofelon [e.g. , which acts by inhibiting lipoxygenase (LOX) and COX], and / or H-HA harpagide, and combinations thereof.

[0143] As will be appreciated by one of skill in the art, in some embodiments, e.g., in FIG. Bikkavilli et al., "p38 mitogen-activated protein kinase regulates canonic al Wnt-β-catenin signaling by inactivation of GSK3β” Journal of Cell Science, As described in J. Med. 121: 3598-3607 (2008), p38 MAPK inhibitors inhibit the Wnt-β-catenin The pathway or its components can be modulated (e.g., inhibited). In some embodiments, the inhibitor of a proinflammatory immune response mediated by the p38 MAPK pathway is a Wnt In some embodiments, the p38 MAPK pathway is an inhibitor of the p38 MAPK pathway. Inhibitors of the proinflammatory immune response mediated by GSK3β may or may not be GSK3β inhibitors. In some embodiments, the p38 MAPK pathway mediated proinflammatory immunity may include The inhibitor of immune response may be or include a β-catenin inhibitor.

[0144] Those skilled in the art will also appreciate that certain Wnt / β-catenin pathway inhibitors inhibit the p38 MAPK pathway or its components. It will be appreciated that the present invention may act as a modulator (e.g., inhibitor) of the agonist activity (e.g., Andre et al. , “Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation”Devel opment 142: 1516-1527 (2015); and Ma et al., "Crosstalk between Wnt / β-catenin and NF-κB signaling pathway during inflammation” Front Immunol. 7: 378 (2016). Thus, in some embodiments, the Wnt / β-catenin pathway is The pathway inhibitor may be a p38 MAPK inhibitor as described herein (and / or may be used as such); alternatively, or in addition, in some embodiments, Such Wnt / β-catenin pathway inhibitors include other p38 MAPK inhibitors as described herein. It may also be used in combination with an inhibitor.

[0145] Activators of the innate immune response The drug delivery compositions and devices may include activators of the innate immune response. The delivery compositions and devices may include more than one activator of the innate immune response. A major function of the innate immune response is the production of specialized chemical mediators (e.g., cytokines). Recruiting immune cells to the site of infection through production of bacterial factors; identifying bacteria and activating cells; Activation of the complement cascade, which activates the complement complex and promotes clearance of antibody complexes or dead cells. Activation; the elimination of foreign substances present in organs, tissues, blood, and lymph by specialized white blood cells. activation of the adaptive immune system through a process known as antigen presentation; and Acting as a physical and chemical barrier to infectious agents (e.g., epithelial surfaces, gastric Typically, leukocytes are white blood cells that carry out the functions of the innate immune system. These cells include natural killer cells, mast cells, and eosinophils. These cells include leukocytes, basophils, macrophages, neutrophils and dendritic cells. These cells are involved in the prevention and control of infection. It functions within the immune system by identifying and eliminating potential pathogens.

[0146] In some embodiments, the activator of the innate immune response is a ligand of a pattern recognition receptor (PRR). It is.

[0147] In some embodiments, the activator of the innate immune response is an agonist of a pattern recognition receptor (PRR). It is a strike.

[0148] 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 a recombinant interferon. do.

[0149] In some embodiments, the activator of the innate immune response activates and / or expands NK cells. In one embodiment, an "effective inducer" is an effective inducer of NK cell activation. and / or refers to activators of the innate immune response that directly induce proliferation.

[0150] In some embodiments, the activator of the innate immune response is an activator of dendritic cells. In one embodiment, an "effective inducer" is an effective inducer of dendritic cell activation. Refers to activators of the innate immune response that directly induce activation and / or maturation.

[0151] In one embodiment, the activator of the innate immune response is type I interferon activation by dendritic cells. In one embodiment, an "effective inducer" is an effective inducer of the inflammatory process by dendritic cells. It refers to an activator of the natural immune response that directly induces type I interferon.

[0152] In some embodiments, the activator of the innate immune response is a small molecule or a biologic. In some embodiments, the activator of the innate immune response is a small molecule. Activators of the immune response are biopharmaceuticals.

[0153] In some embodiments, the activator of the innate immune response is stimulator of interferon genes (S TING) agonists, cytosolic DNA sensor (CDS) agonists, Toll-like receptor (TLR) agonists C-type lectin receptor (CLR) agonist, NOD-like receptor (NLR) agonist, RIG-I-like receptor agonist These include RLR agonists, or inflammasome inducers.

[0154] In some embodiments, the activator of the innate immune response is stimulator of interferon genes (S TING agonists, Toll-like receptor (TLR) agonists, or NOD-like receptor (NLR) agonists In some embodiments, the activator of the innate immune response is an interferon gene stimulator. In one embodiment, the agent is a STING agonist or a Toll-like receptor (TLR) agonist. Activators of the innate immune response include stimulator of interferon genes (STING) agonists, TLR7 agonist, or TLR8 agonist.

[0155] 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, lipog lycan, lipopolysaccharide (LPS), lipoteichoic acid, peptidoglycan (PGN), synthetic lipoprotein, Poly(A:U), poly(I:C), monophosphoryl lipid A (MPLA), GSK1795091, g100, sd-101, mgn 1703, cmp-001, Flagellin (FLA), polyU, poly(dT), Guardiquimod, Imiquimod (R837 ), base analogues, adenine analogues, guanosine analogues, purine derivatives, benoazepine analogues Body, imidazoquinoline, thiazoquinoline, loxoribine, resiquimod (R848), ductorhizobium Sumanirole, N1-glycinyl [4-((6-amino-2-(butylamino)-8-hydroxy-9H-propenyl] Phosphorin-9-yl)methyl)benzoyl]spermine (CL307), CL264, CL097, CL075, CL347, CL4 01, CL413, CL419, CL531, CL553, CL572, MEDI9197, MEDI5083, Hypoxanthine, TL8-5 06, PF-4878691, Isatoribine, SM-324405, SM-324406, AZ12441970, AZ12443988, CpG Oligonucleotides, bacterial DNA, beta-glucan, beta from fungal and bacterial cell walls Glucan, 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, Anhydrous calcium pyrophosphate, silicon dioxide, MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), Santenone analogues (e.g., DMXAA; vadimezan), TREX1 inhibitors, cyclic dinucleotides, LH C165, GSK-2245035, RG7854, GS-9620, GS-9688, EMD1201081, PF-3512676, BO-112, RGT -100, MK-1454, SB-11285, NKTR-262, CDX-301, 2'3'-c-di-GMP, cAIMP, cAIM(PS)2(Rp / Sp), their derivatives, or pharma- ceutically acceptable salts thereof.

[0156] In some embodiments, the activator of the innate immune response is a fluorine-containing analog of any of the above activators. In one embodiment, the activator of the innate immune response is a difluorinated cAIMP (c-(2 In one embodiment, the activator of the innate immune response is difluorinated amidophenyl phosphate (FdAMP-2'FdIMP). In one embodiment, the activator of the innate immune response is cAIM(PS)2(Rp / Sp). The O-methylated derivatives of either factor

[0157] 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, Siquimod, CpG oligonucleotides, polyinosinic-polycytidylic acid, LHC165, GSK-22450 35, RG7854, GS-9620, GS-9688, EMD1201081, PF-3512676, BO-112, RGT-100, MK-1454, SB-11285, NKTR-262, CDX-301, 2'3'-c-di-GMP, cAIMP, cAIM(PS)2(Rp / Sp), or is a pharma- ceutically acceptable salt of

[0158] 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, 2' Fluorinated derivatives of 3'-c-di-GMP, cAIMP, cAIM(PS)2(Rp / Sp), or pharma- ceutically acceptable derivatives thereof It is a useful salt.

[0159] 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 O- A methylated derivative, or a pharma- ceutically acceptable salt thereof.

[0160] 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 humans, activators of the innate immune response include 2'3'-cGAMP, 2'3'-c-di-AM (PS)2 (Rp,Rp), In one embodiment, the activator of the innate immune response is 2'3'-c- Di-AM(PS)2(Rp,Rp) or resiquimod. In one embodiment, activation of the innate immune response The agent is cAIMP or a fluorinated derivative thereof. In one embodiment, the agent inhibits the activation of the innate immune response. The activator is cAIMP difluoride.

[0161] In some embodiments, the activator of the innate immune response is 2'3'-cGAMP, or a pharmaceutical equivalent thereof. In particular, 2'3'-cGAMP (cyclic [G(2',5')pA(3',5')p]) is an endogenous sec Functions as a STING end messenger to induce STING-dependent type I interferon responses It has been reported that 2'3'-cGAMP also promotes the production of antigen-specific antibodies and It has been shown to be an effective adjuvant for boosting immune and T cell responses. P serves an antiviral function in the cells in which it is produced, but it also spreads by passive diffusion. They can cross cell membranes and exert their effects on nearby cells. [ka]

[0162] In some embodiments, the activator of the innate immune response is 2'3'-c-di-AM(PS)2(Rp,Rp), and its pharma- ceutically acceptable salts. 2'3'-c-di-AM(PS)2(Rp,Rp) is a 3'3'-cyclic adenine It is the Rp,Rp-isomer of the 2'3' bisphosphorothioate analog of c-di-AMP. It is also a STING agonist. [ka]

[0163] In some embodiments, the activator of the innate immune response is cAIMP, a difluorinated derivative thereof, Difluorinated bisphosphorothioate derivative (cAIM(PS)2(Rp / Sp)), or its pharma- ceutically acceptable derivative cAIMP and its derivatives are also STING agonists. [ka]

[0164] In one embodiment, the activator of the innate immune response is a STING agonist, wherein The TING agonist is a cyclic dinucleotide. In some embodiments, the cyclic dinucleotide The present invention relates to a method for producing a cellular telephone using a method disclosed in U.S. patent application USSN 15 / 234,182, filed on August 11, 2016. and the entire contents of which are incorporated herein by reference. In some embodiments, the cyclic dinucleotide is a cyclic dinucleotide as described in U.S. Pat. Any of the cyclic dinucleotides disclosed in US Ser. No. 14 / 362,441, The entire contents of this application are incorporated herein by reference.

[0165] In some embodiments, the activator of the innate immune response is MK-1454.

[0166] In some embodiments, the activator of the innate immune response is a cytosolic DNA sensor (CDS) agonist. In some embodiments, the CDS agonist is a cyclic GMP-AMP synthase (cGAS) agonist. It is a strike.

[0167] In some embodiments, the activator of the innate immune response is a Any STING agonist or cGAS agonist disclosed in patent application USSN 14 / 653,586 No. 6,399,413, the entire contents of which are incorporated herein by reference. In the present invention, an activator of the innate immune response is disclosed in U.S. patent application Ser. No. 2014 / 0233634, filed on May 2, 2014. Any of the STING agonists or cGAS agonists disclosed in US Pat. No. 5,997,333, issued Dec. 14, 268,967, the disclosure of which is incorporated herein by reference. The entire contents of that application are incorporated herein by reference. The activator of immune response is described in U.S. patent application USSN 14 / 787,611, filed April 29, 2014. Any STING agonist or cGAS agonist disclosed in any of the above applications, The present invention relates to a method for the prevention and treatment of cancer, the disclosure of which is incorporated herein by reference. The activating agent is disclosed in U.S. patent application USSN 14 / 908,019, filed July 31, 2014. Any STING agonist or cGAS agonist that is capable of inhibiting or inhibiting the proliferation and / or proliferation of a cancer cell, the entire contents of which are incorporated herein by reference. This document is incorporated by reference.

[0168] In some embodiments, the activator of the innate immune response is disclosed in U.S. Pat. No. 6,313,943, filed Jun. 14, 2011. Any STING agonist disclosed in USSN 13 / 057,662, The entire contents of which are incorporated herein by reference. In one embodiment, the innate immune response The activator is disclosed in U.S. patent application USSN 14 / 106,687, filed December 13, 2013. Any STING agonist disclosed in any of the above applications, the entire contents of which are hereby incorporated by reference. In one embodiment, the activator of the innate immune response is Any of the STING agonists disclosed in U.S. patent application USSN 15 / 035,432, filed on The entire contents of which are incorporated herein by reference. In this regard, the activator of the innate immune response is disclosed in International Patent Application PCT / US201 and any STING agonist disclosed in US Pat. No. 7,013,049, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is Any ST disclosed in International Patent Application PCT / US2017 / 013066 filed on January 11, 2017 and ING agonists, 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 application PCT / US2014 / 038525, The contents of which are incorporated herein by reference. In one embodiment, the activation of the innate immune response is The activation factor is disclosed in U.S. patent application USSN 13 / 912,960, filed June 7, 2013. and any STING agonist that is capable of inhibiting or inhibiting the agonist receptor ... In one embodiment, the activator of the innate immune response is any of the STING agonists disclosed in international patent application PCT / IB2016 / 057265, No. 60 / 639,933, filed on Dec. 23, 2006, the entire contents of which are incorporated herein by reference.

[0169] In one embodiment, the activator of the innate immune response is MurNAc-L-Ala-γ-D-Glu-mDAP (M-Tri M-TriDAP is a medicament for the treatment of gram-negative bacteria. M-TriDAP is a peptidoglycan (PGN) degradation product found in the intracellular serine / erythrocyte. It is recognized by the sensor NOD1 (CARD4) and, to a lesser extent, NOD2 (CARD15). Recognition of M-TriDAP by NOD1 / NOD2 is mediated by the serine / threonine RIP2 (RICK, CARDIAK) kinase This induces a signaling cascade that includes NF-κB, which interacts with IKK and leads to NF-κB activation. and the production of inflammatory cytokines such as TNF-α and IL-6. It induces -κB activation at a level similar to that of Tri-DAP.

[0170] In some embodiments, the activator of the innate immune response is a TLR7 agonist. In one embodiment, the activator of the innate immune response is a TLR8 agonist. Activators of the immune response are TLR7 and TLR8 agonists.

[0171] In some embodiments, the activator of the innate immune response is an immune response modifier (IRM).

[0172] In some embodiments, the activator of the innate immune response is Any IRM disclosed in USSN 08 / 620,779, the entire contents of which are incorporated herein by reference. In one embodiment, an activator of the innate immune response is disclosed in U.S. patent application USSN 08 / 957,192, filed October 24, 1997. No. 6,399,413, filed on Oct. 23, 2003, the entire contents of which are incorporated herein by reference. In embodiments, the activator of the innate immune response is described in U.S. patent application Ser. No. 10 / 299,333, filed Mar. 20, 2000. Any IRM disclosed in .SSN 09 / 528,620, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is Any of the I 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 this regard, activators of the innate immune response are disclosed in U.S. patent application Ser. No. 09 / 02 / 1994. Any IRM disclosed in US Pat. No. 8 / 303,216, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is any of the IRMs disclosed in U.S. patent application Ser. No. 09 / 210,114, filed on The entire contents of this application are incorporated herein by reference. Activators of immune responses are disclosed in U.S. patent application Ser. No. 09 / 361,544, filed July 27, 1999. No. 6,399,623, the entire contents of which are incorporated herein by reference. In one embodiment, the activator of the innate immune response is Any IRM disclosed in international patent application PCT / US2004 / 032480, filed on October 1, 2004, The entire contents of which are incorporated herein by reference.

[0173] 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 pharma- ceutically acceptable salt thereof. CL307 is a highly potent TLR7 agonist. Titration experiments demonstrated that CL307 potently inhibits NF-κB activation even at concentrations as low as 20 nM (10 ng / ml). It has been shown to induce activation. [ka]

[0174] In one embodiment, the activator of the innate immune response is CL264, or a pharma- ceutically acceptable derivative thereof. CL264 is a potent salt that inhibits NF-κB activation and IFN-α synthesis in TLR7-expressing cells. CL264 is a TLR7-specific ligand that, even at high concentrations (>10 μg / ml), does not inhibit T In HEK293 cells transfected with TLR7, CL264 stimulates TLR8 more effectively than imiquimod. It activates NF-κB at a concentration of 0.1 μM, which is 5 to 10 times lower than that of NF-κB. [ka]

[0175] In one embodiment, the activator of the innate immune response is loxoribine, or a pharmaceutical equivalent thereof. Loxoribine is a guanosine derivative at the N7 and C8 positions. This nucleoside is a highly potent stimulator of the immune system. activates the innate immune system through TLR7, and this activation requires endosomal maturation. Loxoribine recognition is restricted to TLR7. [ka]

[0176] In some embodiments, the activator of the innate immune response is hypoxanthine, or a pharmaceutical equivalent thereof. Hypoxanthine is a naturally occurring purine derivative. [ka]

[0177] In one embodiment, the activator of the innate immune response is TL8-506, or a pharmacopoeitic derivative thereof. TL8-506 is a venom analogue of the Toll-like receptor 8 (TLR8) agonist VTX-2337. TL8-506 is a benzoazepine compound that activates TLR8 more potently than R848 and CL075. TL8-506 induces NF-κB activation in TLR8-transfected HEK293 cells. It is approximately 50x and 25x more potent than R848 and CL075, respectively, in inhibiting TL8-506 is a selective agonist of TLR8. [ka]

[0178] In some embodiments, the activator of the innate immune response is PF-4878691, isatoribine, SM-324 405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854, GS-9620, LHC165, NK TR-262, GS-9688, VTX-2337, or a pharma- ceutically acceptable salt thereof. Satrivin, SM-324405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854 and and GS-9620 are TLR7 agonists. LHC165 and NKTR-262 are TLR7 and TLR8 agonists. GS-9688 and VTX-2337 are TLR8 agonists.

[0179] In some embodiments, the activator of the innate immune response is dactolisib, imiquimod, gardene. Imidazolidinone, including iquimod, resiquimod, smanirole, and pharma- ceutically acceptable salts thereof It is a quinoline derivative.

[0180] In one embodiment, the activator of the innate immune response is CL097, or a pharma- ceutically acceptable derivative thereof. CL097 is a highly water soluble derivative of resiquimod (≧20 mg / ml). , a ligand for TLR7 and TLR8. It was found to be effective in TLR7-transfected HEK293 cells. In TLR8-transfected HEK293 cells, the concentration was 4 μM (1 μg / ml). and induces NF-κB activation. [ka]

[0181] In one embodiment, the activator of the innate immune response is CL075, or a pharma- ceutically acceptable derivative thereof. CL075 (3M002) is a thiazoloquinoline salt that stimulates TLR8 in human peripheral blood mononuclear cells. It is a derivative of thrombin. It activates NF-κB and preferentially promotes the production of TNF-α and IL-12. CL075 also induces the secretion of IFN-α through TLR7, but this is at a lower level. In HEK293 cells transfected with TLR8, the level of ml) induced NF-κB activation and upregulated NF-κB in TLR7-transfected HEK293 cells. Approximately 10-fold more CL075 is required for activation. [ka]

[0182] In one embodiment, the activator of the innate immune response is MEDI9197, or a pharmacopoeitic equivalent thereof. MEDI9197 (3M052) is an injectable TLR7 and TLR8 agonist. It is an imidazoquinoline immune response modifier (IRM) that has a C18 lipid moiety and is It is designed to spread slowly from the site. [ka]

[0183] In one embodiment, the activator of the innate immune response is resiquimod (R848), or a pharmaceutical In particular, resiquimod is an agent that acts as an immune response modifier. It has antiviral and antitumor activity. It is effective in treating skin lesions (herpes simplex virus) and cutaneous T-cell lymphomas) as a topical gel and It is also used as an adjuvant to increase the effectiveness of vaccines. It has several mechanisms of action and binds to Toll-like receptors 7 (TLR7) and 8 (TLR8). It is an agonist for both and an upregulator of opioid growth factor receptors. [ka]

[0184] 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 combination thereof. It is a pharma-ceutically acceptable salt.

[0185] In some embodiments, the activator of the innate immune response is GS-9620. In one embodiment, the activator of the innate immune response is PF-4878691. In one embodiment, the activator of the innate immune response is LHC1. It is 65.

[0186] In some embodiments, the activator of the innate immune response is an inflammasome inducer. Inflammasomes are important for host defense against infection and endogenous danger signals. They are multimeric protein complexes that mediate the production of proinflammatory cytokines, interleukin-1 (IL-1) and IL-2. It promotes the secretion of interleukin (IL)-1β and IL-18, resulting in a rapid, proinflammatory process called pyroptosis. It causes a virulent form of cell death.

[0187] In some embodiments, the activator of the innate immune response is NLRP3, AIM2, NLRC4 or NLRP1. It is an inducer of the inflammasome.

[0188] In one embodiment, the activator of the innate immune response is [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is 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 Habu R is a ethyl group. 2 is -CO2CH3.

[0189] In some embodiments, the activator of the innate immune response is an imidazoquinoline; Midazonaphthyridine;Pyrazolopyridine;Aryl-substituted imidazoquinolines;1-Alkoxy Compounds containing 1H-imidazo ring system;Oxazolo[4,5-c]-quinolin-4-amine;Thiazolo[4,5 -c]-Quinoline-4-amine;Selenazolo[4,5-c]-quinolin-4-amine;Imidazonaphthyridine; ;Imidazoquinolinamines;1-Substituted, 2-Substituted 1H-imidazo[4,5-C]quinolin-4-amines;Condensed Cycloalkylimidazopyridines;1H-Imidazo[4,5-c]quinolin-4-amines;1-Substituted 1H-iso Imidazo-[4,5-c]quinolin-4-amine;Imidazo-[4,5-C]quinolin-4-amine;2-Ethyl 1H- Imidazo[4,5-c]quinolin-4-amine; Olefinic 1H-imidazo[4,5-c]quinolin-4-amine 6,7-Dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinoline Lysine-2-carboxylic acid; Pyridoquinoxaline-6-carboxylic acid; 6,7-Dihydro-8-(imidazo (1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid;Substituted naphthyl [ij]quinolizine;Substituted pyridoquinoxaline-6-carboxylic acids;7-Hydroxy-benzo[ij]quino Lysine-2-carboxylic acid derivatives;Substituted benzo[ij]quinolizine-2-carboxylic acids;7-Hydroxy- Benzo[ij]quinolizine-2-carboxylic acid;Substituted pyrido[1,2,3,-de]-1,4-benzoxazines;Theta N-methylenemalonic acid ester of trahydroquinoline, or a pharma- ceutically acceptable salt thereof.

[0190] In some embodiments, the activator of the innate immune response is disclosed in U.S. Pat. No. 5,393,436, filed Aug. 31, 2016. Any of the NLRP3 agonists disclosed in USSN 15 / 253,215, the entire contents of which are incorporated herein by reference.

[0191] In some embodiments, the activator of the innate immune response is a RORy agonist. The inhibitor can bind to and activate RORγ, e.g., in a patient or in a population of cells. The agent promotes the activity of RORγ by increasing the expression of RORγ. The RORy agonist may be, for example, a small organic molecule, a polypeptide, or a nucleic acid. Such RORγ agonists have been described in the literature, e.g., in U.S. Patent Application USSN 14 / 398,774; G et al., Mol. Pharmacol. (2012) 82, 583-590; and Wang et al., ACS Chem. Biol. (2010), vol. 5, pp. 1029-1034, each of which is incorporated herein by reference. This document is incorporated by reference in its entirety.

[0192] In some embodiments, the activator of the innate immune response is a RORy agonist, e.g., [ka] and pharma-ceutically acceptable salts thereof.

[0193] In some embodiments, the activator of the innate immune response is a compound according to the invention as described in U.S. Patent Application USSN 14 / 398,774. General or specific compounds described in the formula (I): [ka] or a pharma- ceutically acceptable salt thereof; A is an aryl, aralkyl, heteroaryl, cycloalkyl, or heterocyclo. alkyl; each of which is optionally, 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 Alki Ren-C 1~4 Alkoxy, -C 1~4 Alkylene-N(R4 )(R 5 ), -C 1~4 Alkylene-CO 2R 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) p C 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 ) 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(R 6 )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 )(R7 )]-[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 the radical of formula I the bond to the sulfonamide ring nitrogen atom in Y is -N(R 2 )(R 3 ) or -O-aralkyl, wherein the aralkyl is any Optionally, independently, 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 Alki Le, -C(O)-C 1~6 Alkyl, -C(O)N(R 4 )(R 5 ), -S(O) p C 1~6 Alkyl, -S O2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1~6 alkyl) substituted with 1, 2 or 3 substituents selected from the group consisting of aryl, ... and aryl; R 1 is independently, for each occurrence, hydrogen, halogen, or C 1~6 Represents alkyl death; R 2 is -C(O)-aryl, -C(O)-aralkyl, -C(O)-[C(R 6 )2] m -Cycloa Rukyru, -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 optionally , independently, halogen, hydroxyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C1 ~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, -SO 2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1~6 alkyl) , substituted by 2 or 3 substituents; R 3 is hydrogen or C 1~6 is alkyl; R 4 and R 5 are each independently, for each occurrence, hydrogen or C 1~6 Alki or R 4 and R 5 together with the nitrogen atom to which they are attached, Forming a 3- to 7-membered heterocyclic ring; R 6 is independently, for each occurrence, hydrogen or C 1~6 represents alkyl; R 7is hydrogen, hydroxyl, C 1~6 Hydroxyalkyl, C 1~6 Alkyl, C 1~6 Ha Roalkyl, -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 Hydroxy Alkylene-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, too Or C 1~6 Alkylene-N(R 4 )(C(O)N(R 4 )(R 5 ) or R 7 Ha, Hete Cycloalkyl or C 1~4 alkylene-heterocycloalkyl, The tetracycloalkyl is optionally, independently, oxo, halogen, hydroxyl, C 1~6 a Rukill, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, and C 1~6 substituted with 1, 2 or 3 substituents selected from the group consisting of haloalkoxy; ; R8 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 1~6 Alkylene-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 each independently represent 0, 1, or 2 at each occurrence.

[0194] In some embodiments, the activator of the innate immune response is a Any of the RORγ agonists disclosed in USSN 14 / 398,774, The entire contents of this application are incorporated herein by reference. The activator of the answer is disclosed in U.S. patent application USSN 15 / 120,798, filed August 23, 2016. and any RORy agonist disclosed in US Pat. No. 6,399,343, the entire contents of which are incorporated herein by reference. Incorporated by reference.

[0195] In some embodiments, the activator of the innate immune response is a RIG-I-like receptor (RLR) agonist. In one embodiment, the activator of the innate immune response is RGT-100.

[0196] Cytokines The drug delivery compositions and devices may include cytokines. A broad category of small proteins (approximately 5-20 kDa) that are important in cellular signaling Their release has effects on the behavior of cells surrounding them. In autocrine, paracrine, and endocrine signaling They are involved in immune regulation. As cytokines, chemokines, interferons, , interleukins, lymphokines, and tumor necrosis factors. It is involved in immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endocrine It is produced by a wide variety of cells, including epithelial cells, fibroblasts, and a variety of stromal cells. Cytokines act through receptors and play an important role in the immune system. Regulating the balance between cellular and cell-based immune responses, and regulating the maturation of specific cell populations. Some cytokines regulate other cytokines in complex ways. Cytokines play an important role in the host response to infection, immunity, and immune function. It is important in immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

[0197] Furthermore, the immune stimulatory functions of many cytokines and chemokines are fully exploited. To enable this, the following aspects related to the method of delivery, dosing and scheduling, and toxicity are discussed: It is now known in the art that the problem of

[0198] In some embodiments, the cytokine is IL-1, IL-1α, IL-1β, IL-2, IL-2 superkinase, IL-2 phospho ... IL-6, IL-7, IL-9, AM0010, IL-12, IL-15, IL-15 superagonist, ALT-803, NI Z985, IL-16, IL-18, IL-21, IL-21 Superagonist, Denenikokin, IL-21 Super Agonist antibodies, IFN-α, IFN-β, IFN-γ, TNF-α, GM-CSF, cytokine fusions, RG74 61, RG7813, M9241, NKTR-214, NKTR-255, BMS-982470, BG-00001, Flt3L, or CDX-30 The answer is 1.

[0199] In some embodiments, the cytokine is ALT-803, NIZ985, denenikokine, RG7461, RG781 3, M9241, IFN-α, IFN-β, or IFN-γ.

[0200] In some embodiments, the cytokine is an IL-15 superagonist or IL-21. In some embodiments, the cytokine is an IL-15 superagonist.

[0201] In some embodiments, the cytokine is IL-15 superagonist, IL-21, IFN-α, IFN- β, IFN-γ, CCL4, CCL5, CXCL9, or CXCL10. The antagonist is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ. In this case, the cytokine is an IL-15 superagonist or IFN-α.

[0202] IL-15 (interleukin 15) is a cytokine structurally similar to IL-2 and is a viral IL-15 is secreted by mononuclear phagocytes following infection with the virulence It induces the proliferation of natural killer cells, which kill cells infected with R. purpura. The combination of IL-15 and soluble IL-15Rα is called IL-15 superagonist (IL-15sa). IL-15sa produces a complex that inhibits NK cell proliferation and secretion, which has greater biological activity than IL-15 alone. and its ability to selectively expand memory CD8+ T (mCD8+ T) lymphocytes provides antitumor and and antiviral agents.

[0203] In one embodiment, the cytokine is a compound known as ALT-803, an IL-15 superagonist. ALT-803 is a well-known IL-15 superagonist. It induces the proliferation of memory CD8+ T cells, Upregulation of receptors involved in innate immunity, secretion of interferon-γ, and stimulation of antigenic responses It is believed that ALT-80 acquires the ability to kill malignant cells in the absence of 3 promotes the proliferation and activation of memory CD8+ T cells, while transforming them into potent anti-cancer agents. ALT-803 inhibits IL-15 mutants and converts them into active innate immune effector cells. A fusion protein of the antibody and the IL-15Rα / Fc complex has recently been used as a direct immunomodulatory agent. ALT-803 has demonstrated a >25-fold increase in biological activity compared to IL-15. show.

[0204] In one embodiment, the cytokine is NIZ985 (hetIL-15). The administration of CD8+ / T cells promoted increased tumor infiltration and retention of CD8+ T cells, including tumor-specific T cells. These results suggest that tumor-resistant CD8+ T cells may play a key role in increasing the reg ratio of tumor-resistant CD8+ T cells to effector cells. These cells are characterized by increased proliferation (Ki67+) and high cytotoxicity (Granzyme B+). In the absence of hetIL-15, a smaller population of tumor-infiltrating T cells expresses high levels of hetIL-15. These results suggest that PD-1, a marker of cell exhaustion, potentially limits their anti-cancer efficacy. Provision of hetIL-15 resulted in a marked decrease in lymphocyte expression of PD-1, leading to an exhaustion phenotype. One potential mechanism for this is the role of IFN-γ in cancer cell proliferation. A tumor immunotherapy approach to promote the generation of antitumor responses by favoring vectors The authors support the use of hetIL-15 in therapeutic approaches.

[0205] In some embodiments, the cytokine is interferon alpha (IFN-α). Proteins are produced by white blood cells. They are primarily involved in the innate immune response to viral infections. be involved in the answer.

[0206] In some embodiments, the cytokine is interferon beta (IFN-β). IFN-β is It contains proteins produced by fibroblasts and is involved in the innate immune response. IFN-β is a Stimulates both phage and NK cells to induce antiviral responses and also acts on tumors. In mice, IFN-β inhibits immune cells from producing growth factors. It inhibits the growth of tumors, thereby slowing tumor growth and encouraging other cells to produce blood vessels that produce growth factors. This inhibits tumor angiogenesis and prevents tumors from connecting to the vasculature. To interfere.

[0207] In some embodiments, the cytokine is interferon gamma (IFN-γ). Type II interferons are cytokines that play a key role in innate and adaptive immunity. IFN-γ is an important activator of macrophages and a class II major histocompatibility complex (MHC). IFN-γ is an inducer of the expression of the IFN-γ molecule. In vitro studies of IFN-γ in cancer cells have been extensive. The result is either growth inhibition or, generally, apoptosis-induced, but sometimes autosomal recessive, The antiproliferative activity of IFN-γ leads to apoptosis-induced cell death. Clinical administration has led to improved survival rates for patients with ovarian, bladder and melanoma cancers. .

[0208] In some embodiments, the cytokine is a chemokine. Chemokines are small cytokines that act on the Chemokines are a family of chemokines whose main role is to act as chemoattractants that guide cell migration. Several chemokines act as immunosuppressants during the process of immune surveillance. It regulates cells of the immune system, for example by directing lymphocytes to lymph nodes and Screening for invading pathogens by interacting with existing antigen-presenting cells These are known as homeostatic chemokines and their sources They are produced and secreted without the need for cell stimulation. They may play a role in the development of new blood vessels, promote angiogenesis (the growth of new blood vessels), or They guide cells to tissues where they provide specific signals important for cell maturation. The bacteria are inflammatory and fight off bacteria, viruses and other agents that cause damage to the body, such as those that cause gout. It is released by a variety of cells in response to silica or uric acid crystals that cause inflammation. Their release is often stimulated by proinflammatory cytokines such as interleukin-1. Inflammatory chemokines function primarily as chemoattractants for leukocytes, monocytes, and Neutrophils and other effector cells are recruited from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate immune responses or mediate wound healing. They are released by many different cell types and play a key role in the innate and adaptive immune systems. It serves to guide both cells of the system.

[0209] Furthermore, to allow the immune stimulatory functions of many chemokines to be fully exploited , addressing issues related to method of delivery, dosage and scheduling, and toxicity. It is now known in the art that there must be

[0210] In some embodiments, the chemokine is CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CC L21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, or CX3CL1.

[0211] Activators of the adaptive immune response The drug delivery compositions and devices may include one or more activators of the adaptive immune response. stomach.

[0212] The adaptive immune response system, also known as the acquired immune system, is a subsystem of the overall immune system that and the systemic cells that are specialized in the process of eliminating pathogens or preventing their proliferation. The adaptive immune system is one of two major immune strategies found in vertebrates. The adaptive immune system is responsible for the initial response to specific pathogens. This creates immune memory and leads to an enhanced response to subsequent encounters with the pathogen. This process of adaptive immunity is the basis for vaccination. Like the innate immune system, the adaptive The immune system contains both humoral and cell-mediated immune components. In contrast, the adaptive immune system is highly specific for particular pathogens.

[0213] The adaptive immune system is a system that allows pathogens to evade the innate immune system by generating a threshold level of antigens and then targeting dendritic cells. It is induced when the cell receives a "stranger" or "danger" signal that activates the cell. The primary function of the immune system is to recognize specific antigens in the presence of "self" during the process of antigen presentation. Recognition of "non-self" antigens; tailored to eliminate specific pathogens or pathogen-infected cells and the generation of tailored responses; and the ability of pathogens to induce memory B and T cell proliferation. This includes the development of immune memory that is "remembered" throughout the body.

[0214] Useful for activating the adaptive immune response system (e.g., activating therapeutic anti-tumor immunity) One approach is to block immune checkpoints. In order to minimize collateral tissue damage, it is necessary to maintain self-tolerance and maintain physiological function in peripheral tissues. These proteins are physically integrated into the immune system and are important for regulating the duration and amplitude of host immune responses. This refers to the many inhibitory pathways that are hardwired into tumors. Tumors inhibit certain immune checkpoint pathways. , specifically as a major mechanism of immune tolerance to T cells specific for tumor antigens. Many immune checkpoints are initiated by ligand-receptor interactions. These can be easily blocked by antibodies or by recombinant ligands or receptors. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody can modulate this It was the first of its class of immunotherapy drugs to receive FDA approval (ipilimumab). Blockade of additional immune checkpoint proteins such as gram cell death protein 1 (PD-1) Previous clinical findings from drugs have demonstrated broad and diverse opportunities for enhancing antitumor immunity, Demonstrated potential for producing durable clinical responses

[0215] PD-1 plays a role in downregulating the immune system by inhibiting T cell activation, This in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is Promotes and simultaneously inhibits apoptosis (programmed cell death) in antigen-specific T cells This double mechanism is to reduce apoptosis in regulatory T cells (suppressor T cells) This is achieved through the development of a new class of therapeutic agents that block PD-1, PD-1 inhibitors (e.g., anti-PD-1 inhibitors). D-1 antibodies) activate the immune system to attack tumors, thus preventing some types of In addition, antibodies against programmed death-ligand 1 (PD-L1) are used to treat It provides a similar effect to antibodies targeting PD-1 in activating the immune response. Thus, compositions and devices comprising anti-PD-L1 antibodies have similar therapeutic effects to those comprising anti-PD-1 antibodies. It is expected to provide a therapeutic effect.

[0216] In some embodiments, the activator of the adaptive immune response is a small molecule. The activator of the adaptive immune response is a biologic. In some embodiments, the biological agent is a protein. In some embodiments, the biologic agent is a nucleic acid that encodes a protein. be.

[0217] In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA- 4 antibodies, anti-TIM3 antibody, anti-OX40 antibody, anti-GITR antibody, anti-LAG-3 antibody, anti-CD137 antibody, anti-CD3 antibody, Anti-CD27 antibody, anti-CD28 antibody, anti-CD28H antibody, anti-CD30 antibody, anti-CD39 antibody, anti-CD40 antibody, anti-CD43 Antibodies, anti-CD47 antibodies, anti-CD48 antibodies, anti-CD70 antibodies, anti-CD73 antibodies, anti-CD96 antibodies, anti-CD123 antibodies, Anti-CD155 antibody, anti-CD160 antibody, anti-CD200 antibody, anti-CD244 antibody, anti-ICOS antibody, anti-TNFRSF25 antibody, 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-GAL3 antibody, anti-GAL9 antibody, anti-BTNL2 (Butilov anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H5 antibody, anti-B7-H6 antibody, anti-KIR antibody, anti-LI antibody R antibody, anti-ILT antibody, anti-CEACAM1 antibody, anti-CEACAM5 antibody, anti-CEACAM6 antibody, anti-MICA antibody, anti-MIC B antibody, anti-NKG2D antibody, anti-NKG2A antibody, anti-A2AR antibody, anti-C5aR antibody, anti-TGFβ antibody, anti-TGFβR antibody body, 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-neutropilin 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 It is an antibody.

[0218] 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 an antibody fragment listed above. In one embodiment, the activator of the adaptive immune response is a humanized form of any of the above. In one embodiment, the activator of the immune response is a single chain of any of the antibodies listed in , a multimeric form of any of the antibodies listed above (e.g., a dimeric IgA molecule, a pentavalent IgM molecule). It is.

[0219] In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody, an agonist anti-CD137 antibody, or an agonist anti-PD-1 antibody. an agonist anti-CD40 antibody, an agonist anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, or a combination thereof; In some embodiments, the activator of the adaptive immune response is an anti-PD-1 antibody or an anti-CTLA-1 antibody. In one embodiment, 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 one embodiment, the activator of the adaptive immune response is an agonist anti-CD137 antibody. The activator of the adaptive immune response is an anti-LAG-3 antibody. The activator is an anti-TIM3 antibody.

[0220] In some embodiments, the activator of the adaptive immune response is pembrolizumab, nivolumab, Dilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, abe Lumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, Urelma BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS- 986016, BMS-986178, IMP321, IPH2101, IPH2201, IPH5401, IPH4102, IPH4301, IPH52, IPH53, varlilumab, urocupulumab, monalizumab, MEDI 0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002 , CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, C GEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, C hi Lob 7 / 4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, IMC-CS4, Emakuzu Mab, trastuzumab, pertuzumab, obinutuzumab, cabilalizumab, margetuximab Mab, enoblituzumab, mogamulizumab, panitumumab, carlumab , ramucirumab, bevacizumab, rituximab, cetuximab, fresolimumab, denosumab Mab, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, Tepilizumab, FPA150, PF- 04136309, PF-06747143, AZD5069, GSK3359609, FAZ053, TSR022, MBG453, REGN2810, RE GN3767, MOXR0916, PF-04518600, RO7009789, BMS986156, GWN323, JTX-2011, NKTR-214 , GSK3174998, DS-8273a, NIS793, or BGB-A317.

[0221] In some embodiments, the activator of the adaptive immune response is pembrolizumab, nivolumab, Dilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, REGN 2810, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, or avelumab.

[0222] In some embodiments, the activator of the adaptive immune response is an antibody mimetic or an antibody fusion. .

[0223] In some embodiments, the activator of the adaptive immune response is a bispecific antibody. In this study, the bispecific antibody was RG7802, an antibody that targets carcinoembryonic antigen (CEA) and the CD3 receptor. , RG7828, a bispecific monoclonal antibody that targets CD20 on B cells and CD3 on T cells ), RG7221 (a bispecific monoclonal antibody targeting VEGF and angiopoietin 2), RG7386 (bispecific monoclonal antibody targeting FAP and DR5), ERY974 (CD3 and GlcNAc), MGD012 (a bispecific monoclonal antibody targeting lipican-3), MGD012 (a bispecific monoclonal antibody targeting PD-1 and LAG-3) AMG211 (a bispecific monoclonal antibody targeting CD3 and CEA) T cell engaging antibody (bispecific T cell engager), MEDI573 (a bispecific antibody targeting IGF1 and IGF2) bispecific monoclonal antibody), MEDI565 (bispecific monoclonal antibody targeting CD3 and CEA FS17 (targeting undisclosed targets), FS18 (targeting LAG3 and undisclosed targets), FS20 (a bispecific monoclonal antibody targeting an undisclosed target), FS22 (a bispecific monoclonal antibody targeting an undisclosed target), FS101 (a bispecific monoclonal antibody targeting EGFR and HGF), FS1 17 (undisclosed target), FS118 (bispecific monoclonal antibody targeting LAG3 and PD-L1) RO6958688 (bispecific monoclonal antibody targeting CD3 and CEA), MCLA -128 (a bispecific monoclonal antibody targeting HER2 and HER3), M7824 (PD-L1 and T GFβ-targeting bifunctional fusion protein), MGD009 (a human fusion protein that recognizes both B7-H3 and CD3) These include MGD013 (a bispecific PD-1 and LAG-3 antibody), or MGD014 (a bispecific PD-1 and LAG-3 antibody).

[0224] In certain embodiments, the activator of the adaptive immune response is an antibody-drug conjugate. In the present study, the antibody-drug conjugates are trastuzumab emtansine, inotuzumab ozogamicin, Shin, PF-06647020, PF-06647263, PF-06650808, RG7596, RG7841, RG7882, RG7986, DS- 8201, ABBV-399, glembatumumab vedotin, inotuzumab Zogamicin, MEDI4276, or a pharma- ceutically acceptable salt thereof.

[0225] In some embodiments, the activator of the adaptive immune response is a small molecule. Small molecules include IDO inhibitors, TGFβR inhibitors, BRAF inhibitors, KIT inhibitors, A2aR inhibitors, and Tie2 inhibitors. , arginase inhibitors, iNOS inhibitors, HIF1α inhibitors, STAT3 inhibitors, PGE2 inhibitors, PDE5 inhibitors inhibitors, RON inhibitors, mTOR inhibitors, JAK2 inhibitors, HSP90 inhibitors, PI3K-AKT inhibitors, β-catenin inhibitors inhibitors, GSK3β inhibitors, IAP inhibitors, HDAC inhibitors, DNMT inhibitors, BET inhibitors, COX2 inhibitors , PDGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, proteasome inhibitors, angiogenesis inhibitors , MEK inhibitors, BRAF+MEK inhibitors, pan-RAF inhibitors, EGFR inhibitors, PARP inhibitors, glutaminase inhibitor, WNT inhibitor, FAK inhibitor, ALK inhibitor, CDK4 / 6 inhibitor, or FGFR3 inhibitor. .

[0226] In some embodiments, the small molecule is celecoxib, sunitinib, imatinib, vemurafenib, dabrafenib, bortezomib, vorinostat, pomalidomide, thalidomide, Nalidomide, epacadostat, indoximod, GDC0919, BMS986205, AZD8055, AZD46 35, CPI-444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, Pexida Rutinib, galunisertib, virinapanto, 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, abet Maciclib, palbociclib, glasdegib, enzalutamide, AZD9150, PF-06840003, SRF231, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, or pharmaceutical compositions thereof are commercially acceptable salts.

[0227] Further Therapeutic Agents The drug delivery compositions and devices may include additional therapeutic agents.

[0228] In some embodiments, the drug delivery compositions and devices are directed to effectors of macrophages. Macrophages are immune cells derived from circulating monocytes. Macrophages are macrophages that are present in all tissues and are involved in many stages of pathology. They play a dichotomous role in cancer, where they can promote tumor growth but also Macrophages are the most abundant cell in the body, and may also act as important immune effectors of therapeutic antibodies. These cells express Fcγ receptors, which mediate the proliferation and proliferation of tumor cells through the process of antibody-dependent phagocytosis. Numerous studies have demonstrated that macrophage phagocytosis can treat cancer. This indicates that this is the primary mechanism of action of many approved antibodies. Macromolecular targeting of therapeutic antibodies, including the exploration of new targets and the development of antibodies with enhanced function. A number of approaches to enhance phage responses are under investigation. Responses to antibody therapy have also been shown to be robust against IFN-γ-binding domains, including engineered Fc variants, bispecific antibodies, or antibody-specific antibodies. Macrophages are the effectors of cancer immunotherapy. This shows its success as a

[0229] In one embodiment, the modulator of macrophage effector function is a myeloid-derived supramolecular In one embodiment, the compound is a modulator of suppressor myeloid cells, including macrophages, myeloid leukocytes, and lesser myeloid cells (MDSCs). Modulators of phage effector function may mediate the killing and / or proliferation of macrophages and / or MDSCs. In some embodiments, the macrophages may be damaged, depleted, or enhanced. Modulators of phage effector functions include anti-CD40 antibodies, anti-CD47 antibodies, anti-CSF1 antibodies, and or an anti-CSF1R antibody. In one embodiment, the modification of macrophage effector function The agent is SRF231, Hu5F9-G4, CC-900002, or TTI-621 (an anti-CD47 antibody). In this study, the modulator of macrophage effector function is MCS-110 (anti-CSF1 antibody) In one embodiment, the macrophage effector function modulator is FPA008, RG7155 , IMC-CS4, AMG820, or UCB6352 (anti-CSF1R antibody). The modulator of phage effector function is a small molecule inhibitor of CSF1R. Modulators of macrophage effector function were BLZ945, GW2580, or PLX3397 (CS In one embodiment, the effector function of macrophages is modified by the administration of ribosomal protein 1 (RIP1). The decorating factor is a BTK inhibitor, an ITK inhibitor, a PI3Kγ inhibitor, or a PI3Kδ inhibitor. In the present invention, the modulator of macrophage effector function is a compound comprising a compound selected from the group consisting of a compound having a molecular weight of 1000 to 15000; One or more activators of the adaptive immune response may be replaced.

[0230] In some embodiments, the drug delivery compositions and devices further comprise an oncolytic virus. In some embodiments, the oncolytic virus may include, but is not limited to, Herpes simplex viruses (e.g., HSV1716, OncoVex GM-CSF); adenoviruses (e.g., H1 01, Onyx-15); polioviruses (e.g., PV1 (RIPO)); reoviruses (e.g., leolysin (reolysin); Seneca virus (e.g., NTX-010, SVV-001); Rigvir virus; Marabau measles; Newcastle disease virus; vaccinia; or ECHO virus. do.

[0231] In some embodiments, the drug delivery compositions and devices incorporate radioisotopes (e.g., in the molecule In some embodiments, the nucleic acid may further comprise a radioisotope. are Yttrium-90, Palladium-103, Iodine-125, Cesium-131 ​​or Iridium-19 The answer is 2.

[0232] In some embodiments, the drug delivery compositions and devices may further comprise a chemotherapeutic agent. In certain embodiments, chemotherapeutic agents include, but are not limited to, the following: Antiestrogens (e.g., tamoxifen, raloxifene, and megestrol) , LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., , flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin rfin) (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2 -DMHA), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, rofosfamide, chlorambucil, estramustine, and melphalan), nitroso Urea (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates ( busulfan and treosulfan), triazenes (e.g., dacarbazine and and temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, and oxaliplatin), riplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel, or nanoparticle albumin Amino acid-bound paclitaxel (ABRAXANE), docosahexaenoic acid-bound paclitaxel (DHA- Paclitaxel, Taxoprexin, polyglutamic acid-linked paclitaxel (PG-paclitaxel Cell, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrug (TAP ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (erbB2 recognition paclitaxel bound to peptide EC-1, and glucose-conjugated paclitaxel , e.g., 2-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, paclitaxel equivalents such as cyclosporine, epipodophyllin (e.g., etoposide, phosphate Etoposide, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan , irinotecan, crisnatol and mitomycin C), antimetabolites, DHFR inhibitors (e.g. For example, methotrexate, dichloromethotrexate, trimetrexate and edat Rexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxylase inhibitors urea and deferoxamine), uracil analogues (e.g., 5-fluorouracil (5-FU), Floxuridine, doxifluridine, raltitrexed, tegafur-uracil and capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside and and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), bile tamamine D3 analogues (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin tinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B1, omycin B2 and peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, Doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin bicine, zorubicin and mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+ AT Pase inhibitors (e.g., thapsigargin), oblimersen, gemcitabine, carminomicin leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine , prednisolone, dexamethasone, campathecin, plicamycin, Asparaginase, aminopterin, methopterin, porfiromycin, melphalan , leurosidine, leurosine, chlorambucil, trabectedi , procarbazine, discodermolide, carminomycin, aminopterin, hexa Methylmelamine, and pharma-ceutically acceptable salts thereof.

[0233] In some embodiments, the chemotherapeutic agent is an immunomodulatory chemotherapeutic agent. Chemotherapeutic agents have known immunomodulatory functions (e.g., induction of immunogenic cell death or In some embodiments, the chemotherapeutic agent is a conventional cancer cell inhibitor. not for its inherent use as a cytotoxic chemotherapeutic agent, but rather for its immunotherapeutic properties. In some embodiments, the drug delivery compositions and devices include In some embodiments, the drug delivery composition and the device do not include a chemotherapeutic agent. The chair does not contain a cytotoxic agent.

[0234] In certain embodiments, the drug delivery compositions and devices may further comprise a targeting agent. In certain embodiments, targeting agents include, but are not limited to, IDO inhibitors. Inhibitors, TGFβR inhibitors, arginase inhibitors, iNOS inhibitors, HIF1α inhibitors, STAT3 inhibitors, C SF1R inhibitors, PGE2 inhibitors, PDE5 inhibitors, RON inhibitors, mTOR inhibitors, JAK2 inhibitors, HSP90 inhibitors agents, PI3K-AKT inhibitors, β-catenin inhibitors, GSK3 inhibitors, IAP inhibitors, HDAC inhibitors, DNMT inhibitors inhibitors, BET inhibitors, A2AR inhibitors, BRAF+MEK inhibitors, pan-RAF inhibitors, PI3Kγ inhibitors, PI3Kδ inhibitors inhibitors, EGFR inhibitors, VEGF inhibitors, PARP inhibitors, glutaminase inhibitors, BTK inhibitors, ITK inhibitor, WNT inhibitor, FAK inhibitor, ALK inhibitor, CDK4 / 6 inhibitor, or FGFR3 inhibitor.

[0235] In some embodiments, targeting agents include, but are not limited to, the following: tinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib ( AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRY CEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA (registered trademark), imatinib (Gleevec (registered trademark), CGP57148B, STI-571), lapatinib (TYKER B (registered trademark), TYVERB (registered trademark), lestaurtinib (CEP-701), neratinib (HKI-272), Nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), Nitinib (SUTENT®, SU11248), toceranib (PALLADIA®), (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEP TIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®) , cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab nilotinib (TASIGNA®), sorafenib (NEXAVAR®), and rivaroxaban (Renvoi®). (Trademark), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), Mutuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®) , ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK TM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BI BF 1120 (VARGATEF (registered trademark)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-69015 4, 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-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OS I-027(OSI)), epacadostat, indoximod, GDC0919, BMS986205, AZD4635, CPI- 444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, pexidartinib , Galunisertib, Birinapant, Trametinib, Dabrafenib, Vemurafenib, Co Bimetinib, binimetinib, ensartinib, pazopanib, nintedanib, SYM004, beri Paribu, Olaparib, BGB-290, LXH254, Azacitidine, Decitabine, Guadecitabine, R RX001, CC486, romidepsin, entinostat, vorinostat, panobinostat, Tamoxifen, ibrutinib, idelalisib, capmatinib, selumetinib, abemazi Crib, palbociclib, glasdegib, enzalutamide, AZD9150, PF-06840003, SRF2 31, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, anti-Tie2 antibody, or A pharma- ceutically acceptable salt thereof.

[0236] Drug Delivery Compositions and Devices In some embodiments, the drug delivery compositions and devices include hydrogels and inflammatory-induced Includes inhibitors of the tract.

[0237] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, and activators of the innate immune response.

[0238] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, activators of the innate immune response, and further activators of the innate immune response.

[0239] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, activators of the innate immune response, and cytokines.

[0240] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of the innate immune response, further activators of the innate immune response, and sites Including Cain.

[0241] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, activators of the innate immune response, and chemokines.

[0242] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of the innate immune response, further activators of the innate immune response, and chemokines Includes Inn.

[0243] In some embodiments, the drug delivery compositions and devices include hydrogels, inhibitors, and cytokines.

[0244] In some embodiments, the drug delivery compositions and devices include hydrogels, inhibitors, and chemokines.

[0245] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, and activators of the adaptive immune response.

[0246] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors of the innate immune response, activators of the adaptive immune response, and inhibitors of the immune system.

[0247] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors of innate immune responses, activators of innate immune responses, further activators of adaptive immune responses, Contains activators of the immune response.

[0248] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, activators of the adaptive immune response, and further activators of the adaptive immune response.

[0249] In some embodiments, the drug delivery compositions and devices include hydrogels, inhibitor, an activator of the adaptive immune response, and two further activators of the adaptive immune response include.

[0250] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of the innate immune response, cytokines, and activators of the adaptive immune response include.

[0251] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of innate immune responses, further activators of innate immune responses, cytokines , and activators of the adaptive immune response.

[0252] In some embodiments, the drug delivery compositions and devices include hydrogels, inhibitors, activators of the innate immune response, cytokines, activators of the adaptive immune response, and Further activators of the adaptive immune response are included.

[0253] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of innate immune responses, further activators of innate immune responses, cytokines , activators of the adaptive immune response, and further activators of the adaptive immune response.

[0254] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors of immune responses, activators of the innate immune response, chemokines, and activators of the adaptive immune response. nothing.

[0255] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of innate immune response, further activators of innate immune response, chemokines, and activators of the adaptive immune response.

[0256] In some embodiments, the drug delivery compositions and devices include hydrogels, inhibitors, activators of the innate immune response, chemokines, activators of the adaptive immune response, and more The present invention includes activators of adaptive immune responses comprising:

[0257] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, activators of innate immune response, further activators of innate immune response, chemokines, activators of the adaptive immune response, and further activators of the adaptive immune response.

[0258] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, cytokines, and activators of the adaptive immune response.

[0259] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, cytokines, activators of the adaptive immune response, and further activities of the adaptive immune response Contains a factor.

[0260] In some embodiments, the drug delivery compositions and devices include hydrogels, These include inhibitors, chemokines, and activators of the adaptive immune response.

[0261] In some embodiments, the drug delivery compositions and devices include hydrogels, Inhibitors, chemokines, activators of the adaptive immune response, and further activation of the adaptive immune response Includes factors.

[0262] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-1β antibody. Including the body.

[0263] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-6 antibody. Includes.

[0264] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-6R antibody. Including the body.

[0265] In some embodiments, the drug delivery compositions and devices include a hydrogel and a p38 mitochondria. Inhibition of proinflammatory immune responses mediated by the agonist-activated protein kinase (MAPK) pathway Contains agents.

[0266] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a p38 MAPK inhibitor. Contains harmful agents.

[0267] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a P38 MAPK Includes p38α / β MAPK inhibitors that bind to ATP and / or allosteric binding sites.

[0268] In some embodiments, the drug delivery compositions and devices include hydrogels and rosmapimo. Includes do.

[0269] In some embodiments, the drug delivery compositions and devices comprise a hydrogel and a TGFβR inhibitor. Contains agents.

[0270] In some embodiments, the drug delivery compositions and devices include a hydrogel and a CCR2 inhibitor. Includes.

[0271] In some embodiments, the drug delivery compositions and devices include a hydrogel and a CXCR4 inhibitor. Contains agents.

[0272] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1β antibody, and stimulator of interferon genes (STING) agonists.

[0273] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and and stimulator of interferon genes (STING) agonists.

[0274] In some embodiments, the drug delivery composition and device comprise a hydrogel, an anti-IL-6R antibody, and stimulator of interferon genes (STING) agonists.

[0275] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a TGFβR inhibitor, and stimulator of interferon genes (STING) agonists.

[0276] In some embodiments, the drug delivery compositions and devices include a hydrogel, a CCR2 inhibitor, and and stimulator of interferon genes (STING) agonists.

[0277] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, a CXCR4 inhibitor, and stimulator of interferon genes (STING) agonists.

[0278] In some embodiments, the drug delivery compositions and devices include hydrogels, p38 mitogens, and Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and TLR7 / 8 agonists.

[0279] In some embodiments, the drug delivery compositions and devices include hydrogels, p38 MAPK inhibitors, , and TLR7 / 8 agonists.

[0280] In some embodiments, the drug delivery compositions and devices include hydrogels, AT38 MAPK p38α / β MAPK inhibitors that bind to the P and / or allosteric binding sites, as well as TLR7 / Contains 8 agonists.

[0281] In some embodiments, the drug delivery compositions and devices include hydrogels, losmapimod, and TLR7 / 8 agonists.

[0282] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1β antibody, and 2'3'-cGAMP.

[0283] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and and 2'3'-cGAMP.

[0284] In some embodiments, the drug delivery composition and device comprise a hydrogel, an anti-IL-6R antibody, and 2'3'-cGAMP.

[0285] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1β antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0286] In some embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0287] In some embodiments, the drug delivery composition and device comprise a hydrogel, an anti-IL-6R antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0288] In some embodiments, the drug delivery compositions and devices include hydrogels, p38 mitogens, and Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and resiquimod.

[0289] In some embodiments, the drug delivery compositions and devices include hydrogels, p38 MAPK inhibitors, , and resiquimod.

[0290] In some embodiments, the drug delivery compositions and devices include hydrogels, ATPases for P38 MAPK, and / or p38α / β MAPK inhibitors that bind to the allosteric binding site, and resiquimo Includes do.

[0291] In some embodiments, the drug delivery compositions and devices include hydrogels, losmapimod, and resiquimod.

[0292] In some embodiments, the drug delivery compositions and devices include hydrogels and resiquimod. Includes.

[0293] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-1β antibody. Including the body.

[0294] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-6 antibody. Includes.

[0295] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-6R antibody. Including the body.

[0296] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and p38 mitochondrial peptides. Inhibition of proinflammatory immune responses mediated by the agonist-activated protein kinase (MAPK) pathway Contains agents.

[0297] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a p38 MAPK inhibitor. Contains harmful agents.

[0298] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and P38 MAPK. and p38α / β MAPK inhibitors that bind to the ATP and / or allosteric binding sites of p38α / β MAPK.

[0299] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and losmapimonials. Includes do.

[0300] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a TGFβR inhibitor. Contains agents.

[0301] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a CCR2 inhibitor. Includes.

[0302] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a CXCR4 inhibitor. Contains agents.

[0303] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1β antibody, and stimulator of interferon genes (STING) agonists.

[0304] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and and stimulator of interferon genes (STING) agonists.

[0305] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and stimulator of interferon genes (STING) agonists.

[0306] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a TGFβR inhibitor, and stimulator of interferon genes (STING) agonists.

[0307] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a CCR2 inhibitor, and and stimulator of interferon genes (STING) agonists.

[0308] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a CXCR4 inhibitor, and stimulator of interferon genes (STING) agonists.

[0309] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, p38 mitogen Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and TLR7 / 8 agonists.

[0310] In some embodiments, the drug delivery compositions and devices include hyaluronic acid, a p38 MAPK inhibitor, , and TLR7 / 8 agonists.

[0311] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, ATP for P38 MAPK, and / or p38α / β MAPK inhibitors that bind to allosteric binding sites, and TLR7 / 8 Includes agonists.

[0312] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, losmapimod, and TLR7 / 8 agonists.

[0313] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1β antibody, and 2'3'-cGAMP.

[0314] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and and 2'3'-cGAMP.

[0315] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and 2'3'-cGAMP.

[0316] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1β antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0317] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0318] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0319] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, p38 mitogen Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and resiquimod.

[0320] In some embodiments, the drug delivery compositions and devices include hyaluronic acid, a p38 MAPK inhibitor, , and resiquimod.

[0321] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, ATP for P38 MAPK, and / or p38α / β MAPK inhibitors that bind to the allosteric binding site, and resiquimo Includes do.

[0322] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid, losmapimod, and resiquimod.

[0323] In some embodiments, the drug delivery compositions and devices comprise hyaluronic acid and resiquimod. Includes.

[0324] In some embodiments, the drug delivery compositions and devices comprise alginate and an anti-IL-1β antibody. Including the body.

[0325] In some embodiments, the drug delivery compositions and devices comprise alginate and an anti-IL-6 antibody. Includes.

[0326] In some embodiments, the drug delivery compositions and devices comprise alginate and an anti-IL-6R antibody. Including the body.

[0327] In some embodiments, the drug delivery compositions and devices comprise alginate and p38 mitochondrial peptides. Inhibition of proinflammatory immune responses mediated by the agonist-activated protein kinase (MAPK) pathway Contains agents.

[0328] In some embodiments, the drug delivery compositions and devices comprise alginate and a p38 MAPK inhibitor. Contains harmful agents.

[0329] In some embodiments, the drug delivery compositions and devices comprise a combination of alginate and P38 MAPK. Includes p38α / β MAPK inhibitors that bind to ATP and / or allosteric binding sites.

[0330] In some embodiments, the drug delivery compositions and devices comprise alginate and rosmapimono. Includes do.

[0331] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-1β antibody, and stimulator of interferon genes (STING) agonists.

[0332] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-6 antibody, and and stimulator of interferon genes (STING) agonists.

[0333] In some embodiments, the drug delivery composition and device comprises alginate, an anti-IL-6R antibody, and stimulator of interferon genes (STING) agonists.

[0334] In some embodiments, the drug delivery compositions and devices include alginate, p38 mitogen Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and TLR7 / 8 agonists.

[0335] In some embodiments, the drug delivery compositions and devices comprise an alginate, a p38 MAPK inhibitor. , and TLR7 / 8 agonists.

[0336] In some embodiments, the drug delivery compositions and devices include alginate, ATP for P38 MAPK. and / or p38α / β MAPK inhibitors that bind to allosteric binding sites, and TLR7 / 8 Includes agonists.

[0337] In some embodiments, the drug delivery compositions and devices comprise alginate, losmapimod, and TLR7 / 8 agonists.

[0338] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-1β antibody, and 2'3'-cGAMP.

[0339] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-6 antibody, and and 2'3'-cGAMP.

[0340] In some embodiments, the drug delivery composition and device comprises alginate, an anti-IL-6R antibody, and 2'3'-cGAMP.

[0341] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-1β antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0342] In some embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-6 antibody, and and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0343] In some embodiments, the drug delivery composition and device comprises alginate, an anti-IL-6R antibody, and 2'3'-c-di-AM(PS)2(Rp,Rp).

[0344] In some embodiments, the drug delivery compositions and devices include alginate, p38 mitogen Inhibitors of proinflammatory immune responses mediated by the kinase-activated protein kinase (MAPK) pathway, and resiquimod.

[0345] In some embodiments, the drug delivery compositions and devices comprise an alginate, a p38 MAPK inhibitor. , and resiquimod.

[0346] In some embodiments, the drug delivery compositions and devices include alginate, ATP for P38 MAPK. and / or p38α / β MAPK inhibitors that bind to the allosteric binding site, and resiquimo Includes do.

[0347] In some embodiments, the drug delivery compositions and devices comprise alginate, losmapimod, and resiquimod.

[0348] In some embodiments, the drug delivery compositions and devices comprise alginate and resiquimod. Includes.

[0349] In some embodiments, the drug delivery compositions and devices include alginates, COX-2 inhibitors (e.g., e.g., celecoxib), and anti-PD-1 antibodies.

[0350] In some embodiments, the drug delivery compositions and devices comprise 1,3,-bis(2-chloroethyl)-1- Free of nitrosourea (BCNU) and ethylene-vinyl acetate copolymer.

[0351] Characteristics of Drug Delivery Compositions and Devices Biomaterials useful for the drug delivery compositions and devices described herein include In some embodiments, the biomaterial (e.g., hydrogel) is biocompatible. Degradable. Drug delivery compositions and devices are chemically and / or biologically The composition and device are capable of being degraded under physiological conditions, for example, in the body. Degradation can occur at various rates depending on the constituent components and the hydrogel used. For example, the half-life of the composition and device (if 50% of the composition is monomeric and / or other non-polyethylene glycol) The time it takes for the polymer to decompose into its polymeric part (the time it takes for the polymer to decompose into its polymeric part) can be on the order of days, weeks, months, or years. The compositions and devices may be biologically, e.g., by enzymatic activity or cellular mechanisms. In some cases, e.g., through exposure to lysozyme (e.g., at relatively low pH Decomposition products that are decomposed by simple hydrolysis or by In some cases, the compositions and devices may be adapted to allow cells to express the Monomers and / or compounds that can be reused or disposed of without significant toxicity to the or other non-polymeric moieties. but are stable in vivo so as to deliver the drug to the intended target within a suitable period of time.

[0352] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less of the devices 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less than 0.5%, or less than 0.1% may be present during administration (e.g., transfer) of the drug delivery composition or device. persist in vivo 12 months after transplantation.

[0353] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1% after administration (e.g., implantation) of the drug delivery composition or device. persists in vivo after 6 months of

[0354] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1% after administration (e.g., implantation) of the drug delivery composition or device. persist in vivo 5 months after administration.

[0355] 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, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less than 0.1% 4 months after administration (e.g., implantation) of the drug delivery composition or device and persists in vivo.

[0356] 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, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less than 0.1% 3 months after administration (e.g., implantation) of the drug delivery composition or device and persists in vivo.

[0357] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1% after administration (e.g., implantation) of the drug delivery composition or device. persists in vivo 2 months after administration.

[0358] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1% after administration (e.g., implantation) of the drug delivery composition or device. persists in vivo one month after

[0359] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1% after administration (e.g., implantation) of the drug delivery composition or device. persists in vivo one week after

[0360] In some embodiments, the composition is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less or less than 0.5%, or less than 0.1%, less than 0.1%, administration of a drug delivery composition or device (e.g. persist in vivo one day after post-transplantation (e.g., transplantation).

[0361] The storage modulus in a viscoelastic material measures the stored energy in the elastic portion of the material. The storage modulus can be measured by a rheometer. Measurements were performed at room temperature on a TA Instruments AR-G2 magnetic bearing rheometer. The storage modulus of drug delivery compositions and devices will vary based on the components of the composition. Wax.

[0362] Generally, thiol-modified hyaluronic acid (e.g., GLYCOSIL®) and thiol-modified hyaluronic acid (e.g., GLYCOSIL®) are used. The relationship between storage modulus and concentration of a polymer-reactive PEGDA crosslinker (e.g., EXTRALINK®) The relationship is linear (excluding the limit of sensitivity). For example, and 0.2% EXTRALINK® formulations have a storage modulus of approximately 100 Pa, and 1.3% GLYC The formulation with OSIL® and 2% EXTRALINK® has a storage modulus of approximately 1600 Pa. would.

[0363] In some embodiments, the drug delivery compositions or devices described herein comprise at least 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 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, A storage elasticity of at least 2700 Pa, at least 2800 Pa, at least 2900 Pa, or at least 3000 Pa has a rate.

[0364] In some embodiments, the drug delivery composition or device described herein comprises about 50Pa to approx. 100,000,000Pa, approx. 50Pa to approx. 100,000Pa, approx. 50Pa to approx. 10,000Pa, approx. 50Pa to approx. 3,000Pa a, about 100Pa to about 3,000Pa, about 100Pa to about 2,000Pa, about 500Pa to about 3,000Pa, about 500Pa to about 2,000P a, 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 1,4 It has a storage modulus of 0.00 Pa to approximately 1,600 Pa.

[0365] In some embodiments, the drug delivery composition or device described herein comprises about Up to 600 Pa, up to about 700 Pa, up to about 800 Pa, up to about 900 Pa, up to about 1,000 Pa, up to about 1,100 Pa, Up to about 1,200 Pa, up to about 1,300 Pa, up to about 1,400 Pa, up to about 1,500 Pa, up to about 1,600 Pa, up to about 1,7 Up to about 1,800 Pa, Up to about 1,900 Pa, Up to about 2,000 Pa, Up to about 2,500 Pa, Up to about 3,000 Pa up to about 5,000 Pa, up to about 10,000 Pa, up to about 100,000 Pa, up to about 1,000,000 Pa, up to about 10,00 It has a storage modulus of up to 0,000 Pa, or up to about 100,000,000 Pa.

[0366] The drug delivery compositions and devices described herein are capable of delivering therapeutically effective amounts of The release of the one or more therapeutic agents may occur in a composition or in a body. depends on the device components (e.g., identity and concentration of hydrogel) For example, the release rate of one or more therapeutic agents (when the therapeutic agent is no longer in the composition) may occur at various rates. The time it takes for the device to become unusable (i.e., no longer part of the object or device) may be a few minutes, hours, days, weeks, or even months. Therapeutic agents may act by a variety of mechanisms, including For example, release may occur by diffusion, chemical activity, enzymatic activity, or cellular mechanisms. In the present invention, the drug delivery compositions and devices described herein are preferably It is stable in vivo so as to deliver the drug to the intended target within a suitable period of time.

[0367] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less of activators of the innate immune system. below, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 weeks, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 16 days, 18 days, 19 days, 20 days, 22 days, 24 days, 26 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 Within an hour, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes, in vivo is released.

[0368] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more of activators of the innate immune system. % 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, at 18:00 for 1 day after administration (e.g., implantation) of the composition or device 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 The drug is released in vivo within minutes or within 10 minutes.

[0369] In some embodiments, 90% or less, 80% or less, 70% or less of any additional activators of the innate immune system. % 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 at 4 weeks, 3 weeks, 2 weeks, or 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 It is released in vivo within 2-4 hours.

[0370] In some embodiments, 99% or more, 95% or more, 90% or more of any additional activators of the innate immune system. % 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 after administration (e.g., implantation) of the composition or device. Days, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, The release occurs in vivo within 20 minutes, 15 minutes, or 10 minutes.

[0371] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less of activators of the adaptive immune system. below, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less After administration (e.g., implantation) of the composition or device, for 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 Within an hour, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes, in vivo is released.

[0372] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more of activators of the adaptive immune system Above, 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 for 1 day, 18 hours, or more after administration (e.g., implantation) of the composition or device; 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes or within 10 minutes in vivo.

[0373] In some embodiments, 90% or less, 80% or less, 70% or less of any additional activators of the adaptive immune system. % 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 at 4 weeks, 3 weeks, 2 weeks, or 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 It is released in vivo within 2-4 hours.

[0374] In some embodiments, 99% or more, 95% or more, 90% or more of any additional activators of the adaptive immune system. % 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 after administration (e.g., implantation) of the composition or device. Days, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, The release occurs in vivo within 20 minutes, 15 minutes, or 10 minutes.

[0375] In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less of the cytokines. or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of the composition or were administered (e.g., implanted) at 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, and 5 days after device administration (e.g., implantation). 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours released in vivo within 1 hour, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes do.

[0376] In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more of the cytokines above, 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 at 1 day, 18 hours, 12 hours, 8 hours, or 1 hour, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes It is released in vivo within minutes.

[0377] Preparation and Administration of Drug Delivery Compositions and Devices The present disclosure relates to drug delivery compositions and devices comprising a therapeutic agent as described herein. In some embodiments, the therapeutic agent is a compound that is capable of treating a disease (e.g., a proliferative disease such as cancer). in effective amounts in drug delivery compositions and devices for the treatment and / or prevention of In some embodiments, the effective amount is a therapeutically effective amount of a particular therapeutic agent. In the present specification, the effective amount is a prophylactically effective amount of the particular therapeutic agent.

[0378] The drug delivery compositions and devices described herein are well known in the pharmaceutical art. The preparation may be carried out by any method known in the art. In some embodiments, the preparation method may be Adding all-modified hyaluronic acid to the mold; Inhibitors of proinflammatory pathways (e.g. for example, an inhibitor of the p38 MAPK pathway-mediated proinflammatory immune response; Optionally, adding an activator of the adaptive immune response to the template; optionally adding a chemokine or adding a cytokine to the template; optionally adding an activator of the innate immune response to the template. adding a crosslinker into the template (e.g., a thiol-reactive PE GDA crosslinker); and mix for at least 10 minutes, at least 15 minutes, at least 20 minutes for 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 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, or Allowing the mixture to set for at least 6 hours is included.

[0379] In one embodiment, the thiol-modified hyaluronan used for the preparation of hydrogels is The concentration of sucrose (e.g., GLYCOSIL®) is about 1% to about 10%, about 1% by weight / volume. % to about 5%, about 1% to about 3%, or about 1.5% to about 2.5%; and preparation of hydrogels. Thiol-reactive PEGDA crosslinkers (e.g., EXTRALINK®) used for The amount of is about 1% to about 20%, about 10% to about 20%, about 5% to about 15%, or about 1 In a preferred embodiment, the concentration of thiol-modified hyaluronic acid is 0% to about 15%. The concentration of the thiol-reactive PEGDA crosslinker is approximately 12.5% ​​w / v. In one embodiment, the 2% thiol-modified hyaluronic acid and 12.5% ​​formulations have a 100% A hydrogel having a storage modulus of 0 Pa to about 2000 Pa is provided.

[0380] For preparation of standard tissue engineering applications known in the art, thiol-modified A typical concentration of hyaluronic acid (e.g., GLYCOSIL®) is about 1% w / v, and thiol A typical concentration of a reactive PEGDA crosslinker (e.g., EXTRALINK®) is about 1% w / v. Therefore, 2% w / v of thiol-modified hyaluronic acid (e.g., GLYCOSIL (registered trademark)) was used. (Trademark)) and 12.5% ​​w / v of a thiol-reactive PEGDA crosslinker (e.g., EXTRALINK® The use of ) is unexpectedly useful and advantageous in the disclosed drug delivery compositions and devices. To provide a biomaterial.

[0381] Those skilled in the art will appreciate that suitable compositions for forming hydrogels (e.g., hyaluronic acid hydrogels) can be used in the art. It will be appreciated that other cross-linking agents at different concentrations may be used. For example, in some embodiments In this case, hydrogels (e.g., hyaluronic acid hydrogels) contain thiols (e.g., EXTRACE L®, HYSTEM®), methacrylates, hexadecylamides (e.g., HYMOV by adding IS®, and / or tyramine (e.g., CORGEL®). In some embodiments, the hydrogel (e.g., hyaluronan) can be crosslinked. Phosphate hydrogels are made from formaldehyde (e.g., HYLAN-A®), divinyl sulfonate, Diglycidyl ether (DVS) (e.g., HYLAN-B (registered trademark)), 1,4-butanediol diglycidyl ether (BDDE) (e.g., RESTYLANE®), glutaraldehyde, and / or genipin; Crosslinking can be performed directly (see, for example, Khunmanee et al., "Crosslinking method of hyaluronan"). ronic-based hydrogel for biomedical applications” J Tissue Eng. 8: 1-16 (2017) In some embodiments, the hydrogel (e.g., hyaluronic acid hydrogel) , crosslinked with divinylsulfone (DVS) (eg, HYLAN-B®).

[0382] In some embodiments, the concentration of alginate used for the preparation of 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% Al, depending on the amount / volume. In one embodiment, 1M potassium chloride is used for the preparation of the hydrogel. The amount of calcium crosslinker solution is about 5 μL to 25 μL, about 10 μL to 20 μL, or about 15 μL. In one embodiment, the payload of interest is mixed with about 10 μL to 70 μL of solvent (PBS or DMSO), 20 μL ~60 μL of solvent (PBS or DMSO), about 30 μL to 50 μL of solvent (PBS or DMSO), or about 4 The cells can be loaded in 0 μL of solvent (PBS or DMSO).

[0383] The drug delivery compositions and devices may further comprise at least one excipient. In certain embodiments, the excipient is phosphate buffered saline, tris(hydroxymethyl)aminomethyl Calcium chloride, magnesium sulfate, sodium bicarbonate, potassium chloride, calcium chloride, sodium chloride, Sodium, sodium phosphate, potassium phosphate, calcium nitrate, glucose, lactose , trehalose, sucrose, or a combination thereof. The vehicle is phosphate-buffered saline, tris(hydroxymethyl)aminomethane, sodium chloride. or a combination thereof. In some embodiments, the excipient is phosphate buffered saline. It is.

[0384] In some embodiments, the drug delivery compositions and devices include nanoparticles or microparticles. Nanoparticles include particles with sizes between 1 and 100 nm. Microparticles include particles with sizes between 0.1 and 100 μm. In some embodiments, the drug delivery compositions and devices include silica microparticles, Polyethylene microparticles, polystyrene microparticles, polyester microparticles, polyanhydride microparticles particles, polycaprolactone microparticles, polycarbonate microparticles, or polyhydroxy In some embodiments, the drug delivery compositions and devices are porous. Does not contain silica microparticles.

[0385] In certain 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). .

[0386] In some embodiments, the drug delivery compositions and devices are free of organic solvents. In some embodiments, no organic solvents are used in the preparation of the composition or device. In some embodiments, the drug delivery compositions and devices are free of organic solvents. The drug delivery compositions and devices are substantially free of organic solvents. The delivery compositions and devices may contain less than 10%, less than 5%, less than 4%, less than 3%, less than 2% by weight Less than, Less than 1%, Less than 0.5%, Less than 0.1%, Less than 0.01%, Less than 0.001%, or Less than 0.0001% In some embodiments, the drug delivery compositions and devices comprise, by weight, Less than 1000ppm, Less than 500ppm, Less than 400ppm, Less than 300ppm, Less than 200ppm, Less than 100ppm, Less than 50ppm Less than, 40ppm, 30ppm, 20ppm, 10ppm, 1ppm, 10ppb, or 1ppb In some embodiments, the drug delivery composition contains less than 1000 mg of organic solvent. MS0) is not included.

[0387] In some embodiments, the drug delivery composition comprises an organic solvent. Cyclodextrin, methanol, ethanol, isopropanol, ethylene glycol The preferred oils are propylene glycol, propylene glycol, or a combination thereof.

[0388] The drug delivery compositions and devices may be delivered in bulk, as single unit doses, and / or It may be prepared, packaged, and / or sold as a plurality of single unit doses. A "dose" is a discrete amount of a composition or device that contains a predetermined amount of a therapeutic agent. The amount of therapeutic agent is generally equal to the dosage of the therapeutic agent that would be administered to a subject, and and / or any convenient fraction of such a dose, e.g., one-half, one-third, or one-quarter of such a dose. 1, etc.

[0389] The therapeutic agent, excipient, and / or any additional The relative amounts of the components will depend on the identity, size, and / or condition of the subject being treated. By way of example, the composition or device may be 0.1% to 99% (w / w), 0.1% to 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 a therapeutic agent.

[0390] In the manufacture of the provided drug delivery compositions and devices, further pharma- ceutically acceptable These may include inert diluents, dispersing and / or granulating agents, boundary agents, etc. Surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or Excipients such as cocoa butter and suppository wax, coloring agents and coating agents A blocking agent may also be present in the composition or device.

[0391] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, phosphoric acid, Dicalcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose , sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol oleic acid, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and Examples of such combinations include:

[0392] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, and the like. Oka starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus Tangerine pulp, agar, bentonite, cellulose, and wood products, natural sponges, cations Exchange resins, calcium carbonate, silicates, sodium carbonate, crosslinked poly(vinyl-pyrrolidone) Lydon) (crospovidone), sodium carboxymethyl starch (starch glycolate) Sodium), Carboxymethylcellulose, Crosslinked Carboxymethylcellulose Sodium Trisodium (croscarmellose), methylcellulose, pregelatinized starch starch 1500, microcrystalline starch, water-insoluble starch, carboxymethylcellulose Sodium, Magnesium Aluminum Silicate (VEEGUM), Sodium Lauryl Sulfate, Quaternary ammonium compounds, and mixtures thereof.

[0393] 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 terols, waxes and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) (magnesium aluminum silicate) and Veegum (magnesium aluminum silicate), long chain amino acid derivatives, polymers Amount of alcohol (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol) , Triacetin Monostearate, Ethylene Glycol Distearate, Glyceryl Mono stearate, and propylene glycol monostearate, polyvinyl alcohol) , carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers , and carboxyvinyl polymers), carrageenans, cellulose derivatives (e.g., carbo Sodium hydroxymethylcellulose, powdered cellulose, hydroxymethylcellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Methylcellulose ), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (T Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene Tween 80, Sorbitan Monolaurate (Sp an(R) 40), sorbitan monostearate (Span(R) 60), sorbitan tris( Thearate (Span® 65), Glyceryl Monolaurate, Sorbitan Monolaurate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monosulfones), Thearate (MYRJ 45), Polyoxyethylene hydrogenated castor oil, Polyethoxylated castor oil , polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, poly Ethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (BRIJ 30)), poly(vinyl-pyrrolidone Don), Diethylene glycol monolaurate, Triethanolamine oleate, Oleic acid Sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate Tyl, Sodium Lauryl Sulfate, PLURONIC® F-68 (also known as Poloxamer-188), PLURONIC C(R)F-127 (also known as Poloxamer-407), cetrimonium bromide, cetylpyridinium chloride , benzalkonium chloride, docusate sodium, and / or mixtures thereof. can be done.

[0394] 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., arabinose, Guava gum, sodium alginate, Irish moss extract, panwar gum, Ghatti gum, isapol husk mucilage, carboxymethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate , poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM), and kalama Arabinogalactan), alginate, polyethylene oxide, polyethylene glycol , inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or Or a mixture thereof.

[0395] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, arsenic preservatives, and the like. These include choline preservatives, acidic preservatives, and other preservatives. In another embodiment, the preservative is a chelating agent.

[0396] Exemplary antioxidants include alpha tocopherol, ascorbic acid, alpha palmitate, Scorbyl, butyl hydroxyanisole, butyl hydroxytoluene, monothioglyceryl rol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate Examples include sodium, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Can be obtained.

[0397] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates. substances (e.g., sodium edetate, disodium edetate, trisodium edetate, disodium edetate, dipotassium edetate, etc.), citric acid and its salts, and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, apple Acids and their salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid Exemplary antimicrobial preservatives include benzalkonium chloride and its salts and hydrates. Benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetyl chloride Rupyridinium, chlorhexidine, chlorobutanol, chlorocresol, chloroxy Lenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, Phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, Pyrene glycol, and thimerosal.

[0398] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, Propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate Examples of suitable antioxidants include sodium benzoate, sodium propionate, and sorbic acid.

[0399] Exemplary alcohol preservatives include ethanol, polyethylene glycol, and phenol. , phenolic compounds, bisphenols, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0400] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, chloramphenicol ... These include enoic acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. can be.

[0401] Other preservatives include tocopherol, tocopherol acetate, and deteroxime mesylate. (deteroxime mesylate), cetrimide, butyl hydroxyanisole (BHA), butyl hydrochloride BHT, ethylenediamine, sodium lauryl sulfate (SLS), lauryl ether Sodium disulfite (SLES), sodium hydrogen sulfite, sodium disulfite, potassium sulfite , Potassium Metabisulfite, Glydant Plus, Phenonip, Methylparaben, Germal 115, Ger These include MABEN II, NEOLONE, KATHON, and EUXYL.

[0402] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride buffer, and the like. Um, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate , Calcium gluceptate, Calcium gluconate, D-gluconic acid, Calcium glycerophosphate Sodium, calcium lactate, propionate, calcium levulinate, pentanoic acid, dibasic Calcium Phosphate, Phosphoric Acid, Tribasic Calcium Phosphate, Calcium Hydroxide Phosphate, Acetic Acid Potassium, Potassium Chloride, Potassium Gluconate, Potassium Mixture, Dibasic Potassium Phosphate potassium phosphate monobasic, potassium phosphate mixture, sodium acetate, sodium bicarbonate sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate sodium phosphate monobasic, sodium phosphate mixture, tromethamine, magnesium hydroxide Sodium, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's -solution, ethyl alcohol, and mixtures thereof.

[0403] Exemplary lubricants include magnesium stearate, calcium stearate, stearate, Phosphate, Silica, Talc, Malt, Glyceryl Behenate, Hydrogenated Vegetable Oil, Polyethylene Glycol Recall, Sodium Benzoate, Sodium Acetate, Sodium Chloride, Leucine, Lauryl Magnesium sulfate, sodium lauryl sulfate, and mixtures thereof.

[0404] Exemplary natural fats and oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, and oleaginous oil. oil, black currant seed oil, borage oil, cade oil, chamomile oil, canola oil, cabbage oil Lamium oil, carnauba wax oil, castor oil, cinnamon oil, cocoa butter oil, coco Nut oils, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil Oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazel nut oil, Sop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavandin oil, under oil, lemon oil, lily of the valley oil, macadamia nut oil, mallow oil, mango seed oil , Meadowfoam seed oil, Mink oil, Nutmeg oil, Olive oil, Orange oil, Orange la Fee 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, sasquat (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 Exemplary synthetic oils include, but are not limited to, sodium hydroxide, sodium phosphate distillate, and wheat germ oil. Butyl stearate, caprylic triglyceride, capric triglyceride, cyclohexyl ester Cyclomethicone, diethyl sebacate, dimethicone 360, iso myristate Propyl, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and Combinations of these are possible.

[0405] The description of drug delivery compositions provided herein is primarily suitable for administration to humans. Although the present invention is directed to compositions suitable for use in animals of all kinds, those skilled in the art will appreciate that such compositions are generally suitable for use in animals of all kinds. It will be appreciated that the compositions can be suitable for administration to a variety of animals. The modification of drug delivery compositions suitable for administration to humans to make them suitable for and a pharmacologist of ordinary skill would be able to design and / or produce such modifications by routine experimentation. or may be implemented.

[0406] The drug delivery compositions and devices provided herein typically have a dosage of For ease of use, the device should be of an appropriate size (e.g., volume) and shape for its intended use (e.g., surgical implantation). However, the total amount of the composition or device of the present disclosure (e.g., the amount of the implanted The number of devices administered will be determined by the attending physician within the scope of sound medical judgment. It will be understood that the specific therapeutic effect for any particular subject or organism may be The dosage levels effective for will depend on the severity of the disease or disorder being treated; the particular active agent being used; the activity of the ingredients; the particular composition used; the age, weight, general health, sex and diet of the subject the time of administration, route of administration, and rate of excretion of the particular active ingredient used; duration of treatment ; drugs used in combination with specific active ingredients; and in the field of medicine The accuracy of the results will depend on a variety of factors, including similar factors well known in the art.

[0407] The drug delivery compositions and devices provided herein are administered by surgical implantation. For example, the drug delivery composition or device may be used to fill the void volume of a resected tumor. As a further example, the drug delivery composition or Alternatively, the device can be administered by surgical implantation and secured in place with a bioadhesive. In some embodiments, the drug delivery composition or device is administered to the tumor in the void volume of the resected tumor. The tissue can be fixed in place using a bioadhesive.

[0408] In some embodiments, the drug delivery composition or device is administered to a patient by surgical implantation into a resected tumor. Tumor void volume 100cm, 90cm, 80cm, 70cm, 60cm, 50cm, 40cm, 30cm, 20cm, 10cm, 9cm , 8cm, 7cm, 6cm, 5cm, 4cm, 3cm, 2cm, 1cm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm, 2mm In some embodiments, the tumor is administered to a site within 1 mm of the void volume of the resected tumor. is a tumor-bearing resected organ (e.g., lung, kidney, pancreas, liver, colon, testis, ovary, In one embodiment, the void volume of a resected tumor is The amount is determined by the tumor-bearing organ (e.g., lung, kidney, pancreas, liver, colon, testis, ovary, breast, The void volume of the resected portion of the bladder (abdominal cavity, bladder, etc.)

[0409] In some embodiments, the precursor components of the hydrogel (e.g., hyaluronic acid) and crosslinking The agents are administered separately to the subject (e.g., at the site of tumor resection), thus providing in vivo In some embodiments, the drug delivery composition is formed by mixing the precursor components of the hydrogel (e.g., For example, hyaluronic acid) and the crosslinker are administered sequentially. The gel precursor components (e.g., hyaluronic acid) and the crosslinker are administered simultaneously. In embodiments, the precursor components of the hydrogel (e.g., hyaluronic acid) and the crosslinker are It is administered as a mixture. In some embodiments, administration is via injection.

[0410] In some embodiments, the alginate and crosslinker are administered to a subject (e.g., at the site of tumor resection). In one embodiment, the two drugs are administered separately (in a separate administration step) and thus form a drug delivery composition in vivo. In some embodiments, the alginate and the crosslinking agent are administered sequentially. In some embodiments, the alginate and crosslinking agent are administered simultaneously. The agents are administered as a mixture, hi some embodiments, administration is via injection.

[0411] The precise amount of therapeutic agent required to achieve an effective dose will vary depending, for example, on the species, age and dosage of the subject. and general condition, the severity of the side effect or disorder, the identity of the specific agent, etc. The results will vary from subject to subject.

[0412] In one embodiment, an effective amount of the composition or device for administration to a 70 kg adult human is , about 0.0001mg to about 3000mg, about 0.0001mg to about 2000mg, about 0.0001mg to about 1000mg, about 0.001mg to About 1000mg, about 0.01mg to about 1000mg, about 0.1mg to about 1000mg, about 1mg to about 1000mg, about 1mg to about 100mg , about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg.

[0413] In some embodiments, the composition or device is administered to a subject to achieve a desired therapeutic effect. Approximately 0.001 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 50 mg / kg, approximately 0.1 mg / kg per kg of body weight per day g / kg~about 40mg / kg, about 0.5mg / kg~about 30mg / kg, about 0.01mg / kg~about 10mg / kg, about 0.1mg / kg~about 10 1 mg / kg, or from about 1 mg / kg to about 25 mg / kg of therapeutic agent present in the composition. The dosage level may be sufficient to

[0414] Dose ranges as described herein are based on the drug delivery compositions and devices provided. It will be appreciated that the present invention provides guidance for the administration of the drug to adults. The amount to be administered to a child or adolescent can be determined by a physician or person skilled in the art and is the same as that administered to an adult. It may be lower than or the same as the specified value.

[0415] The compositions and devices as described herein may also comprise one or more further It will be appreciated that the compositions may be administered in combination with other pharmaceutical agents. The objects and devices slow and / or modify their metabolism or Further therapeutic options exist that inhibit the excretion of these compounds and / or modify their distribution in the body. The additional treatments used may be administered in combination with other drugs to treat the same disorder. may achieve the desired effect and / or it may achieve a different effect. Good things will be understood.

[0416] The compositions and devices may contain one or more additional agents that may be useful, for example, as combination therapeutic agents. The pharmaceutical agent may be administered simultaneously with, prior to, or subsequent to the administration of the pharmaceutical agent. , a therapeutically active agent. The pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent is Administer the pharmaceutical agent at the dose and / or time schedule determined for the pharmaceutical agent. The additional pharmaceutical agent may be administered in a different dose and / or by a different route of administration. , will be administered separately. Specific combinations for use in the regimen include The compatibility of the drug delivery composition with additional pharmaceutical agents and / or the desired therapeutic effect to be achieved. Therapeutic and / or prophylactic effects will be considered. Additional medicinal agents may be administered at levels not exceeding the levels at which they are utilized individually. It is expected that the compositions will be used in combination in some embodiments. The levels achieved will be lower than those utilized individually.

[0417] Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-inflammatory agents, Pharmaceutical agents include drug compounds (e.g., , compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR), etc. Small molecule therapeutics, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins Proteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, proteins Small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleic acids Leucides, oligonucleotides, antisense oligonucleotides, lipids, hormones, bilirubin Examples include tamins and cells.

[0418] In some embodiments, the drug delivery compositions and devices do not contain cells. In some embodiments, the drug delivery compositions and devices do not include adoptively transferred cells. In some embodiments, the drug delivery compositions and devices do not include T cells. In some embodiments, the additional pharmaceutical agent is a T cell. In some embodiments, the drug delivery compositions and devices do not contain tumor antigens. In some embodiments, the drug delivery compositions and devices are administered ex vivo loaded tumor antigens. Does not include Hara.

[0419] In some embodiments, a "drug delivery composition" refers to a composition in liquid form (e.g., a viscous In some embodiments, the term "drug delivery device" refers to a drug in a solid form. In some embodiments, the transition from the composition to the device is referred to as a composition (e.g., a hydrogel). The resulting material can be physically manipulated and implanted by surgical techniques. By sufficient crosslinking, the polymer has a storage modulus consistent with the solid form that can be obtained. Thus, the drug delivery device, in its solid form, is within the scope of the present disclosure. The present invention may be particularly amenable to performing prescribed uses, such as surgical implantation.

[0420] In some embodiments, the drug delivery composition and / or drug delivery device is a drug delivery composition for in vivo transport. The drug delivery system is prepared immediately prior to implantation (e.g., in or near the operating room). The delivered composition and / or drug delivery device is administered at 24 hours, 18 hours, 12 hours, or 48 hours after implantation in vivo. , 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour , within 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0421] In some embodiments, the drug delivery composition and / or drug delivery device is a drug delivery composition for in vivo transport. In some embodiments, the drug delivery composition and / or drug delivery device are prepared prior to implantation. Vice versa, 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days of in vivo implantation , prepared within a day.

[0422] In some embodiments, the drug delivery composition has a therapeutic effect for up to one year of its use in a therapeutic setting. , 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 In some embodiments, the prepared drug delivery system is prepared within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The resulting composition is then cross-linked by the addition of a cross-linking agent as described herein. 31 days, 28 days, 21 days, 14 days, 7 days of in vivo implantation to prepare drug delivery devices 6th, 5th, 4th, 3rd, 2nd, 1st, 18 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours 1 hour, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or less than 1 minute Used within

[0423] Also encompassed by the present disclosure are kits. The kits provided herein include The compositions and / or devices described herein, as well as containers (e.g., vials, amps, etc.) The composition may be in a container, a bottle, a syringe, and / or a dispenser package, or other suitable container. In some embodiments, the kits provided may optionally include a The pharmaceutical composition or compound described in the above is preferably a pharmaceutical excipient for dilution or suspension. In some embodiments, the kit further comprises a second container containing a drug delivery composition. Precursor components for the drug and / or drug delivery device (e.g., hyaluronic acid and crosslinker; or alginate and a crosslinker).

[0424] In some embodiments, the kit comprises a hydrogel and an inhibitor of a pro-inflammatory pathway (e.g., p38 In one embodiment, the present invention comprises an inhibitor of the proinflammatory immune response mediated by the MAPK pathway. The solution contains hydrogels, inhibitors of proinflammatory pathways (e.g., mediated by the p38 MAPK pathway), and In some embodiments, the immune response includes an activator of the innate immune response, an inhibitor of the proinflammatory immune response, and an activator of the innate immune response. The kit includes a hydrogel, an inhibitor of a proinflammatory pathway (e.g., an inhibitor of the p38 MAPK pathway), and In one embodiment, the present invention includes an inhibitor of the proinflammatory immune response mediated by the inflammatory cytokines. The kit includes a hydrogel, an inhibitor of a proinflammatory pathway (e.g., an inhibitor of the p38 MAPK pathway), In some embodiments, the immune response includes an activator of the adaptive immune response, an inhibitor of the proinflammatory immune response, and an activator of the adaptive immune response. In one embodiment, the kit further comprises an activator of innate immune function. In one embodiment, the kit further comprises a cytokine. In one embodiment, the kit further comprises a factor for enhancing macrophage effector function. In some embodiments, the kit further comprises a modulator of activation of an adaptive immune response. In some embodiments, the kit further comprises an oncolytic virus, a radioisotope, In some embodiments, the therapeutic agent further comprises an immunomodulatory chemotherapeutic agent, a targeted agent, or a combination thereof. In some embodiments, the kit comprises any of the drug delivery compositions described herein. In the above, the kit comprises any of the drug delivery devices described herein.

[0425] In some embodiments, the kit does not include a chemotherapeutic agent. Contains no cytotoxic agents.

[0426] In some embodiments, the kits described herein include instructions for using the kits. The kits described herein may be approved by the U.S. Food and Drug Administration (FDA), etc. In some embodiments, the kit may include information required by regulatory agencies. The included information is prescription information. In some embodiments, the kit and instructions include a method for treating cancer. The kits described herein include one or more of the components described herein. The above additional pharmaceutical agents may be included as separate compositions.

[0427] Treatment Methods and Uses The present disclosure relates to a method for treating cancer (e.g., a sarcoma, carcinoma, lymphoma, germ cell tumor, or blastoma) in a subject. The present invention relates to the use of the compounds described herein for the treatment and / or prevention of proliferative diseases such as myocardial infarction, ... and myocardial infarction. In some embodiments, the present invention provides a method for using the drug delivery composition and device. The compositions and / or devices described herein are useful in the treatment of resectable tumors. In some embodiments, the compositions described herein are for use in The compositions and / or devices may be administered to tissues outside the spleen or lymphatic system, such as the thyroid or stomach. The present invention is for use in the treatment of lymphoma present in

[0428] In some embodiments, the drug delivery compositions and devices described herein are useful in treating cancer. The drug delivery compositions and devices described herein delay or alleviate the onset of cancer symptoms. In some embodiments, the method is useful for slowing the progression of or ameliorating the symptoms of the disease. In the present invention, the drug delivery compositions and devices described herein prevent cancer. In some embodiments, the drug delivery compositions described herein are useful for The articles and devices are useful for preventing the regrowth of a primary tumor. In the present invention, the drug delivery compositions and devices described herein are capable of preventing tumor metastasis. In some embodiments, the drug delivery methods described herein are useful. The compositions and devices may be combined with other compounds, drugs or therapeutic agents to treat cancer. It is administered in a time-dependent manner.

[0429] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a sarcoma, carcinoma, In one embodiment, the cancer is a lymphoma, a germ cell tumor, a blastoma, or a combination thereof. In this case, the tumor is a sarcoma, carcinoma, lymphoma, germ cell tumor, blastoma, or a combination thereof. It is a combination.

[0430] In some embodiments, the drug delivery compositions and devices described herein is useful for treating cancers including, but not limited to, acoustic neuroma adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphatic endothelial sarcoma, hemangiosarcoma); 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; pediatric Cervical cancer (e.g., adenocarcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ductal carcinoma in situ; ependymoma; epithelium Sarcomas (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine esophageal cancer (e.g., adenocarcinoma of the esophagus, 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 cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer ( oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); Cancers of the blood system (e.g., lymphoma, primary pulmonary lymphoma, lymphoma of the bronchus-associated lymphoid tissue, splenic peritoneal lymphoma, nodal marginal zone lymphoma, childhood B-cell non-Hodgkin's lymphoma); hemangioblastoma; histiocytosis hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; renal 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 lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma); leiomyosarcoma (LMS); melanoma; midline carcinoma; multiple endocrine neoplasia syndrome; myocarcinoma; mesothelioma nasopharyngeal carcinoma; neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannoma) neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); bone Sarcomas (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); parathyroid carcinoma ;papillary adenocarcinoma;penile cancer (eg, Paget's disease of the penis and scrotum);pharyngeal cancer;pinealoma;lower Pituitary carcinoma; Pleuropulmonary blastoma; Primitive neuroectodermal tumor (PNT); Plasma cell neoplasia; Paraneoplastic syndrome group;intraepithelial neoplasia;prostate cancer (e.g., adenocarcinoma of the prostate);rectal cancer;rhabdomyosarcoma;retinoblastoma cancer; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthocytoma (KA), melanoma, basal cell carcinoma; cancer (BCC); cancer of the small intestine (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; stomach Cancer; small intestine cancer; cancer of the sweat glands; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thymic carcinoma; Thyroid cancer (e.g., papillary thyroid cancer, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; uterine cancer; vaginal cancer; vulvar cancer (eg, Paget's disease of the vulva), or any combination thereof.

[0431] 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. It is.

[0432] In some embodiments, the drug delivery compositions and devices described herein is useful for treating: adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma, appendix carcinoma, bile duct Cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, carcinoid tumor, cardiac tumor, cervical cancer, cholangiocarcinoma Hair carcinoma, Chordoma, Colorectal cancer, Connective tissue cancer, Craniopharyngioma, Ductal carcinoma in situ, Epithelial sarcoma, Uterine 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, blood Tuboblastoma, Histiocytosis, Hodgkin's lymphoma, Hypopharyngeal carcinoma, Inflammatory myofibroblastic tumor, Intraepithelial Neoplasms, immune cell amyloidosis, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (L MS), melanoma, midline carcinoma, multiple endocrine neoplasia syndrome, muscle cancer, mesothelioma, myeloproliferative disorder (MPD) , nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroendocrine carcinoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian Cancer, pancreatic cancer, paraneoplastic syndrome, parathyroid cancer, papillary adenocarcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, Pinealoma, pituitary carcinoma, pleuropulmonary blastoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasia, Prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sebaceous gland cancer, skin cancer, small intestine cancer , small intestine cancer, soft tissue sarcoma, gastric cancer, sweat gland cancer, synovium, testicular cancer, thymic cancer, thyroid cancer, urethral cancer , uterine cancer, vaginal cancer, blood vessel cancer, vulvar cancer, or a combination thereof.

[0433] In some embodiments, the drug delivery compositions and devices described herein are useful in treating and / or preventing solid tumors and metastases.

[0434] For example, in some embodiments, the method comprises administering to a subject a drug delivery composition as described herein. and a method for treating a subject comprising administering to the subject a therapeutically effective amount of a hydrogel biomaterial comprising administering to the subject a therapeutically effective amount of a p38 MAPK pathway inhibitor. ) to a target site in a subject that has recently undergone tumor resection. In some embodiments, the target site is a tumor resection site. In some embodiments, the target site is a draining lymph node. In some embodiments, the target site is a site of cancer therapy, e.g., chemotherapy or radiation. This is the site where cancer cells have previously been treated or killed.

[0435] In some embodiments, the drug delivery composition (e.g., a hydrogel) administered to the target site The gel (containing the cellulose biomaterial and an inhibitor of the p38 MAPK pathway) is a preformed gel, It can be administered to the target site by implantation. In some embodiments, the target site The drug delivery composition (e.g., the precursor components of the hydrogel and the p38 MAPK pathway) administered to the The therapeutic agent (including an inhibitor of the tract) is in an injectable format (eg, liquid). In some embodiments, the administration described herein is in situ interactive or reacts to form a gel composition as described herein. In some such embodiments, the method includes administering precursor components of the material (e.g., hydrogel). In some embodiments, such interactions or reactions include cross-linking. In some embodiments, this can occur spontaneously, or in some embodiments, by application of an agent (e.g., a catalyst and / or or reactants) and / or conditions (e.g., heat, pH, pressure, at a particular wavelength). In some embodiments, the electromagnetic radiation may be one or more of the following: In addition, the biomaterial (e.g., hydrogel) may be modified with a thiol (e.g., EXTRACEL®, HYSTE M®), methacrylates, hexadecylamides (e.g., HYMOVIS®), and and / or tyramine (e.g., CORGEL®) can be added to crosslink the In some embodiments, the biomaterial (e.g., hydrogel) is aldehydes (e.g., HYLAN-A®), divinyl sulfones (DVS) (e.g., HYLAN-B®), 1,4-butanediol diglycidyl ether (BDDE) (e.g., RESTYLANE®) , glutaraldehyde, and / or genipin ( For example, Khunmanee et al., "Crosslinking method of hyaluronic-based hydrogel for biom (See, "Edical applications" J Tissue Eng. 8: 1-16 (2017)). The biomaterial (e.g., hydrogel) may be made of divinyl sulfone (DVS) (e.g., HYLAN-B®). It is crosslinked by

[0436] In some embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount of the compound described herein. Implanting an effective amount of the drug delivery composition or device described herein (e.g., into a biomaterial). via administration of a set of collagen gels or precursors thereof as described herein In some embodiments, the methods described herein comprise administering to a subject the method described herein. and surgically implanting an effective amount of the drug delivery composition or device described in In some embodiments, the methods described herein include, following surgical removal of the tumor, In some embodiments, the present invention further comprises implanting the drug delivery composition or device. The methods described herein involve administering a drug delivery composition or device to a patient at the site of tumor resection. In one embodiment, the methods described herein further include implanting the tumor in a tissue sample. implanting a drug delivery composition or device in the void volume of the resected tumor. In some embodiments, the methods described herein further comprise a tumor resection surgical procedure. and implanting a drug delivery composition or device at the tumor resection site during surgery. Included.

[0437] In some embodiments, the methods described herein involve the determination of tumor mass by weight after resection. 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more , after removal of 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more In some embodiments, the drug delivery composition or device is administered (e.g., implanted). In accordance with the present invention, the method described herein provides a method for the treatment of tumors in which 50% or more of the resected tumor is removed by volume. , 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more After removal of 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more of the drug delivery composition, This includes administering (eg, implanting) a composition or device.

[0438] In some embodiments, the methods described herein involve drug delivery to a site adjacent to a tumor. The method does not include administering (e.g., implanting) a delivery composition or device. The methods described herein provide for drug delivery adjacent to a tumor without tumor resection. The method does not include administering (eg, implanting) a delivery composition or device.

[0439] In some embodiments, the drug delivery compositions and devices described herein are It is administered in combination with one or more additional therapeutic agents described herein. In such cases, the additional therapeutic agent is an anti-cancer agent.

[0440] In some embodiments, the subject being treated is a mammal. is a human. In some embodiments, the subject has undergone neoadjuvant (preoperative) chemotherapy. In some embodiments, the subject is a human patient who has undergone neoadjuvant radiation therapy. In some embodiments, the subject is a patient who has received neoadjuvant chemotherapy and radiation therapy. In some embodiments, the subject is a human patient who has received a neoadjuvant molecular targeted therapy. In some embodiments, the subject is a human patient who has been treated with immune checkpoint blockade (e.g., Humans who have received neoadjuvant immunotherapy including anti-CTLA-4, anti-PD-1 and / or anti-PD-L1 In some embodiments, the subject is a patient receiving immune checkpoint blockade (e.g., anti-CTLA-4 Human patients who have not received neoadjuvant immunotherapy including anti-PD-1 and / or anti-PD-L1 In some embodiments, the subject is a patient whose tumor responds objectively to neoadjuvant treatment. Response Evaluation Criteria in Solid Tumors rs:RECIST) or immune-related Response Criteria (irRC) The subject is a human patient (e.g., stable disease, progressive disease) (as defined by the above references). Subjects must have had their target lesions objectively respond to neoadjuvant treatment ( For example, partial response, complete response) in human patients. Non-target lesions may be incomplete responses, stable disease, etc. In some embodiments, the subject may be presenting with an adjuvant (surgical) disease. Humans who would be eligible to receive immunotherapy as a standard of care in post-marketing settings In some embodiments, the subject is a human, such as a dog, cat, cow, pig, 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 one embodiment, the subject is a zoo animal. In another embodiment, the subject is a rodent. In some embodiments, the subject is a research animal, such as a rodent, pig, dog, or non-human primate. a non-human transgenic animal, such as a transgenic mouse or a transgenic pig; Nick is an animal.

[0441] example In order that the invention described herein may be more fully understood, the following examples are set forth. These examples are for illustrative purposes only and are not intended to illustrate, or be construed as limiting the invention in any manner whatsoever. It should be understood that the above should not be construed as limiting.

[0442] Example 1. Preparation and Use of Exemplary Drug Delivery Compositions To prepare hydrogels according to some embodiments described herein, crosslinking Crosslinkable hyaluronic acid (e.g., thiol-modified hyaluronic acid such as GLYCOSIL® hyaluronic acid) hyaluronic acid) and chemical crosslinkers (e.g., thiol such as polyethylene diacrylate). reactive crosslinkers, such as EXTRALINK® polyethylene glycol diacrylate The hydrogel was formed by combining the combined The reagents were allowed to stand for at least 1 hour to form the hydrogel. The shelf moduli were measured using a rheometer and are summarized in Table 1. Table 1. [Table 1]

[0443] The hydrogel for Figure 1 was prepared according to the method described for Hydrogel 1 in Table 1. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. 1 mg of a p38 MAPK inhibitor (e.g., losmapimod (Selleckchem)) was added to 10 μL of DMSO. The hyaluronic acid was dissolved in 1000g of ... After mixing to create the fabric, add 30 μL of PEG-diacrylate crosslinker solution (12.5% ​​w / v E The crosslinked hydrogel was then pipetted into the mold. Female BALB / cJ mice were orthotopically implanted in their fourth mammary fat pad. Each mouse was inoculated with 4T1-Luc2 breast cancer cells. Ten days after tumor inoculation, tumors (approximately 100 mm 3 ) is removed Then, hydrogels (e.g., crosslinked hydrogels) loaded with p38 MAPK inhibitors (e.g., losmapimod) were The empty hydrogel was placed in the tumor resection site. The p38 inhibitor was used as a negative control. The benefit of extended local release of the p38 inhibitor in terms of increased survival was observed. (Figure 1).

[0444] The hydrogel for Figure 2 was prepared according to the method described for Hydrogel 1 in Table 1. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. 500 μg (40 μL) of anti-IL-1β antibody (e.g., clone B122 (BioXCell)) was added to the template. After mixing to produce a uniform distribution of the payload, Pipette 30 μL of PEG-diacrylate crosslinker solution (12.5% ​​w / v EXTRALINK) into the mold. The crosslinked hydrogel solidified in the mold over the course of a few minutes. BALB / cJ mice were orthotopically seeded with 4T1-Luc2 breast cancer cells in their fourth mammary fat pad. On the 10th day after tumor inoculation, the tumor (approximately 100 mm 3 ) and anti-IL-1β antibody (e.g., Hydrogels (e.g., cross-linked hyaluronic acid hydrogels) loaded with lysine B122) was placed into the tumor resection site. An empty hydrogel was used as a negative control. A survival benefit was observed due to the extended local release of antibody (Figure 2).

[0445] The hydrogel for Figure 3 was prepared according to the method described for Hydrogel 1 in Table 1. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. 500 μg (40 μL) of anti-IL-6 antibody (e.g., clone MP5-20F3 (BioXCell)) was added to the template. After mixing to produce a uniform distribution of the payload, Pipet 30 μL of PEG-diacrylate crosslinker solution (12.5% ​​w / v EXTRALINK) into the mold. The crosslinked hydrogel solidified in the mold over the course of a few minutes. BALB / cJ mice were orthotopically seeded with 4T1-Luc2 breast cancer cells in their fourth mammary fat pad. On the 10th day after tumor inoculation, the tumor (approximately 100 mm 3 ) and anti-IL-6 antibody (e.g., Clomid) was administered. Hydrogels (e.g., cross-linked hyaluronic acid hydrogels) loaded with erythrocyte spheroids (MP5-20F3) ) was placed into the tumor resection site. An empty hydrogel was used as a negative control. Anti-IL-6 A survival benefit was observed due to the extended local release of antibody (Figure 3).

[0446] Equivalents and Scope In the claims, articles such as "a," "an," and "the" are used interchangeably with the context. Unless otherwise indicated or clear, it may mean one or more than one. Any claim or description containing "or" between one or more members of a group is understood to be non-negotiable unless the context requires otherwise. Unless otherwise indicated or made clear by the Are one, more than one, or all of them present in a given product or process? , as used herein or otherwise related thereto, are considered to be satisfied. The present invention relates to a method for producing a compound comprising the steps of: Aspects present in, used in, or otherwise related to the process The present invention includes the methods of producing a compound according to the present invention, wherein more than one or all of the groups are present in a given product or is present in, used in, or otherwise related to the process Certain embodiments include.

[0447] Furthermore, the present invention may be practiced without limitation, element, clause or other limitation from one or more of the enumerated claims. and all variations, combinations and descriptive terms are included in the claims. For example, any claim that is dependent on another claim may be treated as if it were the same base claim. may be modified to include one or more limitations found in any other claim that depends on it. If the elements exist as lists, e.g. in the form of a Markush group, Each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, it will be understood that the invention or aspects of the invention include certain elements and / or features. When referred to as such, an embodiment or aspect of the invention refers to such elements and / or It should be understood that the features consist of or consist essentially of the features. As such, these aspects are not specifically described in the present specification. The terms "comprising" and "containing" mean open Note that the present invention is intended to allow for the inclusion of additional elements or steps. Additionally, unless otherwise indicated by the context and the understanding of one of ordinary skill in the art, endpoints are included. Unless otherwise specified or clearly stated, values ​​expressed as ranges are intended to be within the meaning of the present invention in various aspects. Any specific value or subrange stated herein is understood to be false, unless the context clearly dictates otherwise. This allows for a range up to one-tenth of the unit of the lower limit.

[0448] This application is incorporated herein by reference in its entirety. The following references are cited: In the event of a conflict between any of the cited references and this specification, the present specification shall control. In addition, any particular aspect of the present invention that falls within the prior art is not necessarily limited to the claimed invention. Any one or more of the following aspects are expressly excluded from the scope of the present invention: Therefore, they are considered to be exempt from exclusion even if the exclusion is not expressly set forth herein. Any particular aspect of the invention may be excluded from any claim. may be excluded for arbitrary reasons, whether or not related to the existence of prior art. do.

[0449] Those skilled in the art will recognize many equivalents to the specific embodiments described herein. or could be ascertained using no more than routine experimentation. The scope of the embodiments of the present invention described herein is not intended to be limited to the above description. The present invention is not limited to the above-mentioned embodiments, but is as set forth in the appended claims. Without departing from the spirit or scope of the present invention as defined in the appended claims, the present invention may be modified in any manner without departing from the spirit or scope of the present invention as defined in the appended claims. It will be understood that various changes and modifications can be made to the.

[0450] The entire contents of International Patent Publication No. WO 2018 / 045058 (e.g., compositions, devices, methods of preparation, The methods of use, and kits are as described herein for the purposes described herein. This document is incorporated by reference in its entirety.

Claims

1. Biomaterials and p38 mitogenic activity at tumor resection sites in cancer-affected subjects Contains inhibitors of proinflammatory immune responses mediated by the activator protein kinase (MAPK) pathway Intraoperative Administration of the Composition A method comprising the steps of:

2. 10. The biomaterial of claim 1, wherein the biomaterial is characterized by a storage modulus of about 500 Pa to about 50,000 Pa. How to do it.

3. 10. The method of claim 1, wherein the step of administering does not include adoptive transfer of T cells into the subject.

4. 10. The method of claim 1, wherein the step of administering does not include administering a tumor antigen to the subject.

5. 10. The method of claim 1, wherein the step of administering does not include administering microparticles to the subject.

6. The method of claim 1 , wherein the biomaterial is or comprises a hydrogel.

7. The method of claim 6, wherein the biomaterial is or comprises hyaluronic acid.

8. 8. The method of claim 7, wherein the biomaterial is or comprises cross-linked hyaluronic acid. method.

9. The biomaterial is hyaluronic acid cross-linked with a polyethylene glycol cross-linker, or The method of claim 8, comprising:

10. The inhibitor binds to the ATP and / or allosteric binding sites of p38 MAPK.

10. The method of claim 1, wherein the compound is or comprises a toxic agent.

11. The inhibitor binds to the ATP and / or allosteric binding sites of p38 MAPK.

10. The method of claim 1, which is or comprises a PK inhibitor.

12. 12. The method of claim 11, wherein the p38α / β MAPK inhibitor is or comprises losmapimod. method.

13. The method of claim 1, wherein the composition further comprises an activator of innate immunity.

14. Innate immune activators are stimulator of interferon genes (STING) agonists 14. The method of claim 13, comprising or

15. Activators of innate immunity are Toll-like receptor (TLR) 7 and / or TLR8 ("TLR7 / 8") agonists.

14. The method of claim 13, being or comprising:

16. The composition modulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells.

10. The method of claim 1, further comprising activators of adaptive immunity and / or cytokines. 。

17. The composition may further comprise cytokines that regulate T cells, NK cells, monocytes, and / or dendritic cells. and the cytokines include IL-15 superagonist, IFN-α, IFN-β, IFN-γ 10. The method of claim 1, wherein the hydroxyl group is selected from the group consisting of:

18. The method of claim 1 , wherein the composition further comprises a COX inhibitor.

19. The method of claim 1, wherein the composition further comprises a COX-2 inhibitor.

20. The method of claim 1. The biomaterial forms a matrix or depot and the inhibitor is in biomaterials.

21. 21. The method of claim 20, wherein the inhibitor is released by diffusion through the biomaterial.

22. The method of claim 1 , wherein the biomaterial is biodegradable in vivo.

23. The biomaterial is implanted in the mammary fat pad of a mouse subject. When tested in vivo, less than 10% of the biomaterial remains in vivo 4 months after implantation 2. The method according to claim 1 .

24. The biomaterial is placed in PBS (pH 7.4) to form a composition containing the biomaterial and losmapimod. When tested in vitro by 2. The method of claim 1, wherein the material is released.

25. The biomaterial is administered to a mouse subject using a composition comprising the biomaterial and losmapimod in the mammary fat pad of the subject. When tested in vivo by implantation in 2. The method of claim 1, wherein the compound is released in vivo 8 hours after implantation.

26. When the inhibitor is administered in solution, the biomaterial is evaluated 24 hours after administration. There is more inhibitor present at the tumor resection site compared to what is observed 10. The method of claim 1, wherein the release of the inhibitor is prolonged.

27. The method of claim 1, wherein the administration is by implantation.

28. 10. The method of claim 1, wherein the administration is by injection.

29. The administration may include injecting one or more precursor components of the biomaterial and administering the biomaterial to the tumor resection site.

30. The method of claim 28, comprising allowing the biomaterial to form in a

30. The method of claim 1, wherein the tumor resection site is characterized by the absence of residual tumor antigens to the naked eye. How to post.

31. The method of claim 1, wherein the cancer is metastatic cancer.

32. and further comprising monitoring at least one metastatic site in the subject after administration.

32. The method of claim 31 , comprising:

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