Cancer Treatment

Abstract

Provided herein is a technology suitable for treating certain immune-related disorders. The disclosure provides certain insights regarding effective immunomodulatory therapy. In certain embodiments, the provided technology is particularly useful for treating cancer. In particular, the disclosure provides the insight that certain immunomodulatory compositions can have an effective effect when administered to a resection site where at least one lymph node is partially or entirely removed. For example, the disclosure describes the use of certain biomaterial preparations as immunomodulatory compositions in particular.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 143,836, filed January 30, 2021, the contents of which are incorporated herein in their entirety. [Background technology]

[0002] Cancer diagnosis and treatment each often involve the partial or complete removal of one or more lymph nodes. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides certain insights into effective immunomodulatory therapies. In certain embodiments, the provided technology is particularly useful for the treatment of cancer.

[0004] In particular, the present disclosure provides insight that certain immunomodulatory compositions can have an effective effect when administered to a resection site where at least one lymph node has been partially or entirely removed. For example, the present disclosure describes the use of certain biomaterial preparations as inter alia immunomodulatory compositions.

[0005] The present disclosure further recognizes that certain biomaterial preparations characterized by immunomodulatory properties may be particularly useful in the practice of the technology described herein, in some cases even without an immunomodulatory payload (see, e.g., PCT / US20 / 31169, filed May 1, 2020; WO2018 / 045058 and / or WO2019 / 183216).

[0006] Thus, among other things, the present disclosure provides insight that certain biomaterial preparations may be particularly useful and / or may provide particular beneficial effects when administered in certain manners, e.g., as described herein.

[0007] In some embodiments, the present disclosure identifies the source of problems with certain existing technologies, including, for example, problems with certain systemic administration and / or delivery routes of anti-cancer therapeutics.

[0008] Additionally, the present disclosure provides insight that unexpected benefits and / or advantages may be achieved by combining administration of the immunomodulatory compositions (e.g., biomaterial preparations) described herein with lymph node dissection, particularly since lymph node dissection is often performed relatively early in the process of diagnosing and / or treating a cancer patient, early intervention may be particularly useful.

[0009] Furthermore, the present disclosure recognizes that the immunomodulatory effects of administration described herein may be particularly effective because the immune system component(s) (e.g., T cells, B cells, etc.) modulated by the treatment provided may act in the lymph node itself and may also migrate, for example, via the lymphatic and / or circulatory systems, to other locations, including the primary tumor and / or one or more metastases.

[0010] Still further, the present disclosure recognizes that various investigators have reported activation of metastatic lesions following lymphadenectomy (see, e.g., Sukhbaatar et al., Cancer Sci. 110(2):509-518, 2019 Feb (published online as doi:10.1111 / cas.13898)), and teaches that in some embodiments, the provided techniques may provide a therapeutic effect on existing tumors and / or metastases and / or reduce the risk or incidence of adverse effect(s) (e.g., activation of metastases) that may otherwise accompany a lymphadenectomy event.

[0011] In some embodiments, the present disclosure provides methods of treating cancer comprising, inter alia, administering an immunomodulatory composition to a lymph node dissection site in a cancer subject, hi some embodiments, such methods comprise administering a composition comprising an effective amount of an immunomodulatory composition to a target site in a cancer subject, where the target site is or comprises a lymph node dissection site.

[0012] In some embodiments, immunomodulatory compositions that may be useful according to the present disclosure may be characterized by an ability to induce an innate immune response. In some embodiments, immunomodulatory compositions that may be useful according to the present disclosure may be characterized by an ability to induce an adaptive immune response. In some embodiments, immunomodulatory compositions that may be useful according to the present disclosure may be characterized by an ability to induce an innate and adaptive immune response. In some embodiments, immunomodulatory compositions that may be useful according to the present disclosure may be characterized by an ability to inhibit an immunosuppressive inflammatory response.

[0013] In some embodiments, an immunomodulatory composition that may be useful according to the present disclosure is or comprises a biomaterial preparation. In some embodiments, a biomaterial preparation included in an immunomodulatory composition described herein may be or comprise a polymeric biomaterial preparation. In some embodiments, such a polymeric biomaterial preparation may comprise one or more polymers (e.g., at least one polymer, at least two polymers, or more). In some embodiments, such a polymeric biomaterial preparation may comprise a thermoresponsive polymer. In some embodiments, such a thermoresponsive polymer may be or comprise a poloxamer. Additionally or alternatively, in some embodiments, the polymeric biomaterial preparation may comprise a carbohydrate polymer. For example, in some embodiments, the carbohydrate may comprise hyaluronic acid and / or chitosan or modified chitosan. In some embodiments, polymeric biomaterial preparations that may be useful according to the present disclosure include 7-12.5% ​​(w / w) poloxamer, and 0.5-7% (w / w) hyaluronic acid and / or 0.5-7% (w / w) chitosan or modified chitosan.

[0014] In some embodiments, immunomodulatory compositions that may be useful according to the present disclosure may include a biomaterial preparation (e.g., as described herein) and at least one immunomodulatory payload. In some embodiments, such immunomodulatory payload is or includes a modulator of innate immunity. In some embodiments, such immunomodulatory payload is or includes a modulator of myeloid cell function. In some embodiments, such immunomodulatory payload is or includes a modulator of adaptive immunity. In some embodiments, such immunomodulatory payload is or includes a modulator of inflammation. In some embodiments, such immunomodulatory payload is or includes a Toll-like receptor (TLR) agonist (e.g., a TLR7 / 8 agonist). In some embodiments, such immunomodulatory payload is or includes resiquimod. In some embodiments, such immunomodulatory payload is or includes a cyclooxygenase (COX) inhibitor. In some embodiments, such immunomodulatory payloads are or include nonsteroidal anti-inflammatory drugs (NSAIDs), such as, but not limited to, ketorolac. In some embodiments, such immunomodulatory payloads are or include angiotensin II receptor inhibitors, such as, for example, valsartan. In some embodiments, such immunomodulatory payloads are or include a CXCR4 receptor antagonist, such as, for example, plerixafor. In some embodiments, such immunomodulatory payloads are or include an immunomodulatory cytokine, such as, for example, IL-2 or IL-12.

[0015] In some embodiments, the techniques described herein may be suitable for cancer subjects who are candidates for tumor resection surgery.

[0016] In some embodiments, the disclosure provides a method of treating cancer comprising removing at least one lymph node proximal to a tumor in a cancer subject prior to administration of an immunomodulatory composition to a lymph node dissection site. In some embodiments, such removal of at least one lymph node may be performed during tumor resection surgery. Alternatively, in some embodiments, such removal of at least one lymph node may be performed in a separate operation from the tumor resection surgery.

[0017] In some embodiments involving tumor resection surgery, a second immunomodulatory composition may be administered to the tumor resection site. In some embodiments, the second immunomodulatory composition administered to the tumor resection site may be the same as the immunomodulatory composition administered to the lymph node dissection site of the cancer subject. Alternatively, in some embodiments, the second immunomodulatory composition administered to the tumor resection site may be different from the immunomodulatory composition administered to the lymph node dissection site.

[0018] In some embodiments involving tumor resection surgery, such tumor resection surgery may include removal of at least a portion of an organ containing the tumor, hi some embodiments, such tumor resection surgery may further include anastomosis following removal of at least a portion of an organ containing the tumor.

[0019] In some embodiments, the techniques described herein are suitable for lymph nodes that may be or include sentinel lymph nodes, draining lymph nodes, axillary lymph nodes, inguinal lymph nodes, femoral lymph nodes, facial lymph nodes, cervical lymph nodes, supraclavicular lymph nodes, inclavicular lymph nodes, pectoral lymph nodes, mediastinal lymph nodes, pelvic lymph nodes, mesenteric lymph nodes, and / or retroperitoneal lymph nodes. In some embodiments, such lymph nodes may be or include sentinel lymph nodes. In some embodiments, such lymph nodes may be or include draining lymph nodes.

[0020] In some embodiments, the disclosure provides a method of treating cancer comprising intraoperatively administering an immunomodulatory composition (e.g., as described herein) to a target site that is or includes a lymph node dissection site in a subject with cancer undergoing lymph node dissection surgery. In some embodiments, the lymph node dissection surgery may further include anastomosis.

[0021] In some embodiments, the techniques described herein may be useful in the treatment of cancer, including, for example, but not limited to, carcinoma, sarcoma, germ cell tumor, blastoma, lymphoma, skin cancer, melanoma, laryngeal head and neck cancer, thyroid cancer, brain cancer, bladder cancer, gastrointestinal cancer (e.g., gastric cancer), breast cancer, lung cancer, breast cancer, colorectal cancer, genitourinary cancer, renal cancer, prostate cancer, gynecological cancer, testicular cancer, ovarian cancer, and / or uterine cancer. In some embodiments, the techniques described herein may reduce the likelihood of developing one or more symptoms associated with lymphedema and / or lymphocele, as compared to lymph node dissection without administration of an immunomodulatory composition described herein.

[0022] In some embodiments, the techniques described herein may reduce the likelihood of developing one or more metastatic foci compared to lymph node dissection without administration of an immunomodulatory composition.

[0023] In one aspect, the disclosure provides, among other things, improvements in methods of treating cancer by administration of an immunomodulatory composition during surgery. In some embodiments, such improvements include administering an immunomodulatory composition to a lymph node dissection site rather than or in addition to a tumor resection site. In some embodiments, such immunomodulatory compositions include a combination of a biomaterial preparation and an immunomodulatory agent payload, or are a combination of a biomaterial preparation and an immunomodulatory agent payload. In some embodiments, such immunomodulatory compositions include a biomaterial preparation in the absence of an immunomodulatory agent payload. [Brief description of the drawings]

[0024] [Figure 1]A graphical representation of a survival analysis is shown. Data are presented as Kaplan-Meier survival curves showing survival of BALB / cJ female mice orthotopically seeded with 4T1-Luc2 cells. These cells were allowed to generate primary tumors. The primary tumors and proximal lymph nodes were then surgically removed. Immediately following removal of the primary tumors and proximal lymph nodes, an exemplary composition comprising a biomaterial preparation (a thermoresponsive polymer solution that forms a hydrogel at body temperature) and an immunomodulatory payload (resiquimod (R848)) was implanted at a target site at and / or near the lymph node resection site. Administration of the composition containing the immunomodulatory payload resulted in an increase in the lifespan of the animals when compared to a composition lacking the immunomodulatory payload. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] definition Activator of adaptive immune response: The term "activator of adaptive immune response" refers to an agent in the presence of which the adaptive immune system is more active than in the absence of the agent. Without wishing to be bound by any particular theory, in some embodiments, it has been proposed that the activity (e.g., activation) of the adaptive immune system can restore or enhance anti-tumor function, for example, by neutralizing inhibitory immune checkpoints and / or activating costimulatory receptors, ultimately resulting in helper and / or effector T cell responses against immunogenic antigens expressed by cancer cells, and generating memory B cell and / or T cell populations. Alternatively or additionally, in certain embodiments, the activity (e.g., activation) of the adaptive immune system can be involved in regulating adaptive immune responses and / or leukocyte trafficking.

[0026] Activator of the innate immune response: The term "activator of the innate immune response" refers to an agent in the presence of which the innate immune system is more active than in the absence of the agent. Without wishing to be bound by any particular theory, in some embodiments, it has been proposed that activity (e.g., activation) of the innate immune system can stimulate the expression of molecules that help initiate an inflammatory response and / or induce an adaptive immune response, for example, thereby resulting in the development of antigen-specific adaptive immunity. In some embodiments, activity (e.g., activation) of the innate immune system can result in cytokine production, immune cell proliferation and / or survival, and / or improved T cell priming, for example, by increasing the presentation of antigens by antigen-presenting cells and / or the expression of costimulatory molecules.

[0027] Administration: The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a composition as described herein into a site or subject.

[0028] Agonist: The term "agonist" refers to an agent that (i) enhances or induces one or more effects of another agent, and / or (ii) increases or induces one or more biological events. In some embodiments, an agonist can increase the level and / or activity of one or more agents to which it targets. In various embodiments, agonists can be or include agents of various chemical classes, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or other substances that exhibit related agonist activity. Agonists can be direct (where the agonist directly affects the target) or indirect (where the agonist exerts its effect other than by binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered). A partial agonist may act as a competitive antagonist in the presence of a full agonist because it competes with the full agonist to interact with its target and / or its modulator, thereby causing (i) a decrease in one or more effects of another agent, and / or (ii) a decrease in one or more biological events compared to that observed with the full agonist alone.

[0029] Antagonist: The term "antagonist" refers to an agent that (i) attenuates or inhibits one or more effects of another agent, and / or (ii) reduces or inhibits one or more biological events. In some embodiments, an antagonist may reduce the level and / or activity of one or more agents to which it targets. In various embodiments, antagonists can be or include agents of various chemical classes, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or other substances that exhibit related antagonist activity. Antagonists can be direct (where the antagonist directly affects the target) or indirect (where the antagonist affects the target other than by binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered). In some embodiments, the antagonist may be a receptor antagonist, e.g., a receptor ligand or a drug, that inhibits or attenuates a biological response by binding to and blocking the receptor rather than activating the receptor as an agonist does.

[0030] Antibody: As used herein, the term "antibody" refers to a polypeptide that contains sufficient canonical immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, naturally produced intact antibodies are approximately 150 kD tetrameric agents composed of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other in what is commonly referred to as a "Y-shaped" structure. Each heavy chain is composed of at least four domains (each about 110 amino acids long): an amino-terminal variable (VH) domain (at the tip of the Y structure), followed by three constant domains: CH1, CH2, and a carboxy-terminal CH3 (at the base of the stem portion of the Y). A short region known as the "switch" links the heavy chain variable region and the heavy chain constant region. A "hinge" links the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region link two heavy chain polypeptides together in an intact antibody. Each light chain is composed of two domains, an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain, separated from each other by another "switch". An intact antibody tetramer is composed of two heavy-light chain dimers in which the heavy and light chains are linked to each other by a single disulfide bond. Two other disulfide bonds link the heavy chain hinge regions together so that the dimers are linked to each other to form a tetramer. Naturally produced antibodies are also typically glycosylated in the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold" formed by two β-sheets (e.g., 3-, 4-, or 5-stranded sheets) bundled together into a compressed antiparallel β-barrel. Each variable domain contains three hypervariable loops known as "complementarity determining regions" (CDR1, CDR2, and CDR3) and four more invariant "framework" regions (FR1, FR2, FR3, and FR4).When a natural antibody folds, the FR regions form beta sheets that provide a structural framework for the domains, and the CDR loop regions of both the heavy and light chains assemble in three-dimensional space to produce a single hypervariable antigen-binding site located at the tip of a Y-structure. The Fc region of a naturally occurring antibody binds to components of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region for the Fc receptor can be modulated by glycosylation or other modifications. In some embodiments, the antibodies produced and / or utilized according to the present invention comprise a glycosylated Fc domain, including Fc domains in which such glycosylation has been modified or engineered. For purposes of the present invention, in certain embodiments, any polypeptide or complex of polypeptides that contains a sufficient immunoglobulin domain sequence found in a natural antibody may be referred to as and / or used as an "antibody," regardless of whether such polypeptide is naturally generated (e.g., generated by an organism in response to an antigen) or generated by recombinant engineering, chemical synthesis, or other artificial systems or methodologies. In some embodiments, the antibody is polyclonal. In some embodiments, the antibody is monoclonal. In some embodiments, the antibody has constant region sequences characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody sequence elements are humanized, primatized, chimeric, etc., as is well known in the art. Furthermore, the term "antibody," as used herein, may, in appropriate embodiments (unless otherwise specified or otherwise clear from the context), refer to any of the constructs or formats known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative applications.For example, in some embodiments, the antibodies utilized in accordance with the present invention are in a format selected from, but not limited to, intact IgA, IgG, IgE, and IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies, alternative scaffolds or antibody mimetics (e.g., anticalins, FN3 monobodies, DARPins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Avimers, Fynomers, Im7, VLRs, VNARs, Trimbabs, CrossMab, Tridents); nanobodies, bi-nanobodies, F(ab')2, Fab', di-sdFvs, single domain antibodies, trifunctional antibodies, diabodies, and minibodies, etc. In some embodiments, suitable formats may be or may include: Adnectin®; Affibody®; Affilin®; Anticalin®; Avimer®; BiTE®; camelid-like antibodies; Centyrin®; Ankyrin repeat proteins or DARPIN®; Dual Affinity Retargeting (DART) agents; Fynomer®; Shark single domain antibodies such as IgNAR; Immunomobilizing anti-cancer monoclonal T cell receptors (ImmTACs); KALBITOR®; MicroProteins; Nanobodies®, minibodies; masked antibodies (e.g., Probody®); Small Modular ImmunoPharmaceutical ("SMIP™"); single chain or tandem diabodies (TandAb®); TCR-like antibodies; Trans-body®; TrimerX®; VHHs. In some embodiments, the antibody may lack covalent modifications (eg, glycan attachment) that it has when produced in nature.In some embodiments, the antibodies may contain covalent modifications (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant groups (e.g., polyethylene glycol, etc.).

[0031] Bioadhesive: The term "bioadhesive" refers to a biocompatible agent that can adhere to a target surface, e.g., a tissue surface. In some embodiments, the bioadhesive can adhere to a target surface, e.g., a tissue surface, and can remain on the target surface for a period of time. In some embodiments, the bioadhesive can be biodegradable. In some embodiments, the bioadhesive can be a natural agent, e.g., that may be prepared or obtained by isolation or synthesis. In some embodiments, the bioadhesive can be a non-natural agent, e.g., that may be designed and / or manufactured by the hand of man, e.g., by processing, synthesis, and / or recombinant production depending on the agent, as will be appreciated by those of skill in the art. In some particular embodiments, the bioadhesive can be or include, for example, a polymeric material that can be composed of or contain multiple monomers, e.g., sugars. Certain exemplary bioadhesives include various FDA approved agents, e.g., cyanoacrylates (Dermabond, 2-octyl cyanoacrylate; Indermil, n-butyl-2-cyanoacrylate; Histoacryl and Histoacryl). Blue, n-butyl-2-cyanoacrylate), albumin and glutaraldehyde (BioGlue™, bovine serum albumin and 10% glutaraldehyde), fibrin glues (Tisseel™, pooled human plasma fibrinogen and thrombin; Evicel™, pooled human plasma fibrinogen and thrombin; Vitagel™, autologous plasma fibrinogen and thrombin; Cryoseal™ system, autologous plasma fibrinogen and thrombin), gelatin and / or resorcinol crosslinked with formaldehyde and / or glutaraldehyde, polysaccharide-based adhesives (gelatin, collagen, dextran, chitosan, alginate), PEG, acrylate, polyamine, or urethane derivatives (isocyanate-terminated prepolymers), and / or combinations thereof.Other examples of bioadhesives known in the art, such as those described in Mehdizadeh and Yang "Design Strategies and Applications of Tissue Bioadhesives" Macromol Biosci 13:271-288 (2013), may be used for the methods described herein. In some embodiments, the bioadhesive may be a degradable bioadhesive. Examples of such degradable bioadhesives include, but are not limited to, fibrin glues, gelatin-resorcinol-formaldehyde / glutaraldehyde adhesives, poly(ethylene glycol) (PEG)-based hydrogel adhesives, polysaccharide adhesives, polypeptide adhesives, polymer adhesives, biomimetic bioadhesives, and those described in Bhagat and Becker "Degradable Adhesives for Surgery and Tissue Engineering" Biomacromolecules 18:3009-3039 (2017).

[0032] Biocompatible: The term "biocompatible" refers to a material that is substantially non-toxic in its intended in vivo environment and is not substantially rejected by the patient's physiological system (i.e., is non-antigenic). Biocompatibility may be evaluated by the ability of the material to pass the biocompatibility tests set forth in International Organization for Standardization (ISO) Standard No. 10993 and / or United States Pharmacopeia (USP) 23 and / or U.S. Food and Drug Administration (FDA) Blue Book Memorandum #G95-1 entitled "Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing." Typically, these tests measure the toxicity, infectivity, pyrogenicity, irritancy, reactivity, hemolytic activity, carcinogenicity, and / or immunogenicity of the material. A biocompatible structure or material, when introduced into the majority of patients, does not cause undesirable, harmful, long-lasting, or increasing biological reactions or responses, as distinguished from the mild, transient inflammation that is typically associated with surgery or the implantation of a foreign body into the living body.

[0033] Biological products: The terms "biological product", "biological drug", and "biological product" refer to a wide range of products, such as vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biological products may contain sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living organisms such as cells and tissues. Biological products may be isolated from a variety of natural sources (e.g., human, animal, microbial) and / or produced by biotechnological methods and / or other techniques.

[0034] Biological sample: The term "biological sample" refers to a primary sample obtained from a biological source and / or, in some embodiments, a sample obtained therefrom (e.g., by processing). Those skilled in the art will appreciate that biological samples can include or be selected from, for example, tissue samples (e.g., tissue sections and needle biopsies of tissues); cell samples (e.g., cytological smears (e.g., Pap smears or blood smears) or samples of cells obtained by microdissection); whole organism samples (e.g., yeast or bacterial samples); or cell fractions, cell debris, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, a swab (e.g., a buccal swab), or any substance containing a biological molecule derived from a primary biological sample.

[0035] Biomaterial: The term "biomaterial" refers to a biocompatible substance characterized by the ability to be administered to a subject for medical purposes (e.g., treatment, diagnosis) without eliciting an unacceptable reaction (according to sound medical judgment). Biomaterials can be obtained or derived from nature, or can be synthetic. In some embodiments, the biomaterial can be in the form of a gel. In some embodiments, the biomaterial can be in an injectable form. For example, the biomaterial can include precursor components of a gel that is formed in situ in vivo (e.g., upon administration to a subject).

[0036] Cancer: The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Of particular interest in the context of some embodiments of the present disclosure are cancers that are treated by cell-killing and / or ablative therapy (e.g., surgical resection and / or certain chemotherapeutic drug therapy, such as cytotoxic therapy). In some embodiments, the cancer treated according to the present disclosure is one that has been surgically resected (i.e., at least one tumor has been surgically removed). In some embodiments, the cancer treated according to the present disclosure is one where resection is the standard of care. In some embodiments, the cancer treated according to the present disclosure is one that has metastasized. In certain embodiments, exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bile duct carcinoma; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colon rectal adenocarcinoma;connective tissue cancer;epithelial carcinoma;ductal intraepithelial carcinoma;ependymoma;endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma);endometrial cancer (e.g., uterine carcinoma, uterine sarcoma);esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma);Ewing's sarcoma;eye cancer (e.g., intraocular melanoma, retinoblastoma);familial hypereosinophilia;gallbladder cancer;gastric cancer (e.g., gastric adenocarcinoma);gastrointestinal stromal tumor (GIST);germ cell carcinoma;head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma);Hematopoietic cancers (e.g., leukemias, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas, 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 ... Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a combination of one or more leukemias / lymphomas as above; multiple myeloma; heavy chain disease ( e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma (also known as Wilms' tumor), renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); melanoma; midline carcinoma; multiple endocrine neoplasia syndrome; muscle carcinoma; myelodysplastic syndrome (MDS); mesothelioma;Myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); nasopharyngeal carcinoma; neuroblastoma; neurofibromas (e.g., neurofibromatosis type 1 or type 2, schwannomatosis); Neuroendocrine cancers (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 tumors); parathyroid carcinoma; papillary adenocarcinoma; penile cancer (e.g., Paget's disease of the penis and scrotum); pharyngeal cancer; pinealoma; ptosis Corpus cancer; pleuropulmonary blastoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasms; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH ), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; gastric cancer; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thymic carcinoma; thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0037] Chemotherapeutic agent: The term "chemotherapeutic agent" refers to a therapeutic agent known to be useful in the chemotherapy of cancer.

[0038] Co-crystal: The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal contains a compound of interest (e.g., as disclosed herein) and one or more other component(s), such as one or more atoms, ions, or molecules (e.g., solvent molecules). In certain embodiments, a co-crystal contains a compound of interest and one or more solvent molecules. In certain embodiments, a co-crystal contains a compound of interest and one or more acids or bases.

[0039] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more treatment regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, two or more treatment regimens may be administered simultaneously. In some embodiments, such treatment regimens may be administered sequentially (e.g., all "doses" of a first treatment regimen are administered before any dose of a second treatment regimen is administered). In some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administration of one or more agent(s) or therapy(s) in combination to a subject receiving other agent(s) or therapy(s). For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents or active portions thereof may be administered together as a mixed composition or even as a combination of compounds (e.g., as part of a single chemical complex or covalent conjugate).

[0040] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to each other, but are sufficiently similar to allow a comparison between them so that a person skilled in the art will understand that a conclusion can be reasonably drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, situations, individuals, or populations is characterized by a number of substantially identical characteristics and one or a few varying characteristics. A person skilled in the art will understand what degree of identity is required for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable in any given situation in the context. For example, a person skilled in the art will understand that a set of situations, individuals, or populations is comparable to each other when it is characterized by a sufficient number and type of substantially identical characteristics to ensure a reasonable conclusion that differences in results obtained or phenomena observed under or with the different sets of situations, individuals, or populations are caused by or indicate the existence of differences in various of those characteristics. Those skilled in the art will also understand that when the term "comparable" is used in the context of comparing two or more values, such values ​​are comparable to each other such that the difference in the values ​​does not result in a substantial difference in the therapeutic outcome, e.g., induction of anti-tumor immunity and / or incidence of tumor regrowth and / or metastasis. For example, in some embodiments, comparable release rates refer to such release rate values ​​within 15% over 48 hours. In some embodiments, comparable release rates refer to such release rate values ​​within 20% over 48 hours. In some embodiments, comparable release rates refer to such release rate values ​​within 15% over 24 hours.

[0041] Condition, Disease, or Disorder: The terms "condition," "disease," and "disorder" are used interchangeably.

[0042] Corresponding: As used herein, the term "corresponding" refers to a relationship between two or more entities. For example, the term "corresponding" may be used to indicate the position / identity of a structural element in a compound or composition relative to another compound or composition (e.g., relative to an appropriate reference compound or composition). For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as "corresponding" to a residue in an appropriate reference polymer. For example, one skilled in the art will understand that for simplicity, residues in a polypeptide are often designated based on the relevant reference polypeptide using a standard numbering system, and thus an amino acid "corresponding" to a residue at position 190, for example, does not necessarily actually be the 190th amino acid in a particular amino acid chain, but rather corresponds to the residue found at position 190 in the reference polypeptide. One skilled in the art will readily understand how to identify a "corresponding" amino acid. For example, one of skill in the art will be aware of a variety of sequence alignment means, including, for example, software programs such as BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE, which may be utilized to identify "corresponding" residues in polypeptides and / or nucleic acids in accordance with the present disclosure. One of skill in the art will also appreciate that in some cases, the term "corresponding" may be used to describe an event or entity that shares relevant similarity with another event or entity (e.g., a suitable reference event or entity).By way of example only, a gene or protein in one organism may, in some embodiments, be described as "corresponding to" a gene or protein in another organism to indicate that it plays a similar role or performs a similar function, and / or that it exhibits a particular degree of sequence identity or homology or shares certain characteristic sequence elements.

[0043] Crosslinker: The term "crosslinker" refers to an agent that links one entity (e.g., one polymer chain) to another entity (e.g., another polymer chain). In some embodiments, the bond between the two entities (i.e., "crosslink") is or includes a covalent bond. In some embodiments, the bond between the two entities is or includes an ionic bond. In some embodiments, the crosslinker is a small molecule (e.g., dialdehyde or genipin) to induce the formation of a covalent bond between an aldehyde group and an amino group. In some embodiments, the crosslinker includes a photosensitive functional group. In some embodiments, the crosslinker includes a pH-sensitive functional group. In some embodiments, the crosslinker includes a heat-sensitive functional group.

[0044] Effective amount: An "effective amount" is an amount sufficient to induce a desired biological response, e.g., treatment of a condition from which the subject may be afflicted. As will be appreciated by those skilled in the art, the effective amount of a drug delivery composition may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent in the composition, the condition being treated, and the age and health of the subject. In some embodiments, the amount may be effective for a therapeutic treatment. Alternatively or additionally, in some embodiments, the amount may be effective for a prophylactic treatment. For example, in the treatment of cancer, an effective amount may prevent tumor regrowth, reduce tumor burden, or halt tumor growth or spread. Those skilled in the art will appreciate that an effective amount need not be contained in a single dosage form. Rather, administration of an effective amount may require multiple administrations (e.g., according to a dosing regimen), possibly over time. For example, in some embodiments, an effective amount may be an amount administered in a dosing regimen established to achieve a particular result with statistical significance when administered to an appropriate population.

[0045] Hydrate: As used herein, the term "hydrate" has its art-understood meaning and refers to an aggregate of a compound (which may be, for example, a salt form of the compound) and one or more water molecules. Usually, the number of water molecules contained in a hydrate of a compound is a certain ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R×xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower order hydrate (x is a number greater than 0 and less than 1 (e.g., hemihydrate (R×0.5H2O)), and a polyhydrate (x is a number greater than 1 (e.g., dihydrate (R×2H2O) and hexahydrate (R×6H2O)).

[0046] Hydrogel: The term "hydrogel" has its art-understood meaning and refers to a material formed from a network of hydrophilic polymer chains, sometimes found as a colloidal gel in which the aqueous phase is the dispersion medium. In some embodiments, hydrogels are natural or synthetic polymer networks that are highly absorbent (e.g., capable of absorbing and / or retaining more than 90% water). In some embodiments, hydrogels have a degree of flexibility comparable to that of natural tissues, for example, due to their significant water content.

[0047] Immunotherapy: The term "immunotherapy" refers to therapeutic agents that promote the treatment of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to induce or amplify an immune response are classified as activating immunotherapies, while immunotherapies that reduce or suppress an immune response are classified as suppressing immunotherapies. Immunotherapies are usually, but not always, biological drugs. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapies may include, but are not limited to, inducers of type I interferon, interferons, agonists of stimulators of interferon genes (STING), TLR7 / 8 agonists, IL-15 superagonists, COX inhibitors (e.g., COX-1 inhibitors and / or COX-2 inhibitors), anti-PD-1 antibodies, anti-CD137 antibodies, and anti-CTLA-4 antibodies.

[0048] Implantable: The terms "implantable," "implant," "implanting," and "graft" refer to the placement of a drug delivery composition at a specific location in a subject, for example, within a tumor resection site or in a sentinel lymph node, typically by conventional surgical methods.

[0049] Inhibit: In the context of modulating the level (e.g., expression and / or activity) of a target (e.g., p38 MAPK), the term "inhibit" or "inhibition" is not limited to complete inhibition only. Thus, in some embodiments, partial inhibition or relative reduction is included within the scope of the term "inhibition". In some embodiments, the term refers to a reduction in the level (e.g., expression and / or activity) of a target (e.g., p38 MAPK) to a level that is reproducibly and / or statistically significantly lower than an initial level, which may be, for example, a baseline level of the target, or other suitable reference level. In some embodiments, the term refers to a decrease in the level (e.g., expression and / or activity) of a target to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may be, for example, a baseline level of the target.

[0050] Inhibitor: As used herein, the term "inhibitor" refers to an agent whose presence or level is associated with a decrease in the level or activity of a regulated target. In some embodiments, an inhibitor may act directly (wherein the inhibitor exerts an effect on a target directly, e.g., by binding to the target). In some embodiments, an inhibitor may act indirectly (wherein the inhibitor exerts an effect by interacting with and / or otherwise altering a regulator of the target such that the level and / or activity of the target is reduced). In some embodiments, an inhibitor is one whose presence or level correlates with a level or activity of a target that is reduced compared to a particular reference level or activity (e.g., observed under appropriate reference conditions, e.g., in the presence of a known inhibitor or in the absence of an inhibitor disclosed herein).

[0051] Inhibitors of proinflammatory pathways: As used herein, the term "inhibitors of proinflammatory pathways" refers, in some embodiments, to agents that prevent the recruitment of immunosuppressive cells or prevent acute inflammation. Such acute inflammation and / or recruitment of immunosuppressive cells may occur following local trauma, including that caused by surgery. In some embodiments, inhibitors of proinflammatory pathways may inhibit immune responses that induce inflammation, including, for example, the production of inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), increased activity and / or proliferation of Th1 cells, recruitment of myeloid cells, and the like.

[0052] Isomers: It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0053] Lymph node: As known in the art, the term "lymph node" refers to a component of the lymphatic system, which are small structures found throughout the body through which lymphatic fluid flows. Lymph nodes are known to filter certain substances from lymphatic fluid. Lymph nodes may contain immune cells that may participate in immune responses throughout the body, for example. In some embodiments, lymph nodes may be or include sentinel lymph nodes (i.e., lymph nodes from which cancer cells are most likely to spread from a primary tumor).

[0054] Marker: Marker, as used herein, refers to an entity or moiety whose presence or level is characteristic of a particular condition or event. In some embodiments, the presence or level of a particular marker may be characteristic of the presence or stage of a disease, disorder, or condition. By way of example only, in some embodiments, the term refers to a gene expression product that is characteristic of a particular tumor, tumor subclass, tumor stage, etc. Alternatively or additionally, in some embodiments, the presence or level of a particular marker correlates with the activity (or activity level) of a particular signaling pathway that may be characteristic of a particular class of tumor, for example. The statistical significance of the presence or absence of a marker may vary depending on the particular marker. In some embodiments, the detection of a marker is highly specific in that it reflects a high probability that the tumor is of a particular subclass. Such specificity may be obtained at the expense of sensitivity (i.e., a negative result may occur even when the tumor is one that is expected to express the marker). Conversely, a marker with high sensitivity may be less specific than one with a lower sensitivity. Those skilled in the art will understand that in many embodiments, a useful marker may not be identified with 100% accuracy.

[0055] Metastasis: The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor that is not of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is said to be metastatic prostate cancer, which includes cancerous prostate cancer cells growing in the bone tissue.

[0056] Microparticles: "Microparticles" is used herein to refer to discrete entities of small size, typically having a longest dimension that is less than about 1000 micrometers (μm), and often less than 500 μm, or even 100 μm or less. In many embodiments, the microparticles can be characterized by a longest dimension of about 1 μm to about 100 μm, or about 1 μm to about 500 μm, or about 1 μm to 1000 μm. In many embodiments, a population of microparticles is characterized by an average size (e.g., longest dimension) of less than about 1000 μm, less than about 500 μm, less than about 100 μm, less than about 50 μm, less than about 40 μm, less than about 30 μm, less than about 20 μm, or less than about 10 μm, and often more than about 1 μm. In many embodiments, the microparticles can be approximately spherical (e.g., such that the longest dimension can be its diameter).

[0057] Modulator: As used herein, the term "modulator" can be or include an entity whose presence or level in a system in which an activity of interest is observed correlates with a change in the level and / or nature of the activity compared to the level and / or nature observed under otherwise comparable conditions in the absence of the modulator. In some embodiments, a modulator is an activator or agonist in that in its presence, the activity of interest is increased compared to the activity observed under otherwise comparable conditions in the absence of the modulator. In some embodiments, a modulator is an antagonist or inhibitor in that in its presence, the activity of interest is decreased compared to the activity observed under otherwise comparable conditions in the absence of the modulator. In some embodiments, a modulator interacts directly with a target entity whose activity is of interest. In some embodiments, a modulator interacts indirectly with a target entity whose activity is of interest (e.g., interacts with the target entity and / or interacts with one or more entities associated with the target entity). In some embodiments, a modulator affects the level of a target entity of interest. Alternatively or additionally, in some embodiments, a modulator affects the activity of a target entity of interest without affecting the level of the target entity of interest, hi some embodiments, a modulator affects both the level and activity of a target entity of interest, such that the observed difference in activity is not fully explained by or commensurate with the observed difference in level.

[0058] Modulators of macrophage effector function: The term "modulators of macrophage effector function" refers to agents that activate macrophage effector function or reduce immunosuppressive macrophages or macrophage-derived suppressor cells. Such potentiation can recruit macrophages and bone marrow components to destroy tumors and their substrates, including tumor vasculature. Macrophages can be induced to secrete anti-tumor cytokines and / or perform phagocytosis, including antibody-dependent cellular phagocytosis.

[0059] Neutrophil function modulator: The terms "neutrophil modulator" and "neutrophil function modulator," as used interchangeably herein, refer to a modulator of one or more biological functions and / or phenotypes of neutrophils. For example, in some embodiments, a neutrophil function modulator may inhibit neutrophil recruitment, survival, and / or proliferation. Additionally or alternatively, in some embodiments, a neutrophil function modulator may modulate neutrophil-associated effector functions, which may include, but are not limited to, modulating the production and / or secretion of one or more immunomodulatory molecules (e.g., immunomodulatory cytokines and / or chemokines), and / or alter the ability of neutrophils to alter the extracellular matrix. In some embodiments, a neutrophil function modulator (e.g., those described herein) may act or target only neutrophils. In some embodiments, a modulator of neutrophil function (e.g., those described herein) may act on neutrophils and at least one additional type of immune cell, e.g., myeloid-derived suppressor cells (MDSCs), macrophages, and / or other subsets of monocytes.Those skilled in the art will appreciate that at least some subsets of neutrophils may exhibit immune activity similar to one or more certain subsets of MDSCs and thus may be considered polymorphonuclear MDSCs and / or granulocytic MDSCs (see, e.g., Mehmeti-Ajradini et al., "Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer" Life Science Alliance, September 21, 2020, and Brandau et al., "A subset of mature neutrophils contains the strongest PMN-MDSC activity in blood and tissue of patients with head and neck cancer" The Journal of Immunology, May 1, 2020, the contents of each of which are incorporated herein by reference for the purposes set forth herein).

[0060] Nanoparticles: As used herein, the term "nanoparticles" refers to discrete entities of small size, e.g., typically having a longest dimension that is less than about 1000 nanometers (nm) and often less than 500 nm or even 100 nm or less. In many embodiments, nanoparticles can be characterized by a longest dimension of about 1 nm to about 100 nm, or about 1 μm to about 500 nm, or about 1 nm to 1000 nm. In many embodiments, a population of microparticles is characterized by an average size (e.g., longest dimension) of less than about 1000 nm, less than about 500 nm, less than about 100 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or less than about 10 nm, and often more than about 1 nm. In many embodiments, the microparticles can be approximately spherical (e.g., such that the longest dimension can be its diameter). In some embodiments, the nanoparticles have a diameter of less than 100 nm as defined by the National Institutes of Health.

[0061] Neoplasms and Tumors: The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue whose proliferation exceeds and is not coordinated with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, have characteristically slower growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors may subsequently give rise to malignant neoplasms, which may arise as a result of further genetic alterations in a subpopulation of the tumor's tumor cells; these tumors are referred to as "pre-malignant neoplasms." One example of a pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissue. Moreover, malignant neoplasms generally have the ability to metastasize to distant sites.

[0062] Payload: Generally, as used herein, the term "payload" refers to an agent that can be delivered or transported by association with another entity. In some embodiments, such association can be or include a covalent bond. In some embodiments, such association can be or include a non-covalent interaction(s). In some embodiments, the association can be direct. In some embodiments, the association can be indirect. The term "payload" is not limited to a particular chemical identity or chemical type. For example, in some embodiments, the payload can be or include any chemical class of entity, including, for example, lipids, metals, nucleic acids, polypeptides, saccharides (e.g., polysaccharides), small molecules, or combinations or complexes thereof. In some embodiments, the payload can be or include a biological modifier, a detectable agent (e.g., dyes, fluorophores, radiolabels, etc.), a detection reagent, a nutrient, a therapeutic agent, etc., or a combination thereof. In some embodiments, the payload can be or include a cell or organism, or a fraction, extract, or component thereof. In some embodiments, the payload may be or include a natural product in that it is found in nature and / or obtained in nature. Alternatively or additionally, in some embodiments, the term may be used to refer to one or more entities that are artificial in that it is designed, engineered, and / or produced by the hand of man and / or is not found in nature. In some embodiments, the payload may be or include an agent in isolated or pure form. In some embodiments, such an agent may be in crude form.

[0063] Pharmaceutically acceptable salts: The term "pharmaceutical acceptable salts" refers to salts that are suitable for use, for example, in contact with human and / or animal tissues without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the contents of which are incorporated herein by reference for the purposes set forth herein. Pharmaceutically acceptable salts that can be utilized according to certain embodiments of the present disclosure include, for example, those derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Examples of suitable salts include, but are not limited to, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4- salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0064] Poloxamer: As used herein, the term "poloxamer" refers to a polymer preparation of one or more poloxamers or a polymer preparation containing one or more poloxamers. In some embodiments, the poloxamer in the polymer preparation may not be conjugated or modified, for example, it is usually a triblock copolymer that contains a hydrophobic chain of polyoxypropylene (polypropylene glycol, PPG) flanked by two hydrophilic chains of polyoxyethylene (polyethylene glycol, PEG). In some embodiments, the polymer preparation of one or more poloxamers or a polymer preparation containing one or more poloxamers may not be filtered (for example, such a polymer preparation may contain impurities and / or polymer molecules with relatively low molecular weight compared to a comparable polymer preparation that is filtered). Examples of poloxamers include, but are not limited to, poloxamer 124 (P124, also known as Pluronic® L44 NF), poloxamer 188 (P188, also known as Pluronic® F68 NF), poloxamer 237 (P237, also known as Pluronic® F87 NF), poloxamer 338 (P338, also known as Pluronic® F108 NF), poloxamer 407 (P407, also known as Pluronic® F127 NF), and combinations thereof.

[0065] Polymer: The term "polymer" is given its ordinary meaning as used in the art, i.e., a molecular structure that includes one or more repeating units (monomers) that are covalently linked. The repeating units may all be identical, or in some cases, there may be more than one type of repeating unit present in the polymer. In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring). In some embodiments, the polymer used in accordance with the present disclosure is a polypeptide. In some embodiments, the polymer used in accordance with the present disclosure is not a nucleic acid.

[0066] Polymer combination preparation: As used herein, the term "polymer combination preparation" refers to a polymer biomaterial that comprises at least two different polymer components. For example, in many embodiments, the polymer combination preparation described herein is a polymer biomaterial that comprises a first polymer component and a second first polymer component, where the first polymer component is or comprises at least one poloxamer, and the second polymer component is or comprises a non-poloxamer polymer. In some embodiments, the polymer combination preparation described herein is a precursor state polymer biomaterial that may be useful, for example, for administration to a subject. In some embodiments, the polymer combination preparation described herein is a polymer biomaterial in a polymer network state.

[0067] Polymeric biomaterial: A "polymeric biomaterial" is a material that is or comprises at least one polymer or at least one polymer moiety, as described herein, and is biocompatible. In many embodiments, the polymeric biomaterial is or comprises at least one polymer. In some embodiments, the polymer can be or comprise a copolymer. In some embodiments, the polymeric biomaterial is or comprises a preparation of at least two different polymeric components (e.g., a preparation containing a poloxamer and a second polymeric component that is not a poloxamer). Those skilled in the art will know that a particular polymer may exist and / or be available in a variety of forms (e.g., length, molecular weight, charge, topography, surface chemistry, degree and / or type of modification, e.g., alkylation, acylation, quaternization, hydroxyalkylation, carboxyalkylation, thiolation, phosphorylation, glycosylation, etc.). In some embodiments, such a preparation of a polymer may include such a form or forms at a specified level and / or distribution. Additionally or alternatively, in some embodiments, one or more immunomodulatory properties of the polymeric biomaterial may be tuned by the biomaterial property(s) of the polymeric biomaterial, including, for example, the surface chemistry of the polymeric biomaterial (e.g., controlled by the hydrophobic and / or hydrophilic moieties, chemical moieties, and / or charge properties of the polymeric biomaterial) and / or the topography of the polymeric biomaterial (e.g., controlled by the size, shape, and / or surface texture), as described, for example, in Mariani et al. “Biomaterials: Foreign Bodies or Tuners for the Immune Response?” International Journal of Molecular Sciences, 2019, 20, 636. One of skill in the art will appreciate that.

[0068] Polymer Network: The term "polymer network" is used herein to describe a collection of polymer chains that interact with each other. In some embodiments, the polymer network forms a three-dimensional structural material. In some embodiments, the polymer network can be formed by linking polymer chains using a crosslinker (e.g., as described herein) ("crosslinked polymer network"). In some embodiments, the polymer network is transitioned from a precursor state when the precursor state is exposed to a temperature equal to or greater than a critical gelation temperature, where the polymer network state has a viscosity that is substantially greater (e.g., at least 50% greater) than that of the precursor state, and the polymer network state includes crosslinks that are not present in the precursor state. In some embodiments, the polymer network can be formed by non-covalent or non-ionic intermolecular bonds of the polymer chains, for example, by hydrogen bonding. In some embodiments, the polymer network can be formed by a combination of chemical crosslinking of the polymer chains and non-covalent or non-ionic intermolecular bonds of the polymer chains.

[0069] Polymorph: The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). Many compounds can have a variety of different crystalline forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or may differ in some or all properties, such as melting point, density, hardness, crystal shape, optical properties, electrical properties, stability, solubility, bioavailability, etc. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may dominate in a given preparation. Various polymorphs of a compound can usually be prepared by crystallization under different conditions.

[0070] Prodrug: The term "prodrug" refers to a form of an active compound that contains one or more cleavable group(s) that are removed by solvolysis or under physiological conditions to release the active compound. Exemplary prodrug forms include, but are not limited to, choline ester derivatives and the like and N-alkylmorpholine esters and the like. In some embodiments, the prodrug may be an acid derivative, such as, for example, an ester prepared by reacting the parent acid with a suitable alcohol, an amide prepared by reacting the parent acid compound with a substituted or unsubstituted amine, an acid anhydride, or a mixed anhydride, as known in the art. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups associated with the compound of interest are specific examples of prodrug forms. In some cases, it may be desirable to prepare double ester type prodrugs of the compound of interest, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters, C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, C7-C12 substituted aryl esters, and C7-C12 arylalkyl esters.

[0071] Proinflammatory immune response: As used herein, the term "proinflammatory immune response" refers to an immune response that induces inflammation, including, for example, the production of inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), increased activity and / or proliferation of Th1 cells, recruitment of myeloid cells, etc. In some embodiments, a proinflammatory immune response can be or can include one or both of acute and chronic inflammation.

[0072] Proliferative disease: "Proliferative disease" refers to a disease caused by abnormal growth or expansion due to proliferation of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases may be associated with 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteases such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis or diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0073] Prophylactically effective amount: A "prophylactically effective amount" is an amount sufficient to prevent a condition (e.g., significantly delay the onset or recurrence of one or more symptoms or characteristics of a condition, e.g., so that it / they are not detected at the time that would be expected in the absence of administration of the amount). A prophylactically effective amount of a composition means an amount of a therapeutic agent(s), alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. One of skill in the art will appreciate that a prophylactically effective amount need not be contained in a single dosage form. Rather, administration of an effective amount may require multiple administrations, optionally over time (e.g., according to a dosing regimen).

[0074] Risk: As understood from the context, "risk" of a disease, disorder, and / or condition refers to the likelihood that a particular individual will develop the disease, disorder, and / or condition. In some embodiments, the risk is expressed as a percentage. In some embodiments, the risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, up to 100%. In some embodiments, the risk is expressed as a risk relative to the risk associated with a reference sample or a group of reference samples. In some embodiments, the reference sample or a group of reference samples has a known risk of the disease, disorder, condition, and / or event. In some embodiments, the reference sample or a group of reference samples is from an individual comparable to the particular individual. In some embodiments, the relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. In some embodiments, risk may reflect, for example, one or more genetic traits that may (or may not) predispose an individual to developing a particular disease, disorder, and / or condition, hi some embodiments, risk may reflect one or more epigenetic events or traits and / or one or more lifestyle or environmental events or traits.

[0075] Salts: As used herein, the term "salts" refers to any salt, including pharma- ceutically acceptable salts.

[0076] Sample: As used herein, the term "sample" refers to an aliquot of material, typically obtained from or derived from a source of interest, as described herein. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest can be or include a cell or organism, such as a microorganism, a plant, or an animal (e.g., a human). In some embodiments, the source of interest is or includes a biological tissue or biological fluid. In some embodiments, the biological tissue or fluid may be or include amniotic fluid, aqueous humor, peritoneal fluid, bile, bone marrow, blood, breast milk, cerebrospinal fluid, earwax, chyle, chyme, ejaculated fluid, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, perilymph, peritoneal fluid, pleural fluid, pus, mucosal secretions, saliva, sebum, semen, serum, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vitreous humor, vomit, and / or combinations or component(s) thereof. In some embodiments, the biological fluid may be or include intracellular fluid, extracellular fluid, intravascular fluid (plasma), interstitial fluid, lymph, and / or transcellular fluid. In some embodiments, the biological fluid may be or include plant exudates. In some embodiments, the biological tissue or biological sample may be obtained, for example, by aspiration, biopsy (e.g., fine needle biopsy or tissue biopsy), swab (e.g., oral swab, nasal swab, skin swab, or vaginal swab), scraping, surgery, lavage or washing (e.g., bronchoalveolar lavage or washing, ductal lavage or washing, nasal lavage or washing, ocular lavage or washing, oral lavage or washing, uterine lavage or washing, vaginal lavage or washing, or other lavage or washing). In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. In some embodiments, as is clear from the context, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents). For example, filtration using a semipermeable membrane.Such a "processed sample" can include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to one or more techniques, such as, for example, amplification or reverse transcription of nucleic acids, isolation and / or purification of certain components, etc.

[0077] Small molecule: The term "small molecule" or "small molecule therapeutic agent" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., by chemical synthesis). Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocycles, etc.). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges are also possible (e.g., at least about 200 g / mol and up to about 500 g / mol). In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as listed in the U.S. Code of Federal Regulations (CFR)). The small molecule may be complexed with one or more metal atoms and / or metal ions. In this example, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug has already been deemed safe and effective for use in humans or animals by an appropriate governmental or regulatory agency.For example, drugs approved for human use are listed by the FDA under 21 C.FR §§ 330.5, 331-361, and 440-460, and drugs for veterinary use are listed by the FDA under 21 C.FR §§ 500-589, the contents of each of which are incorporated herein by reference for the purposes described herein. Such drugs are generally considered acceptable for use in accordance with the present disclosure.

[0078] Solvate: As used herein, the term "solvate" has its art-understood meaning and refers to an aggregate of a compound (e.g., which may be a salt form of the compound) and one or more solvent atoms or molecules. In some embodiments, the solvate is a liquid. In some embodiments, the solvate is in a solid form (e.g., a crystalline form). In some embodiments, the solid form of the solvate is suitable for isolation. In some embodiments, the association between the solvent atom(s) and the compound in the solvate is a non-covalent association. In some embodiments, such association is or includes hydrogen bonding, van der Waals interactions, or a combination thereof. In some embodiments, the solvent whose atom(s) are included in the solvate may be or include one or more of water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. A suitable solvate may be a pharma-ceutically acceptable solvate. In some particular embodiments, the solvate is a hydrate, an ethanolate, or a methanolate. In some embodiments, the solvate may be a stoichiometric solvate or a non-stoichiometric solvate.

[0079] Subject: A "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal (e.g., a primate (e.g., cynomolgus monkey, rhesus monkey); a domestic animal, e.g., a cow, a pig, a horse, a sheep, a goat, a cat, and / or a dog; and / or a bird (e.g., a chicken, a duck, a goose, and / or a turkey)). In certain embodiments, the animal is a mammal (e.g., at any stage of development). In some embodiments, the animal (e.g., a non-human animal) can be a transgenic or genetically engineered animal. In some embodiments, the subject is a tumor resection subject, e.g., a subject that has recently undergone tumor resection. In some embodiments, the subject of the tumor resection is a subject who has undergone tumor resection less than 72 hours (including, for example, less than 48 hours, less than 24 hours, less than 12 hours, less than 6 hours, or less than a short time) before being administered the drug delivery composition or device described herein. In some embodiments, the subject of the tumor resection is a subject who has undergone tumor resection less than 48 hours before being administered the drug delivery composition or device described herein. In some embodiments, the subject of the tumor resection is a subject who has undergone tumor resection less than 24 hours before being administered the drug delivery composition or device described herein. In some embodiments, the subject of the tumor resection is a subject who has undergone tumor resection less than 12 hours before being administered the drug delivery composition or device described herein.

[0080] Substantially: As used herein, the term "substantially" refers to a qualitative state of exhibiting a feature or characteristic of interest to a complete or nearly complete extent or degree. Those skilled in the art will understand that the agent of interest will achieve or avoid, if at all, an absolute result, e.g., the agent of interest will have virtually no effect on immune response, e.g., inflammation. Thus, the term "substantially" is used herein to express the potential lack of absoluteness inherent in many biological and chemical effects.

[0081] Sustained: As used interchangeably herein, the terms "extended" or "sustained" generally refer to prolonging an effect and / or process over a desired period of time. For example, in the context of sustained immunomodulation (e.g., in the presence of a composition or preparation described and / or utilized herein), the term may refer to an immunomodulatory effect observed following administration of a particular immunomodulatory payload in a composition, including a biomaterial preparation described herein and others, as compared, for example, to administration of the same payload in the absence of such biomaterial preparation and / or to other administrations that differ from those described herein (e.g., administrations that are not to a lymph node dissection site). Alternatively or additionally, the term "sustained" may refer to the characteristics of the release of a payload from a composition described herein, as compared, for example, to the release observed with an immediate release administration. In some embodiments, such sustained or sustained release may occur over a time scale ranging from about 30 minutes to several weeks or more. In some embodiments, the extent of sustained or sustained release may be characterized in vitro or in vivo. For example, in some embodiments, the release kinetics can be tested in vitro by placing the preparations and / or compositions described herein in an aqueous buffer (e.g., PBS at pH 7.4). In some embodiments, when the preparations and / or compositions described herein are placed in an aqueous buffer (e.g., PBS at pH 7.4), less than 100% or less (e.g., including 90% or less, 80% or less, 70% or less, 50% or less, or less) of the one or more agents of interest (e.g., degradation or dissolution products and / or soluble components of the incorporated payloads described herein and / or polymer preparations described herein that modulate one or more aspects of the immune response, such as, but not limited to, innate immune agonism) are released from the biomaterial within 3 hours. In some embodiments, the release kinetics can be tested in vivo, for example, by implanting the composition into a target site (e.g., mammary fat pad) of an animal subject (e.g., a murine subject).In some embodiments, when the composition is implanted into a target site (e.g., mammary fat pad) of an animal subject (e.g., a murine subject), no more than 70% or less (including, e.g., no more than 60%, no more than 50%, less than 40%, less than 30%, or less) of the one or more agents of interest (e.g., degradation or dissolution products and / or soluble components of a payload described herein and / or a polymer preparation described herein that modulate one or more aspects of an immune response, including but not limited to innate immune agonism) are released in vivo 8 hours after implantation.

[0082] Targeted drugs: The term "targeted drugs," when used in reference to anticancer drugs, refers to those that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") involved in the growth, progression, and / or spread of cancer. Targeted drugs are sometimes referred to as "targeted cancer treatments," "molecularly targeted drugs," "molecularly targeted therapies," or "precision medicine." Targeted drugs differ from traditional chemotherapy in that targeted drugs usually act on specific molecular targets that are specifically associated with cancer and / or a particular tumor or tumor type, stage, etc., whereas many chemotherapy drugs act on all rapidly dividing cells (e.g., whether the cells are cancerous or not). Targeted drugs are deliberately selected or designed to interact with their targets, whereas many standard chemotherapeutics are identified because they kill cells.

[0083] Tautomer: The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., from a single bond to a double bond, a triple bond to a double bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that results in a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different) enamine tautomerization.

[0084] Test subject: As used herein, the term "test subject" refers to a subject to which the techniques provided herein are applied for experimental studies to evaluate the effectiveness of compositions and / or preparations described herein, for example, in biomaterial degradation and / or anti-tumor immunity. In some embodiments, the test subject may be a human subject or a population of human subjects. For example, in some embodiments, the human test subject may be a normal healthy subject. In some embodiments, the human test subject may be a tumor resection subject. In some embodiments, the test subject may be a mammalian non-human animal or a population of mammalian non-human animals. Non-limiting examples of such mammalian non-human animals include mice, rats, dogs, pigs, rabbits, etc., which in some embodiments may be normal healthy subjects, while in some embodiments may be a tumor resection subject. In some embodiments, the mammalian non-human animal may be a transgenic or genetically engineered animal.

[0085] Therapeutic Agent: The term "therapeutic agent" refers to an agent that has one or more therapeutic properties that provide a desired, usually beneficial effect. For example, a therapeutic agent may treat, ameliorate, and / or prevent a disease, disorder, or condition (e.g., substantially delay the onset or progression of one or more symptoms or characteristics of a disease, disorder, or condition). In some embodiments, a therapeutic agent may be or include a nucleic acid, a polypeptide, a small molecule, or a combination thereof. In some embodiments, a therapeutic agent may be subject to government regulation (e.g., premarket approval review) as a biologic, a device, a drug, or a combination thereof.

[0086] Therapeutically effective amount: A "therapeutically effective amount" is an amount sufficient to provide a therapeutic effect in the treatment of a condition, which may be or may include, for example, a reduction in frequency and / or severity and / or a delay in the occurrence of one or more characteristics or symptoms associated with the condition. A therapeutically effective amount refers to an amount or amounts of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic effect in the treatment of a condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a condition, or enhances the therapeutic effectiveness of another therapeutic agent. Those skilled in the art will understand that a therapeutically effective amount need not be contained in a single dosage form. Rather, administration of an effective amount may require multiple administrations, possibly over time (e.g., according to a dosing regimen, particularly one that has been established to provide an appropriate effect with a desired degree of statistical reliability when applied to an appropriate population).

[0087] Temperature-responsive: As used herein, in the context of a temperature-responsive polymer or biomaterial (e.g., a polymeric biomaterial), the term "temperature-responsive" refers to a polymer or biomaterial (e.g., a polymeric biomaterial) that exhibits an instantaneous or intermittent change in one or more of its properties at a critical temperature (e.g., a critical gelation temperature). For example, in some embodiments, one or more of such properties is or includes the solubility of the polymer or biomaterial in a particular solvent. By way of example only, in some embodiments, a temperature-responsive polymer or biomaterial (e.g., a polymeric biomaterial) is characterized by being a homogenous polymer solution or colloid that is stable below a critical temperature (e.g., a critical gelation temperature) and instantaneously forming a polymer network (e.g., a hydrogel) when the critical temperature (e.g., a critical gelation temperature) is reached or exceeded. In some embodiments, a temperature-responsive polymer or biomaterial (e.g., a polymeric biomaterial) may be temperature reversible, where, for example, in some embodiments, a polymer solution may instantaneously form a polymer network at or above a critical gelation temperature, and such resulting polymer network may instantaneously revert to a homogenous polymer solution when the temperature is reduced below the critical gelation temperature.

[0088] Treatment: The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a "pathology" as described herein (e.g., a disease, disorder, or condition, including one or more signs or symptoms thereof), e.g., a cancer or tumor. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or been observed. Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence and / or spread.

[0089] Treatment: The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a "pathology" as described herein (e.g., a disease, disorder, or condition, including one or more signs or symptoms thereof). In some embodiments, treatment may be administered after one or more signs or symptoms have developed or been observed. Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence and / or spread.

[0090] Tumor site: In some embodiments, the term "tumor site" can be the site where at least a portion of a tumor is present or was present prior to a surgical resection. In some embodiments, the tumor site can still have the entire tumor present. However, in some embodiments, the tumor site can have the entire tumor removed, for example, by tumor resection.

[0091] Tumor: The terms "tumor" and "neoplasm" are used interchangeably herein and refer to an abnormal mass of tissue whose proliferation exceeds and is not coordinated with the growth of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, have characteristically slower growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors may subsequently give rise to malignant neoplasms, which may arise as a result of further genetic alterations in a subpopulation of the tumor's tumor cells; these tumors are referred to as "pre-malignant neoplasms." One example of a pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissue. Moreover, malignant neoplasms generally have the ability to metastasize to distant sites.

[0092] Tumor removal: As used herein, the term "tumor removal" encompasses partial or complete removal of a tumor, which may result from cancer treatment, e.g., surgical resection. In some embodiments, tumor removal refers to the physical removal of part or all of a tumor by surgery (i.e., "tumor resection"). In some embodiments, tumor removal may result from surgical tumor resection and adjuvant therapy (e.g., chemotherapy, immunotherapy, and / or radiation therapy). In some embodiments, the adjuvant therapy may be administered after surgical tumor resection, e.g., at least 24 hours or more after surgical tumor resection.

[0093] Tumor resection subjects: As used herein, the term "tumor resection subjects" refers to subjects who are undergoing or have recently undergone tumor resection. In some embodiments, a tumor resection subject is a subject in which at least 70% or more of the total tumor mass (including at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or more (including 100%)) has been removed by surgical resection. In some cases, even if gross visual examination shows that all of the total tumor mass has apparently been removed, those skilled in the art will understand that there may be some residual cancer cells present microscopically at the visible margins. In some embodiments, a tumor resection subject may be determined to have negative margins (i.e., no cancer cells are present microscopically at the margins, for example, based on histological evaluation of the tissue surrounding the tumor resection site). In some embodiments, a tumor resection subject may be determined to have positive margins (i.e., cancer cells are present microscopically at the margins, for example, based on histological evaluation of the tissue surrounding the tumor resection site). In some embodiments, the tumor resection subject may have micrometastases and / or dormant disseminated cancer cells that may be encouraged to progress / grow due to a physiological response to surgery. In some embodiments, the tumor resection subject is administered a composition (e.g., as described and / or utilized herein) immediately after the tumor resection is performed (e.g., intraoperative administration). In some embodiments, the tumor resection subject is administered a composition (e.g., as described and / or utilized herein) within 24 hours or less (e.g., including within 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or less) after surgery.

[0094] Variant: As used herein, the term "variant" refers to a substance that exhibits significant structural identity with a reference substance, but is structurally different from the reference substance in the presence or level of one or more chemical moieties compared to the reference substance. In many embodiments, a variant is also functionally different from the reference substance. In general, whether a particular substance is properly considered to be a "variant" of a reference substance is based on the degree of structural identity with the reference substance. As will be understood by those skilled in the art, any biological or chemical reference substance has certain characteristic structural elements. By definition, a variant is a different chemical substance that shares one or more such characteristic structural elements. To name just a few examples, small molecules may have a characteristic core structural element (e.g., a macrocyclic core) and / or one or more characteristic pendant moieties, such that variants of small molecules share a core structural element and characteristic pendant moieties but differ in other pendant moieties and / or in the type of linkages (single vs. double, E vs. Z, etc.) present within the core; polypeptides may have characteristic sequence elements comprised of multiple amino acids that have designated positions relative to one another in linear or three-dimensional space and / or that contribute to a particular biological function; and nucleic acids may have characteristic sequence elements comprised of multiple nucleotide residues that have designated positions relative to one another in linear or three-dimensional space. For example, a variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising a variant polymer) may differ from a reference biomaterial (e.g., a reference polymer or a reference polymeric biomaterial) as a result of one or more structural modifications (e.g., but not limited to, addition, removal, and / or modification, and / or grafting of chemical moieties), provided that the variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising such a variant polymer) may retain a desired property(ies) and / or function(s) (e.g., immunomodulation and / or temperature responsiveness) of the reference biomaterial.For example, a variant of an immunomodulatory biomaterial may differ from an immunomodulatory reference biomaterial (e.g., a reference polymer or reference polymeric biomaterial) as a result of one or more structural modifications (e.g., but not limited to, addition, removal, and / or modification, and / or grafting of chemical moieties), however, the variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising such a variant polymer) may affect the immune system (e.g., by stimulating innate immunity), e.g., when used in the methods described herein. In some embodiments, an immunomodulatory variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising a variant polymer) is characterized in that the amount of one or more inflammatory cytokines (e.g., including but not limited to, CXCL10, IFN-α, IFN-β, IL-1β, IL-6, IL-18, and / or TNF-α) observed at a target site in a subject and / or in the systemic circulation when assessed 24 hours after administration of such immunomodulatory variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising a variant polymer) to the target site is at least 60% or more (e.g., including at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or up to 100%) of the amount observed when a reference biomaterial (e.g., a reference polymer or reference polymeric biomaterial) is administered to the target site.In some embodiments, an immunomodulatory variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising a variant polymer) is characterized in that, when assessed 24 hours after administration of such variant biomaterial (e.g., a variant polymer or a polymeric biomaterial comprising a variant polymer) to a target site in a subject, the amount of one or more inflammatory cytokines (e.g., including but not limited to, CXCL10, IFN-α, IFN-β, IL-1β, IL-6, IL-18, and / or TNF-α) observed at the target site and / or in the systemic circulation of the subject is at least 1.1-fold or more (e.g., including at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or more) the amount observed when a reference biomaterial (e.g., a reference polymeric biomaterial) is administered to the target site. In some embodiments, a variant biomaterial (e.g., a variant polymeric biomaterial) exhibits at least one physical property that differs from that of a reference biomaterial (e.g., a reference polymeric biomaterial). For example, in some embodiments, the variant biomaterial (e.g., variant polymeric biomaterial) may exhibit increased water solubility (e.g., at physiological pH) compared to the water solubility of a reference biomaterial (e.g., reference polymeric biomaterial). In some embodiments, the variant has 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 structural modifications compared to the reference. In some embodiments, the variant has a small number (e.g., less than 5, 4, 3, 2, or 1) structural modifications (e.g., alkylation, acylation, quaternization, hydroxyalkylation, carboxyalkylation, thiolation, phosphorylation, glycosylation, etc.). In some embodiments, the variant has no more than 5, 4, 3, 2, or 1 chemical moiety additions or deletions compared to the reference, and in some embodiments, no additions or deletions. In some embodiments, the variant is a material that can be generated from the reference by chemical manipulation. In some embodiments, a variant is a substance that may be produced by performing a synthetic process that is substantially similar (eg, shares multiple steps) to that which produces the reference.

[0095] The present disclosure provides, inter alia, technology including particular administration methods that may be particularly useful for and / or provide particular beneficial effects to certain patient populations, e.g., as described herein.

[0096] Among other things, the present disclosure recognizes that partial or complete lymphadenectomy is commonly utilized in the diagnosis and / or treatment of cancer, and provides insight that the lymphadenectomy bed may be a particularly attractive administration site for certain immunomodulatory agents described herein.

[0097] In some embodiments, the present disclosure utilizes materials that can be prepared in a variety of different states and / or can be in a variety of different states (e.g., a dry state, a liquid state, a gel state that in some embodiments may be or include a continuous gel, and in some embodiments may be or include gel particles, or both).

[0098] In some embodiments, the present disclosure administers a preparation in a liquid state. In some embodiments, the present disclosure administers a preparation in a preformed gel state, which may be characterized, for example, by soft, space-filling properties. In some such embodiments, the present disclosure utilizes a preparation comprised of a suitable material in particulate form (e.g., such that the preparation includes a plurality of particles characterized, for example, by size distribution and / or other parameters as described herein).

[0099] In some embodiments, the present disclosure utilizes temperature-responsive biomaterial preparations that can transition from an injectable state to a polymeric network state, e.g., having material properties that provide the beneficial effects described herein, e.g., without the introduction of crosslinkers, e.g., UV irradiation and / or chemical crosslinkers (e.g., small molecule crosslinkers), that are toxic to cells. Some such embodiments may be particularly useful for in situ formation of gelling materials, and may have various advantages over alternative techniques and may provide solutions to certain problems associated with such alternative techniques identified herein. For example, the present disclosure identifies a source of problems associated with many such techniques, as various alternative techniques for in situ gelation require treatments (e.g., exposure to UV irradiation and / or chemical crosslinkers, e.g., small molecule crosslinkers) that may be toxic or otherwise adverse to the recipient and / or agents that may be included in or with the material.

[0100] In some embodiments, immunomodulatory compositions (eg, biomaterial preparations) used in accordance with the present disclosure may exhibit one or more immunomodulatory properties even in the absence of an immunomodulatory agent payload.

[0101] I. Lymph node dissection Lymph nodes are part of the lymphatic system, a network of vessels that carry lymphatic fluid throughout the body. Human adults normally have about 450 lymph nodes, which are classified by location: for example, axillary lymph nodes are found in and around the armpits, inguinal lymph nodes are found in the groin, and cervical lymph nodes are found in the head and neck.

[0102] Lymph nodes are thought to be responsible for filtering lymphatic fluid that passes through them. Lymph nodes contain lymphocytes (both T and B cells), which enter the lymph nodes from the circulating blood.

[0103] Lymph node dissection (or resection) is a surgical procedure in which one or more lymph nodes are partially or completely removed from a subject, e.g., a subject suspected or known to have cancer. Regional lymph node dissection involves removing some lymph node(s) from a site (e.g., a site known or believed to be near a tumor). Radical lymph node dissection involves removing most or all lymph nodes from a site. As used herein, "lymph node dissection" and "lymph node resection" are used interchangeably to generally refer to a surgical procedure in which one or more lymph nodes are partially or completely removed from a subject. In certain embodiments, "lymph node dissection" may refer to the removal of an entire lymph node population from a site, while in certain embodiments, "lymph node dissection" may refer to the removal of some lymph node(s) from a site, e.g., at least one or more, but not all, lymph nodes.

[0104] In some embodiments, tissue removed during lymph node dissection is processed (e.g., subjected to analysis under a microscope) to assess evidence of cancer and / or its type, stage, etc.

[0105] When a subject is known to have cancer and has undergone partial or total surgical resection of one or more tumors, it is common to perform a lymphadenectomy of adjacent lymph nodes as part of the same surgical procedure in which the tumor is removed. In practice, lymph node evaluation is central to the well-established "TNM" tumor staging system, which classifies tumors based on the size of the primary tumor and the presence of adjacent tissue invasion (or noninvasion) ("T"), metastasis to adjacent lymph nodes ("N"), and distant metastasis ("M").

[0106] II. Immunomodulatory composition Among other things, the present disclosure provides insight that certain immunomodulatory compositions, including biomaterial preparations, when administered as described herein, may be particularly useful in the treatment of cancer.

[0107] Certain exemplary immunomodulatory compositions, including biomaterial preparations, that may be useful according to the present disclosure include those described in one or more of International Patent Application No. WO2018 / 045058 (see also U.S. Patent Nos. 10,435,469, 10,413,612, 10,836,826, and U.S. Patent Application Publication No. US2020 / 00311930), International Patent Application No. WO2019 / 183216 (see also U.S. Patent Application No. 16 / 982333), International Patent Application No. WO2020 / 223698, U.S. Patent Application No. 63 / 053488, and / or U.S. Patent Application No. 63 / 108861, the contents of each of which are incorporated herein by reference for purposes described herein.

[0108] In some embodiments, the immunomodulatory composition utilized may include a biomaterial preparation and a payload agent that, in many embodiments, is an immune system modulator (e.g., an immunomodulatory agent payload) as described herein. Alternatively, in some embodiments, the immunomodulatory composition utilized, including a biomaterial preparation, may be substantially free of known immunomodulatory agent payload(s).

[0109] In some embodiments, the biomaterial preparations described herein are characterized in that they form a polymeric network. Without wishing to be bound by any particular theory, it is noted that in some embodiments, such a network may function as a scaffold or depot for a payload (e.g., an immunomodulatory agent payload) in an immunomodulatory composition.

[0110] In some embodiments, an immunomodulatory composition comprising a biomaterial preparation and a payload agent (e.g., in some embodiments, an immunomodulatory agent payload) may function as a sustained release formulation, in that, for example, the payload is released from the composition more slowly (i.e., over a longer period of time) than would be observed in an otherwise comparable composition lacking the biomaterial preparation (e.g., lacking one or all of its polymer component(s)).

[0111] In some embodiments, the biomaterial preparation used as described herein comprises one or more polymers (e.g., those described herein). In certain embodiments, the biomaterial preparation may comprise one or more positively charged polymers. In some embodiments, the biomaterial preparation used as described herein may comprise one or more negatively charged polymers. In certain embodiments, a suitable biomaterial preparation may comprise one or more neutral polymers. In certain embodiments, a suitable biomaterial preparation comprises one or more polymeric components selected from the following: hyaluronic acid, alginate, chitosan, chitin, chondroitin sulfate, dextran, gelatin, collagen, starch, cellulose, polysaccharides, fibrin, poly-L-lysine, methylcellulose, ethylene vinyl acetate (EVA), polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), PEG diacrylate (PEGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), polydioxanone (PDO), polyhydroxybutyric acid (PHB), poly(2-hydroxyethyl methacrylate) (pHEMA), polycaprolactone (PCL), poly(β-amino ester) (PBAE), poly(ester amide), poly(propylene glycol), poly(propylene glycol amide ... poly(propylene glycol) (PPG), poly(aspartic acid), poly(glutamic acid), poly(propylene fumarate) (PPF), poly(sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl tyrosine alkyl ester carbonate) (PDTE), poly[bis(trifluoroethoxy)phosphazene], polyoxymethylene, single-walled carbon nanotubes, polyphosphazenes, polyanhydrides, poly(N-vinyl-2-pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), polyacetals, poly(alpha esters), poly(ortho esters), polyphosphoesters, polyurethanes, polycarbonates, polyamides, polyhydroxyalkanoates, polyglycerols, polyglucuronic acid, and / or combinations thereof and / or derivatives thereof.

[0112] In many embodiments, biomaterial preparations useful according to the present disclosure are characterized by in situ gelation at the target site in vivo in the absence of crosslinking treatments (e.g., UV irradiation and / or introduction of chemical crosslinkers) that may be toxic or otherwise adverse to the recipient and / or payload that may be contained in or with the biomaterial.

[0113] In some embodiments, biomaterial preparations useful according to the present disclosure are temperature responsive, such that, for example, their gelation (e.g., transition from a liquid state to a gelled state) can occur upon exposure to a particular temperature. In many such embodiments, exposure to body temperature (e.g., by application to a site) is sufficient to cause such gelation. In some embodiments, heat can also be applied. By way of example only, in some embodiments, the temperature responsive biomaterial preparations described herein are characterized by a transition from a precursor state (e.g., a liquid state or an injectable state) to a polymer network state (e.g., a more viscous state or a hydrogel) having a viscosity and / or storage modulus substantially exceeding that of the precursor state when such biomaterial preparations are exposed to a temperature at or above the critical gelation temperature (CGT) of the biomaterial preparation. In some embodiments, the CGT of the biomaterial preparation used according to the present disclosure is at least 10°C or higher (including, for example, at least 10°C, at least 11°C, at least 12°C, at least 13°C, at least 14°C, at least 15°C, at least 16°C, at least 17°C, at least 18°C, at least 19°C, at least 20°C, at least 21°C, at least 22°C, at least 23°C, at least 24°C, at least 25°C, at least 26°C, at least 27°C, at least 28°C, at least 29°C, at least 30°C, at least 31°C, at least 32°C, 33°C, at least 34°C, at least 35°C, at least 36°C, at least 37°C, at least 38°C, at least 39°C, at least 40°C, or higher). In some embodiments, the CGT of a suitable biomaterial preparation is about 10°C to about 15°C. In some embodiments, the CGT of a suitable biomaterial preparation is about 12°C to about 17°C. In some embodiments, the CGT of a suitable biomaterial preparation is from about 14° C. to about 19° C. In some embodiments, the CGT of a suitable biomaterial preparation is from about 16° C. to about 21° C. In some embodiments, the CGT of a suitable biomaterial preparation is from about 18° C. to about 23° C. In some embodiments, the CGT of a suitable biomaterial preparation is from about 20° C. to about 25° C.In some embodiments, the CGT of a suitable biomaterial preparation is about 22° C. to about 27° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 24° C. to about 29° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 26° C. to about 31° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 28° C. to about 33° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 30° C. to about 35° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 32° C. to about 37° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 34° C. to about 39° C. In some embodiments, the CGT of a suitable biomaterial preparation is about 35° C. to about 39° C. In some embodiments, the CGT of a suitable biomaterial preparation is at or near the physiological temperature of a subject (e.g., a human subject) to which such biomaterial preparation is administered.

[0114] In some embodiments, the biomaterial preparations used according to the present disclosure are thermoreversible. For example, in some embodiments, a suitable biomaterial preparation is characterized by a transition from a precursor state (e.g., a liquid state or an injectable state) to a polymer network state (e.g., a more viscous state or a hydrogel) having a viscosity and / or storage modulus substantially greater than that of the precursor state when such biomaterial preparation is exposed to a temperature at or above the critical gelation temperature (CGT) of the biomaterial preparation, and the biomaterial preparation can revert from the polymer network state to a state (e.g., a liquid state or the original state of the suitable biomaterial preparation) having a viscosity and / or storage modulus substantially lower than that of the polymer network state.

[0115] In some embodiments, the biomaterial preparations described herein do not include chemical crosslinkers. One skilled in the art will appreciate that in some embodiments, chemical crosslinkers are characterized by facilitating the formation of covalent crosslinks between polymer chains. In some embodiments, the chemical crosslinker is or includes a small molecule crosslinker that can be derived from natural sources or can be synthesized. Non-limiting examples of small molecule crosslinkers include genipin, dialdehydes, glutaraldehyde, glyoxal, diisocyanates, glutaric acid, succinic acid, adipic acid, acrylic acid, diacrylates, and the like. In some embodiments, the chemical crosslinker may involve crosslinking using thiols (e.g., EXTRACEL®, HYSTEM®), methacrylates, hexadecylamides (e.g., HYMOVIS®), and / or tyramines (e.g., CORGEL®). In some embodiments, chemical crosslinkers may involve crosslinking using formaldehyde (e.g., HYLAN-A®), divinyl sulfone (DVS) (e.g., HYLAN-B®), 1,4-butanediol diglycidyl ether (BDDE) (e.g., RESTYLANE®), glutaraldehyde, and / or genipin (see, e.g., Khunmanee et al. “Crosslinking method of hyaluronic-based hydrogel for biomedical applications” J Tissue Eng. 8:1-16 (2017)). Thus, in some embodiments, the crosslinks formed during the transition from the precursor state to the polymer network state include covalent crosslinks.

[0116] In some embodiments, the biomaterial preparations (e.g., temperature-responsive biomaterial preparations) used as described herein are or include a poloxamer or variant thereof. In some embodiments, the poloxamer or variant thereof is present in a suitable biomaterial preparation at a concentration of 12.5% ​​(w / w) or less (including, for example, 12% (w / w) or less, 11.5% (w / w) or less, 11% (w / w) or less, 10.5% (w / w) or less, 10% (w / w) or less, 9.5% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, or 5% (w / w) or less). In some embodiments, the poloxamer or variant thereof is present in a suitable biomaterial preparation at a concentration of 5% (w / w) to 12.5% ​​(w / w), or 8% (w / w) to 12.5% ​​(w / w), or 5% (w / w) to 10% (w / w), or 8% (w / w) to 10% (w / w).

[0117] Among other things, the present disclosure recognizes that hydrogel technologies, including certain crosslinking techniques, may generate toxic by-products and / or adversely affect the stability and / or efficacy of agent(s) (e.g., therapeutic agents) that may be combined with the polymeric biomaterial prior to or during crosslinking.

[0118] Alternatively or additionally, the present disclosure recognizes that, in some embodiments, certain advantages may be achieved by administering the component(s) of the biomaterial preparation to form during and / or upon administration of the immunomodulatory composition described herein, as compared to preforming (e.g., by crosslinking) the polymeric biomaterial prior to introduction into a subject. For example, administration of a preformed biomaterial requires a corresponding incision and / or surgical intervention to facilitate administration. For example, in some embodiments, the present disclosure recognizes that such preforming produces a material having a defined size and / or structure, which may limit administration options, as the dimensions of the preformed material may differ from the dimensions of the resection cavity. In some embodiments, an immunomodulatory composition comprising a biomaterial preparation in the form of a hydrogel may form during and / or upon administration. In some embodiments, an immunomodulatory composition administered to a target site may comprise a preformed hydrogel biomaterial preparation.

[0119] In some embodiments, the present disclosure contemplates that the biomaterial preparation may form a viscous solution when administered to a target site described herein. For example, in some embodiments, a liquid biomaterial preparation may be introduced to a target site such that, when administered to the target site, an immunomodulatory composition described herein in the form of a viscous solution (e.g., a solution having a viscosity of about 5,000-15,000 centipoise at body temperature, e.g., a solution having a viscosity of about 10,000 centipoise at body temperature) is formed.

[0120] In some embodiments, the present disclosure recognizes that biomaterial preparations useful for administration to a target site described herein can be viscous solutions that can be substantially retained at the target site for a period of time when administered. In some embodiments, such viscous liquid biomaterial preparations have a viscosity that is low enough to be injectable (e.g., through a syringe tip or catheter and / or syringe needle) but high enough to be substantially retained at the target site for a period of time when administered. In some embodiments, such viscous liquid biomaterial preparations can have a viscosity of about 500-10,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations can have a viscosity of about 500-3,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations can have a viscosity of about 1,000-8,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations can have a viscosity of about 2,000-6,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations may have a viscosity of about 3,000-7,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations may have a viscosity of about 4,000-8,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations may have a viscosity of about 5,000-9,000 centipoise at room temperature. In some embodiments, such viscous liquid biomaterial preparations may have a viscosity of about 6,000-10,000 centipoise at room temperature.

[0121] In some embodiments, the present disclosure recognizes that there may be viscosity requirements and / or limitations on the injectability of a liquid biomaterial preparation. For example, in some embodiments, an injectable biomaterial preparation may be characterized by a viscosity suitable for loading and controlling release through a range of gauge needles (e.g., 14-20 gauge needles, e.g., 16-18 gauge needles). Alternatively, in some embodiments, an injectable biomaterial preparation may be characterized by a viscosity suitable for loading and controlling release through a range of diameter syringe tips (i.e., without an attached needle or with a catheter). In some embodiments, a biomaterial preparation included in an immunomodulatory composition (e.g., as described herein) loaded into a syringe may further include a plasticizer.

[0122] The present disclosure provides techniques including specific biomaterial preparations and administration methods that allow for interventions that may be less invasive than implantation and / or less toxic than systemic administration. In some such embodiments, preparations with improved administration properties may be administered in a liquid state. In some embodiments, they may be administered in a preformed gel state characterized by soft space-filling properties. In some embodiments, they may be administered subcutaneously. In some embodiments, they may function as a proximal depot for sustained release of immunomodulatory payloads (e.g., those described herein). In some embodiments, they may allow for reprogramming of tissues, such as sentinel and / or draining lymph nodes. In some embodiments, they may be administered prior to or at the same time as tumor resection surgery. In some embodiments, they may be administered ipsilaterally when compared to the tumor resection site and / or primary tumor site. In some embodiments, they may be administered contralaterally when compared to the tumor resection site and / or primary tumor site. In some embodiments, they may be administered to patients with metastatic, disseminated, and / or recurrent cancer. In some such embodiments, the provided preparation is comprised of a suitable material in particulate form (e.g., such that the preparation comprises a plurality of particles characterized by a size distribution and / or other parameters, e.g., as described herein).

[0123] In particular, in some embodiments, the present disclosure provides methods of administration and treatment involving certain temperature-responsive biomaterial preparations that can transition from an injectable state to another state having material properties that provide, for example, the beneficial effects described herein, without, for example, introducing crosslinkers that are toxic to cells, for example, UV radiation and / or small molecule crosslinkers. Thus, some such embodiments provide beneficial techniques for in situ formation of gelling materials that have various advantages over alternative techniques and provide solutions to certain problems associated with such alternative techniques identified herein. For example, the present disclosure identifies a source of problems associated with many such techniques, since various alternative techniques for in situ gelation require processing (e.g., exposure to UV radiation and / or small molecule crosslinkers that may be toxic or otherwise adverse to the recipient and / or drugs that may be included in or with the material).

[0124] In some embodiments, provided methods of administration and / or treatment utilizing biomaterial preparations (e.g., in some embodiments, temperature-responsive biomaterial preparations as described in U.S. Provisional Application No. 63 / 108,861, filed November 2, 2020, and / or U.S. Provisional Application No. 63 / 053,488, filed July 17, 2020, the contents of each of which are incorporated herein by reference for purposes described herein) may exhibit one or more immunomodulatory properties even in the absence of an immunomodulatory payload. For example, in some embodiments, provided biomaterial preparations in combination with methods of administration that induce an acute inflammatory response may promote innate immunity when administered to a target site in a subject (e.g., a patient diagnosed with cancer) in need of promoting innate immunity.

[0125] A. Exemplary Biomaterials (i) Exemplary Temperature-Responsive Biomaterial Preparations In some embodiments, the temperature-responsive biomaterial preparations useful according to the present disclosure may include one or more poloxamers. Poloxamers are block copolymers that typically contain a hydrophobic chain of polyoxypropylene (e.g., polypropylene glycol (PPG) and / or poly(propylene oxide) (PPO)) flanked by two hydrophilic chains of polyoxyethylene (e.g., polyethylene glycol (PEG) and / or poly(ethylene oxide) (PEO)). Poloxamers are known under the trade names Synperonic, Pluronic®, and / or Kolliphor. In general, poloxamers are non-ionic surfactants that, in some embodiments, may have good solubilizing ability, low toxicity, and / or high compatibility with cells, body fluids, and a wide range of chemicals.

[0126] In some embodiments, the poloxamer used according to the present disclosure can be any poloxamer known in the art.For example, as understood by those skilled in the art, poloxamers are generally named with the letter P (after poloxamer) followed by three numbers, the first two numbers multiplied by 100 indicate the approximate molecular mass of the polyoxypropylene chain, and the last number multiplied by 10 indicates the polyoxyethylene content.Just as an example, P407 refers to a poloxamer with a polyoxypropylene molecular mass of 4000 g / mol and a polyoxyethylene content of 70%. Those skilled in the art will also understand that in the trade names Pluronic® and Synperonic, the coding of such poloxamers begins with a letter indicating the physical form at room temperature (e.g., L=liquid, P=paste, F=flake (solid)), followed by two or three numbers, where the first number in the number symbol (two numbers in a three-digit number) multiplied by 300 indicates the approximate molecular weight of the polyoxypropylene chain, and the last number multiplied by 10 indicates the polyoxyethylene content. By way of example only, L61 refers to a liquid preparation of poloxamer having a polyoxypropylene molecular mass of 1800 g / mol and a polyoxyethylene content of 10%. Furthermore, as will be apparent to those skilled in the art, poloxamer 181 (P181) corresponds to Pluronic L61 and Synperonic PE / L61.

[0127] In some embodiments, the poloxamer that may be included in the biomaterial preparations described herein may be or may include poloxamer 124 (e.g., Pluronic® L44 NF), poloxamer 188 (e.g., Pluronic® F68 NF), poloxamer 181 (e.g., Pluronic® L61), poloxamer 182 (e.g., Pluronic® L62), poloxamer 184 (e.g., Pluronic® L64), poloxamer 237 (e.g., Pluronic® F87 NF), poloxamer 338 (e.g., Pluronic® F108 NF), poloxamer 331 (e.g., Pluronic® L101), poloxamer 407 (e.g., Pluronic® F127 NF), or combinations thereof. In some embodiments, the biomaterial preparations used in accordance with the present disclosure may include at least two or more different poloxamers. Additional poloxamers listed in Table 1 of Russo and Villa “Poloxamer Hydrogels for Biomedical Applications” Pharmaceutics (2019) 11(12):671, the contents of which are incorporated herein by reference for purposes described herein, may also be useful in the biomaterial preparations described herein.

[0128] In some embodiments, a temperature-responsive biomaterial preparation is provided that includes a first polymer component (e.g., a poloxamer) and a second polymer component that is not a poloxamer. In some embodiments, the second polymer component may be present in a suitable biomaterial preparation at a concentration of 10% (w / w) or less (including, for example, 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or less). In some embodiments, the second polymer component is at least 0.1% (w / w) (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 1.5% (w / w), or less. The second polymer component may be present in a biomaterial preparation used in accordance with the present disclosure at a concentration of at least 2% (w / w), at least 2.5% (w / w), at least 3% (w / w), at least 3.5% (w / w), at least 4% (w / w), at least 4.5% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), or more. In some embodiments, the second polymer component in a suitable biomaterial preparation may be present at a concentration of 0.1% (w / w) to 10% (w / w), or 0.1% (w / w) to 8% (w / w), or 0.1% (w / w) to 5% (w / w), or 1% (w / w) to 5% (w / w).

[0129] In some embodiments, the second polymer component included in the biomaterial preparation used in accordance with the present disclosure can be or can include a carbohydrate polymer, e.g., a polymer that is or includes a carbohydrate, e.g., a carbohydrate backbone, including, but not limited to, hyaluronic acid, chitosan, and / or variants thereof.

[0130] In some embodiments, the present disclosure recognizes, among other things, that certain conventional preparations that are or contain poloxamers and that are used to form hydrogels typically utilize a minimum concentration of 16-20% (w / w) poloxamer (e.g., poloxamer 407 (P407)). The present disclosure identifies the source of problems associated with such conventional preparations, including that such conventional preparations may have certain shortcomings with respect to administration to a subject, including, for example, high solution viscosity and / or tissue irritation due to high concentrations of poloxamer that make them less than ideal for injection. Moreover, the present disclosure demonstrates that it is possible to develop useful preparations containing significantly lower concentration(s) of such poloxamers.

[0131] For example, in some embodiments, the present disclosure provides insight that certain poloxamers, e.g., poloxamer 407 (P407), which are typically used at minimum concentrations of 16-20% (w / w) to form hydrogels, when combined with one or more biocompatible polymers, can form useful temperature-responsive biomaterials at concentrations of less than 16% (w / w), including, for example, less than 14% (w / w), less than 12% (w / w), less than 10% (w / w), or less than 8% (w / w). In some embodiments, such biocompatible polymers can be or include polymers that are not temperature-responsive, e.g., in some embodiments, this can be or include hyaluronic acid and / or chitosan or modified chitosan.

[0132] In some embodiments, a biomaterial preparation comprising a poloxamer at a concentration of 12.5% ​​(w / w) or less and at least one additional polymer that is not a poloxamer may itself be immunomodulatory in the absence of an immunomodulatory payload. For example, in some embodiments, such a biomaterial preparation comprising a poloxamer at a concentration of 12.5% ​​(w / w) or less and at least one carbohydrate polymer (e.g., hyaluronic acid or chitosan) may promote natural immunity when administered to a target site in a subject in need thereof (e.g., a tumor resection subject).

[0133] (ii) Exemplary Hyaluronic Acid-Containing Preparations In some embodiments, the biomaterial preparation used in accordance with the present disclosure is or comprises hyaluronic acid or a variant thereof.

[0134] Hyaluronic acid (HA), also known as hyaluronan or hyaluronate, is a nonsulfated member of a class of polymers known as glycosaminoglycans (GAGs) that are widely distributed in body tissues. HA is found as a component of the extracellular matrix of tissues where it forms a pericellular coat on cell surfaces.

[0135] HA is (C 14 H 21 NO 11 ) n (which in some embodiments may be present as a salt, e.g., sodium, potassium, and / or calcium salt), where n may vary depending on the source, isolation technique, and / or measurement method.

[0136] In some embodiments, HA that may be useful according to the present disclosure may be isolated or derived from natural sources. One of skill in the art will know that HA is available from a variety of natural sources. For example, in some embodiments, HA may be isolated or derived from, for example, human umbilical cord, cockscomb, and / or vertebrate connective tissue matrix. In some embodiments, HA may be isolated or derived from capsular components of bacteria such as Streptococci. See, for example, Kendall et al, (1937), Biochem. Biophys. Acta, 279, 401-405. In some embodiments, HA and / or variants thereof may be produced by microbial fermentation. In some embodiments, the HA and / or variants thereof may be recombinant HA or variants thereof, e.g., produced using Gram-positive and / or Gram-negative bacteria (e.g., including but not limited to, Bacillus spp., Lactococcus lactis, Agrobacterium spp., and / or Escherichia coli) as a host.

[0137] In some embodiments, hyaluronic acid and / or variants thereof may be present in a suitable biomaterial preparation at a concentration of 20% (w / w) or less (including, for example, 20% (w / w), 19% (w / w), 18% (w / w), 17% (w / w), 16% (w / w), 15% (w / w), 14% (w / w), 13% (w / w), 12% (w / w), 11% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or less). In some embodiments, hyaluronic acid and / or its variants are at least 0.1% (w / w) (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 1.5% (w / w), at least 2% (w / w), at least 2.5% (w / w), at least 3% (w / w), at least 3.5% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 15% (w / w), at least 10% (w / w), at least 15% (w / w), at least 2% (w / w), at least 2.5% (w / w), at least 3% (w / w), at least 3.5% (w / w), at least 4% (w / w), at least 10 ... (w / w), at least 4.5% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11% (w / w), at least 12% (w / w), at least 13% (w / w), at least 14% (w / w), at least 15% (w / w), at least 16% (w / w), at least 17% (w / w), at least 18% (w / w), at least 19% (w / w), or more. In some embodiments, hyaluronic acid and / or variants thereof may be present in a suitable biomaterial preparation at a concentration of between 0.1% (w / w) and 20% (w / w), between 0.1% (w / w) and 18% (w / w), between 0.1% (w / w) and 16% (w / w), between 0.1% (w / w) and 14% (w / w), between 0.1% (w / w) and 12% (w / w), between 0.1% (w / w) and 10% (w / w), or between 0.1% (w / w) and 8% (w / w), or between 0.1% (w / w) and 5% (w / w).As will be appreciated by those skilled in the art, the concentration of hyaluronic acid and / or variants thereof in the biomaterial preparation may vary depending, for example, on their molecular weight and / or desired mechanical properties (e.g., storage modulus, viscosity, etc.). For example, in some embodiments, low molecular weight hyaluronic acid and / or variants thereof (e.g., as described herein) may be present in the biomaterial preparation at higher concentrations, e.g., in some embodiments, at concentrations of 3% (w / w) to 7% (w / w). In some embodiments, high molecular weight hyaluronic acid and / or variants thereof (e.g., as described herein) may be present in the biomaterial preparation at lower concentrations, e.g., in some embodiments, at concentrations of 1% (w / w) to 3% (w / w).

[0138] In some embodiments, a suitable biomaterial preparation described herein can be a viscous hyaluronic acid solution. For example, in some embodiments, the viscous hyaluronic acid solution can be at least 0.1% (w / w) or more (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 15% (w / w), at least 20% (w / w), at least 30% (w / w), at least 40% (w / w), at least 50% (w / w), at least 60% (w / w), at least 70% (w / w), at least 80% (w / w), at least 90% (w / w), at least 10% (w / w), at least 15% (w / w), at least 10 ... % (w / w), including at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, or more. In some embodiments, the viscous hyaluronic acid solution may comprise hyaluronic acid and / or variants thereof in a concentration of 20% (w / w) or less (including, for example, 15% or less, 14% or less (w / w), 13% or less (w / w), 12% or less (w / w), 11% or less (w / w), 10% or less (w / w), 9% or less (w / w), 8% or less (w / w), 7% or less (w / w), 6% or less (w / w), 5% or less (w / w), 4% or less (w / w), 3% or less (w / w), 2% or less (w / w), 1% or less (w / w), 0.5% or less (w / w), or less. In some embodiments, combinations of the above identified concentration ranges are also possible. For example, in some embodiments, the viscous hyaluronic acid solution may contain hyaluronic acid and / or its variants in a concentration of about 0.1% (w / w) to about 20% (w / w), or about 0.1% (w / w) to about 15% (w / w), or about 0.5% (w / w) to about 10% (w / w).In some embodiments, high molecular weight hyaluronic acid and / or variants thereof (e.g., as described herein) may be present in the viscous hyaluronic acid solution at a concentration of 0.1% (w / w) to about 5% (w / w) or about 0.5% (w / w) to about 3% (w / w). In some embodiments, low molecular weight hyaluronic acid and / or variants thereof (e.g., as described herein) may be present in the viscous hyaluronic acid solution at a concentration of 1.5% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w). As will be appreciated by those skilled in the art, higher concentrations of hyaluronic acid and / or variants thereof may be used when hyaluronic acid and / or variants thereof are present in the biomaterial preparation as the predominant or substantially only polymer.

[0139] In some embodiments, HA or variants thereof that may be included in biomaterial preparations used in accordance with the present disclosure may have a low molecular weight, e.g., an average molecular weight of 500 kDa or less (e.g., including 450 kDa, 400 kDa, 350 kDa, 300 kDa, 250 kDa, 200 kDa, 150 kDa, 100 kDa, 50 kDa, or less). In some embodiments, HA or variants thereof that may be included in suitable biomaterial preparations may have an average molecular weight of about 100 kDa to about 150 kDa. In some embodiments, HA or variants thereof that may be included in suitable biomaterial preparations may have an average molecular weight of about 300 kDa to about 400 kDa.

[0140] In some embodiments, HA or variants thereof that may be included in biomaterial preparations used according to the present disclosure may have a high molecular weight, e.g., an average molecular weight of greater than 500 kDa or more (e.g., including 550 kDa, 600 kDa, 650 kDa, 700 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1 MDa, 1.1 MDa, 1.2 MDa, 1.3 MDa, 1.4 MDa, 1.5 MDa, 1.6 MDa, 1.7 MDa, 1.8 MDa, 1.9 MDa, 2 MDa, 2.5 MDa, 3 MDa, 3.5 MDa, 4 MDa, 4.5 MDa, or more). In some embodiments, HA or variants thereof that may be useful according to the present disclosure may have an average molecular weight of about 600 kDa to about 900 kDa. In some embodiments, HA or variants thereof that may be useful according to the present disclosure may have an average molecular weight of about 1 MDa to about 3 MDa.

[0141] In some embodiments, the biomaterial preparation used according to the present disclosure comprises a hyaluronic acid variant. In some embodiments, the hyaluronic acid variant is water-soluble. In some embodiments, the hyaluronic acid variant can be a chemically modified hyaluronic acid, for example, in some embodiments, the hyaluronic acid is esterified. Examples of chemical modifications to hyaluronic acid include, but are not limited to, the addition of thiol, haloacetate, butanediol, diglycidyl, ether, dihydrazide, aldehyde, glycan, and / or tyramine functional groups. Additional hyaluronic acid modifications and hyaluronic acid variants are known in the art. See, e.g., Highley et al., "Recent advances in hyaluronic acid hydrogels for biomedical applications" Curr Opin Biotechnol (2016) Aug 40:35-40; Burdick & Prestwich, "Hyaluronic acid hydrogels for biomedical applications" Advanced Materials (2011); Prestwhich, "Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine" J. Control Release (2011) Oct 30;155(2):193-199, the contents of each of which are incorporated herein by reference for purposes described herein.

[0142] (iii) Exemplary Chitosan-Containing Preparations In some embodiments, the carbohydrate polymer included in the biomaterial preparation used according to the present disclosure may be or may include chitosan or a variant thereof. Examples of chitosan and / or its variants that may be included in the biomaterial preparation described herein include, but are not limited to, chitosan, chitosan salts (e.g., chitosan HCl, chitosan chloride, chitosan lactate, chitosan acetate, chitosan glutamate), alkyl chitosan, aromatic chitosan, carboxyalkyl chitosan (e.g., carboxymethyl chitosan), hydroxyalkyl chitosan (e.g., hydroxypropyl chitosan, hydroxyethyl chitosan), aminoalkyl chitosan, acylated chitosan, phosphorylated chitosan, thiolated chitosan, quaternary ammonium chitosan (e.g., N-(2-hydroxyl)propyl-3-trimethylammonium chitosan chloride), guanidyl chitosan, chitosan oligosaccharides, glycated chitosan (e.g., N-dihydrogalacto chitosan), and variants or combinations thereof. In some embodiments, the carbohydrate polymer included in a suitable poloxamer-containing biomaterial preparation (e.g., as described herein) can be or can include a carboxyalkylchitosan (e.g., carboxymethylchitosan).

[0143] One of skill in the art will appreciate that in some cases, chitosan and / or variants thereof may be produced by deacetylation of chitin. In some embodiments, chitosan or variants thereof included in a poloxamer-containing biomaterial preparation (e.g., as described herein) are characterized by a degree of deacetylation (i.e., percent of acetyl groups removed) of at least 70% or more (e.g., including at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more (including up to 100%)). In some embodiments, chitosan or variants thereof are characterized by a degree of deacetylation of 99% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, or less. Combinations of the above ranges are also possible. For example, chitosan or variants thereof may be characterized by a degree of deacetylation of 80%-95%, 70%-95%, or 75%-90%. As will be appreciated by one of skill in the art, the degree of deacetylation (% DA) can be determined by a variety of methods known in the art, such as, in some cases, by NMR spectroscopy.

[0144] In some embodiments, chitosan and / or its variants may be present in suitable biomaterial preparations at a concentration of 20% (w / w) or less (including, for example, 20% (w / w), 19% (w / w), 18% (w / w), 17% (w / w), 16% (w / w), 15% (w / w), 14% (w / w), 13% (w / w), 12% (w / w), 11% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or less). In some embodiments, chitosan and / or its variants are present in an amount of at least 0.1% (w / w) (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 1.5% (w / w), at least 2% (w / w), at least 2.5% (w / w), at least 3% (w / w), at least 3.5% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 12% (w / w), at least 14% (w / w), at least 16% (w / w), at least 18% (w / w), at least 19% (w / w), at least 20% (w / w), at least 25% (w / w), at least 26% (w / w), at least 28% (w / w), at least 29% (w / w), at least 30% (w / w), at least 31% (w / w), at least 32% (w / w), at least 33% (w / w), at least 34% (w / w), at least 35% (w / w), at least 36% (w / w), at least 37% (w / w), at least 38% (w / w), at least 39% (w / w), at least 40% (w / w), at least 41% (w / w The α-aminobutyric acid may be present in a suitable biomaterial preparation at a concentration of at least about 10% (w / w), including at least 4.5% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11% (w / w), at least 12% (w / w), at least 13% (w / w), at least 14% (w / w), at least 15% (w / w), at least 16% (w / w), at least 17% (w / w), at least 18% (w / w), at least 19% (w / w), or more. In some embodiments, chitosan and / or its variants may be present in a suitable biomaterial preparation at a concentration of 0.1% (w / w) to 20% (w / w), 0.1% (w / w) to 18% (w / w), 0.1% (w / w) to 16% (w / w), 0.1% (w / w) to 14% (w / w), 0.1% (w / w) to 12% (w / w), 0.1% (w / w) to 10% (w / w), or 0.1% (w / w) to 8% (w / w), or 0.1% (w / w) to 5% (w / w).As will be appreciated by those skilled in the art, the concentration of chitosan and / or its variants in the biomaterial preparation may vary depending, for example, on their molecular weight and / or the desired mechanical properties (e.g., storage modulus, viscosity, etc.). For example, in some embodiments, low molecular weight chitosan (e.g., in some embodiments, less than 500 kDa) and / or its variants may be present in the biomaterial preparation at higher concentrations, for example, in some embodiments, at a concentration of 3% (w / w) to 7% (w / w). In some embodiments, high molecular weight chitosan (e.g., in some embodiments, more than 500 kDa) and / or its variants may be present in the biomaterial preparation at lower concentrations, for example, in some embodiments, at a concentration of 1% (w / w) to 3% (w / w).

[0145] In some embodiments, a suitable biomaterial preparation described herein can be a chitosan viscous solution. For example, in some embodiments, the chitosan solution can be at least 0.1% (w / w) or more (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 15% (w / w), at least 20% (w / w), at least 30% (w / w), at least 40% (w / w), at least 50% (w / w), at least 60% (w / w), at least 70% (w / w), at least 80% (w / w), at least 90% (w / w), at least 10% (w / w), at least 15 ... (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, or more. In some embodiments, the chitosan viscous solution may comprise chitosan and / or its variants in a concentration of 20% (w / w) or less (including, for example, 15% or less, 14% or less (w / w), 13% or less (w / w), 12% or less (w / w), 11% or less (w / w), 10% or less (w / w), 9% or less (w / w), 8% or less (w / w), 7% or less (w / w), 6% or less (w / w), 5% or less (w / w), 4% or less (w / w), 3% or less (w / w), 2% or less (w / w), 1% or less (w / w), 0.5% or less (w / w), or less. In some embodiments, combinations of the above identified concentration ranges are also possible. For example, in some embodiments, the chitosan viscous solution may contain chitosan and / or its variants in a concentration of about 0.1% (w / w) to about 20% (w / w), or about 0.1% (w / w) to about 15% (w / w), or about 0.5% (w / w) to about 10% (w / w).In some embodiments, high molecular weight chitosan (e.g., in some embodiments, greater than 300 kDa or in some embodiments, greater than 500 kDa) and / or variants thereof may be present in the chitosan viscous solution at a concentration of 0.1% (w / w) to about 5% (w / w) or about 0.5% (w / w) to about 3% (w / w). In some embodiments, low molecular weight chitosan (e.g., in some embodiments, less than 500 kDa or in some embodiments, less than 300 kDa) and / or variants thereof may be present in the chitosan viscous solution at a concentration of 1.5% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w). As will be appreciated by those skilled in the art, higher concentrations of chitosan and / or variants thereof may be used when chitosan and / or variants thereof are present in the biomaterial preparation as the predominant or substantially only polymer.

[0146] In some embodiments, the chitosan or variants thereof included in the biomaterial preparations described herein have a molecular weight of at least 5 kDa or more (e.g., at least 10 kDa or more (e.g., at least 20 kDa, at least 30 kDa, at least 40 kDa, at least 50 kDa, at least 60 kDa, at least 70 kDa, at least 80 kDa, at least 90 kDa, at least 100 kDa, at least 110 kDa, at least 120 kDa, at least 130 kDa, at least 140 kDa, at least 150 kDa, at least 160 kDa, at least 170 kDa, at least 180 kDa, at least 190 kDa, at least 200 kDa, at least 210 kDa, at least 220 kDa, at least 230 kDa, at least 240 kDa, at least 250 kDa, at least 260 kDa, at least 270 kDa, at least 280 kDa, at least 290 kDa, at least 300 kDa, at least 310 kDa, at least 320 kDa, at least 330 kDa, at least 340 kDa, at least 350 kDa, at least 360 kDa, at least 370 kDa, at least 380 kDa, at least 390 kDa, at least 400 kDa, at least 400 kDa, at least 410 kDa, at least 420 kDa, at least 430 kDa, at least 440 kDa, at least 450 kDa, at least 460 kDa, at least Da, at least 170 kDa, at least 180 kDa, at least 190 kDa, at least 200 kDa, at least 210 kDa, at least 220 kDa, at least 230 kDa, at least 240 kDa, at least 250 kDa, at least 260 kDa, at least 270 kDa, at least 280 kDa, at least 290 kDa, at least 300 kDa, at least 350 kDa, at least 400 kDa, at least 500 kDa, at least 600 kDa, at least 700 kDa, or more). In some embodiments, the chitosan or variants thereof included in the biomaterial preparations described herein may have an average molecular weight of 750 kDa or less (including, for example, 700 kDa or less, 600 kDa or less, 500 kDa or less, 400 kDa or less, 300 kDa or less, 200 kDa or less, 100 kDa or less, 50 kDa or less, or less). Combinations of the above ranges are also possible. For example, in some embodiments, the chitosan or variants thereof included in the biomaterial preparations described herein are characterized by an average molecular weight of 10 kDa to 700 kDa, or 20 kDa to 700 kDa, or 30 kDa to 500 kDa, or 150 kDa to 600 kDa, or 150 kDa to 400 kDa, or 50 kDa to 150 kDa, or 10 kDa to 50 kDa. In some embodiments, the chitosan or variants thereof included in the biomaterial preparations described herein are characterized by an average molecular weight of 20 kDa to 700 kDa or 30 kDa to 500 kDa.As stated herein, the average molecular weight can be a number average molecular weight, a weight average molecular weight, or a peak average molecular weight.

[0147] In some embodiments, the chitosan or variant thereof included in the biomaterial preparations described herein is characterized by a molecular weight distribution in the range of 10 kDa to 700 kDa, or 20 kDa, or 700 kDa, or 30 kDa to 500 kDa, or 150 kDa to 600 kDa, or 150 kDa to 400 kDa, or 50 kDa to 150 kDa, or 10 kDa to 50 kDa. In some embodiments, the chitosan or variant thereof included in the biomaterial preparations described herein is characterized by a molecular weight distribution in the range of 20 kDa to 700 kDa, or 30 kDa to 500 kDa.

[0148] In some embodiments, chitosan or variants thereof that may be included in biomaterial preparations used in accordance with the present disclosure may have a low molecular weight, for example, an average molecular weight of 500 kDa or less (including, for example, 450 kDa, 400 kDa, 350 kDa, 300 kDa, 250 kDa, 200 kDa, 190 kDa, 180 kDa, 170 kDa, 160 kDa, 150 kDa, 140 kDa, 130 kDa, 120 kDa, 110 kDa, 100 kDa, 90 kDa, 80 kDa, 70 kDa, 60 kDa, 50 kDa, 40 kDa, 30 kDa, 20 kDa, or less). In some embodiments, chitosan or variants thereof that may be included in a biomaterial preparation used in accordance with the present disclosure may have a low molecular weight of 350 kDa or 300 kDa or less. In some embodiments, chitosan or variants thereof that may be included in a suitable biomaterial preparation may have an average molecular weight of about 50 kDa to about 500 kDa. In some embodiments, chitosan or variants thereof that may be included in a suitable biomaterial preparation may have an average molecular weight of about 100 kDa to about 350 kDa or about 100 kDa to about 300 kDa.

[0149] In some embodiments, chitosan or variants thereof that may be included in biomaterial preparations used in accordance with the present disclosure have a high molecular weight, e.g., greater than 300 kDa or more (e.g., 310 kDa, 320 kDa, 330 kDa, 340 kDa, 350 kDa, 360 kDa, 370 kDa, 380 kDa, 390 kDa, 400 kDa, 410 kDa, 420 kDa, 430 kDa, 440 kDa, 450 kDa, 460 kDa, In some embodiments, chitosan or variants thereof that may be included in biomaterial preparations used in accordance with the present disclosure may have a high molecular weight of greater than 500 kDa or more. In some embodiments, chitosan or variants thereof that may be useful according to the present disclosure may have an average molecular weight of about 310 kDa to about 380 kDa. In some embodiments, chitosan or variants thereof that may be useful according to the present disclosure may have an average molecular weight of about 350 kDa to about 500 kDa. In some embodiments, chitosan or variants thereof that may be useful according to the present disclosure may have an average molecular weight of about 500 kDa to about 750 kDa.

[0150] In some embodiments, the chitosan or variant thereof included in the biomaterial preparations described herein may be characterized by a viscosity of 3500 mPa·s or less (including, for example, 3000 mPa·s or less, 2500 mPa·s or less, 2000 mPa·s or less, 1500 mPa·s or less, 1000 mPa·s or less, 500 mPa·s or less, 250 mPa·s or less, 200 mPa·s or less, 150 mPa·s or less, 100 mPa·s or less, 75 mPa·s or less, 50 mPa·s or less, 25 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 10 mPa·s or less, or less). In some embodiments, chitosan or variants thereof may be characterized by a viscosity of at least 5 mPa·s or more (including, for example, at least 10 mPa·s, at least 20 mPa·s, at least 30 mPa·s, at least 40 mPa·s, at least 50 mPa·s, at least 60 mPa·s, at least 70 mPa·s, at least 80 mPa·s, at least 90 mPa·s, at least 100 mPa·s, at least 125 mPa·s, at least 150 mPa·s, at least 175 mPa·s, at least 250 mPa·s, at least 500 mPa·s, at least 1000 mPa·s, at least 1500 mPa·s, at least 2000 mPa·s, at least 2500 mPa·s or more). Combinations of the above ranges are also possible. For example, in some embodiments, such viscous polymer solutions of or including chitosan or variants thereof may be characterized by a viscosity of 5 mPa·s to 3000 mPa·s, or 5 mPa·s to 300 mPa·s, or 5 mPa·s to 200 mPa·s, or 20 mPa·s to 200 mPa·s, or 5 mPa·s to 20 mPa·s. In some embodiments, the viscosity of chitosan or variants thereof described herein is measured at 1% in 1% acetic acid at 20° C.

[0151] In some embodiments, the biomaterial preparations described herein include at least one or more (e.g., one, two, three, or more) chitosan and / or variants thereof (e.g., including modified chitosan and / or chitosan or a salt of modified chitosan, e.g., chloride or glutamate). For example, in some embodiments, the chitosan and / or variants thereof (e.g., including modified chitosan and / or chitosan or a salt of modified chitosan, e.g., chloride or glutamate) may be characterized by a degree of deacetylation of 70%-95%, or 75%-90%, or 80%-95%, or greater than 90%. In some embodiments, chitosan and / or variants thereof (including, e.g., modified chitosan and / or a salt of chitosan or modified chitosan, e.g., chloride or glutamate) may be characterized by an average molecular weight (e.g., measured as chitosan or a chitosan salt, e.g., chitosan acetate) of 10 kDa to 700 kDa, 20 kDa to 600 kDa, 30 kDa to 500 kDa, 150 kDa to 400 kDa, or 200 kDa to 600 kDa. In some embodiments, chitosan and / or variants thereof (including, for example, modified chitosan and / or a salt of chitosan or modified chitosan, such as the chloride salt or glutamate salt) may be characterized by a molecular weight distribution (e.g., measured as chitosan or a chitosan salt, such as chitosan acetate) in the range of 10 kDa to 700 kDa, 20 kDa to 600 kDa, 30 kDa to 500 kDa, 150 kDa to 400 kDa, or 200 kDa to 600 kDa. In some embodiments, chitosan and / or variants thereof (including, for example, a salt thereof, such as the chloride salt or glutamate salt) may be characterized by a viscosity in the range of 5 to 3000 mPa·s, or 5 to 300 mPa·s, or 20 to 200 mPa·s.In some embodiments, such chitosan and / or variants thereof (e.g., including salts thereof, such as the chloride salt or glutamate salt) may be or include PROTASAN™ UltraPure chitosan chloride and / or chitosan glutamate (e.g., available from NovoMatrix®, a business unit of FMC Health and Nutrition (now part of Du Pont; Product Numbers: CL 113, CL 114, CL 213, CL 214, G 113, G 213, G 214)). In some embodiments, such chitosan and / or variants thereof (including, for example, salts thereof, such as, for example, chloride salts or glutamate salts) may be or include chitosan, chitosan oligomers, and / or variants thereof (including, for example, chitosan HCl, carboxymethyl chitosan, chitosan lactate, chitosan acetate), obtained, for example, from Heppe Medical Chitosan GMBH (e.g., Chitoceuticals® or Chitoscience®).

[0152] In some embodiments, the chitosan or variant thereof included in the biomaterial preparations described herein is or comprises a carboxyalkylchitosan (e.g., carboxymethylchitosan) characterized by at least one or all of the following properties: (1) a degree of deacetylation of 80%-95%, (ii) an average molecular weight of 30 kDa-500 kDa or a molecular weight distribution of 30 kDa-500 kDa, and (iii) a viscosity in the range of 5-300 mPa·s.

[0153] In some embodiments, the chitosan or variant thereof included in the biomaterial preparation described herein is or includes a variant of chitosan (e.g., as described herein). In some embodiments, such a variant of chitosan may include chemical modification(s) of one or more chemical moieties of the chitosan chain, e.g., hydroxyl and / or amino groups. In some embodiments, such a variant of chitosan is or includes a modified chitosan, such as, for example, but not limited to, a glycated chitosan (e.g., a chitosan modified by the addition of one or more mono- or oligosaccharide side chains to one or more of its free amino groups). Exemplary saccharified chitosans that are useful herein include, for example, but are not limited to, those described in US 5,747,475, US 6,756,363, WO 2013 / 109732, US 2018 / 0312611, and US 2019 / 0002594, the contents of each of which are incorporated herein by reference for purposes described herein.

[0154] In some embodiments, the chitosan or variant thereof included in the biomaterial preparations described herein is or includes chitosan conjugated to a polymer (e.g., a hydrophilic polymer such as polyethylene glycol) that increases the solubility of chitosan in an aqueous environment.

[0155] In some embodiments, the chitosan or variant thereof contained in the biomaterial preparation described herein is or comprises a thiolated chitosan.Various modifications to chitosan are known in the art, including, but not limited to, carboxylation, pegylation, galactosylation (or other glycosylation), and / or thiolation, as described, for example, in Ahmadi et al.Res Pharm Sci.,10(1):1-16(2015) (the contents of which are incorporated herein by reference for the purposes described herein).Those skilled in the art who read this disclosure will understand that other modified chitosans may be useful for the particular application in which the method is performed.

[0156] In some embodiments, the biomaterial preparations described herein may be or include polymer combination preparations as described in applicant's co-pending U.S. Provisional Patent Application Nos. 63 / 053,488, filed July 17, 2020, and 63 / 108,861, filed November 2, 2020, the contents of each of which are incorporated herein by reference for purposes described herein. For example, in some embodiments, the biomaterial preparations described herein may include a poloxamer (e.g., P407) and hyaluronic acid. In some embodiments, the biomaterial preparations described herein may include a poloxamer (e.g., P407), hyaluronic acid, and chitosan or a variant thereof.

[0157] (iv) Exemplary features and / or characteristics of the described immunomodulatory compositions In certain embodiments, an immunomodulatory composition comprises a biomaterial preparation that can extend release of an immunomodulatory agent payload when delivered to a target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) compared to administration of the same immunomodulatory agent payload in solution. In certain embodiments, the biomaterial preparation (e.g., a polymeric biomaterial) extends release of an immunomodulatory agent payload at a target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) by at least 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 4 weeks compared to administration of the same immunomodulatory agent payload in solution. In some embodiments, the biomaterial preparations extend the release of the immunomodulatory agent payload such that, when assessed at a particular time point following administration, more immunomodulatory agent payload is present at the target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) compared to the levels observed when the immunomodulatory agent payload is administered in solution. For example, in some embodiments, when assessed 24 hours after administration, the amount of immunomodulatory agent payload released and present at the target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) is at least 30% (including, for example, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) greater than that observed when the immunomodulatory agent payload is administered in solution. In some embodiments, when assessed 48 hours after administration, the amount of immunomodulatory agent payload released and present at the target site (e.g., a target site at a lymphadenectomy site and / or a target site near the lymphadenectomy site) is at least 30% (including, for example, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) greater than that observed when the immunomodulatory agent payload is administered in solution.In some embodiments, when assessed 3 days after administration, the amount of immunomodulatory agent payload released and present at the target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) is at least 30% (including at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) greater than that observed when the immunomodulatory agent payload is administered in solution. In some embodiments, when assessed 5 days after administration, the amount of immunomodulatory agent payload released and present at the target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) is at least 30% (including at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) greater than that observed when the immunomodulatory agent payload is administered in solution.

[0158] In some embodiments, compositions comprising a biomaterial preparation described herein (e.g., a polymeric biomaterial in a precursor state or in a polymer network state) have a viscosity of 10,000 mPa·s or less or a lower viscosity (e.g., 9000 mPa·s or less, 8000 mPa·s or less, 7000 mPa·s or less, 6000 mPa·s or less, 5000 mPa·s or less, 4000 mPa·s or less, 3500 mPa·s or less, 3000 mPa·s or less, 4000 mPa·s or less, 5000 mPa·s or less, 6000 mPa·s or less, 8000 mPa·s or less, 9000 mPa·s or less, 9000 mPa·s or less, 9000 mPa·s or less, 1 ... s or less, 2500 mPa·s or less, 2000 mPa·s or less, 1500 mPa·s or less, 1000 mPa·s or less, 500 mPa·s or less, 250 mPa·s or less, 200 mPa·s or less, 150 mPa·s or less, 100 mPa·s or less, 75 mPa·s or less, 50 mPa·s or less, 25 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 10 mPa·s or less, or lower). In some embodiments, a composition comprising a biomaterial preparation described herein (e.g., a polymeric biomaterial in a precursor state or in a polymer network state) has a viscosity of at least 5 mPa·s or higher (e.g., at least 10 mPa·s, at least 20 mPa·s, at least 30 mPa·s, at least 40 mPa·s, at least 50 mPa·s, at least 60 mPa·s, at least 70 mPa·s, at least 80 mPa·s, at least 90 mPa·s, at least 100 mPa·s, at least 125 mPa·s, at least The viscosity may be characterized by a viscosity of at least 150 mPa·s, at least 175 mPa·s, at least 250 mPa·s, at least 500 mPa·s, at least 1000 mPa·s, at least 1500 mPa·s, at least 2000 mPa·s, at least 2500 mPa·s, at least 3000 mPa·s, at least 4000 mPa·s, at least 5000 mPa·s, at least 6000 mPa·s, at least 7000 mPa·s, at least 8000 mPa·s, at least 9000 mPa·s, or higher). Combinations of the above ranges are also possible.For example, in some embodiments, a composition comprising a biomaterial preparation described herein (e.g., a polymeric biomaterial in a precursor state or a polymer network state) may be characterized by a viscosity of 5 mPa·s to 10,000 mPa·s, or 10 mPa·s to 5000 mPa·s, or 5 mPa·s to 200 mPa·s, or 20 mPa·s to 100 mPa·s, or 5 mPa·s to 20 mPa·s. One of skill in the art reading this disclosure will understand that, in some cases, the viscosity of a composition comprising a biomaterial preparation described herein may be selected or adjusted based on, for example, the route of administration (e.g., injection vs. implantation), the injection volume and / or injection time, and / or the duration of the immunomodulatory effect. As will also be understood by one of skill in the art, the viscosity of a biomaterial preparation depends, for example, on the temperature and the concentration of the polymer in the experimental sample. In some embodiments, the viscosity of a composition comprising a biomaterial preparation described herein may be characterized by a viscosity of, for example, 1000 s. -1 The shear rate may be measured at 20°C.

[0159] In some embodiments, when the biomaterial preparations described herein are in a polymer network state, such polymer network state can be at least 100 Pa, at least 200 Pa, at least 300 Pa, at least 400 Pa, at least 500 Pa, at least 600 Pa, at least 700 Pa, at least 800 Pa, at least 900 Pa, at least 1000 Pa, at least 1100 Pa, at least 1200 Pa, at least 1300 Pa, at least 1400 Pa, at least 1500 Pa, at least 1600 Pa, at least 1700 Pa, at least 1800 Pa, at least 1900 Pa, at least 2000 Pa, at least 2100 Pa, at least 2200 Pa, at least 2300 Pa, at least 2400 Pa, at least 2500 Pa, at least 2600 Pa, at least 2700 Pa, at least 2800 Pa, at least 2900 Pa, at least 3000 Pa, at least 3100 Pa, at least 3200 Pa, at least 3300 Pa, at least 3400 Pa, at least 3500 Pa, at least 3600 Pa, at least 3700 Pa, at least 3800 Pa, at least 3900 Pa, at least 4000 Pa, at least 4100 Pa, at least 4200 Pa, at least 4300 Pa, at least 4400 Pa, at least 4500 Pa, at least 4600 Pa, at least 4700 Pa, at least 4800 Pa, at least 4900 Pa, at least 5000 Pa, at least 5100 Pa, at least 5200 Pa, at least 5300 Pa, at least 5400 Pa, at least 5500 Pa, The polymer network biomaterial preparation may be characterized by a storage modulus of 800 Pa, at least 1900 Pa, at least 2000 Pa, at least 2100 Pa, at least 2200 Pa, at least 2300 Pa, at least 2400 Pa, at least 2500 Pa, at least 2600 Pa, at least 2700 Pa, at least 2800 Pa, at least 2900 Pa, at least 3000 Pa, at least 3500 Pa, at least 4000 Pa, at least 4500 Pa, at least 5000 Pa, at least 6000 Pa, at least 7000 Pa, at least 8000 Pa, at least 9000 Pa, or more. In some embodiments, the polymer network biomaterial preparation may be characterized by a storage modulus of 10 kPa or less, 9 kPa or less, 8 kPa or less, 7 kPa or less, 6 kPa or less, or less. Combinations of the above ranges are also possible. For example, in some embodiments, the polymer network biomaterial preparation may be characterized by a storage modulus of 100 Pa to 10 kPa, or 200 Pa to 5000 Pa, or 300 Pa to 2500 Pa, or 500 Pa to 2500 Pa, or 100 Pa to 500 Pa.Those skilled in the art will appreciate that a variety of rheological characterization methods (e.g., as described in Weng et al., "Rheological Characterization of in situ Crosslinkable Hydrogels Formulated from Oxidized Dextran and N-Carboxyethyl Chitosan" Biomacromolecules, 8:1109-1115 (2007)) can be used to measure the storage modulus of a material, and in some cases, the storage modulus of a material can be measured by a rheometer and / or dynamic mechanical analysis (DMA). Those skilled in the art will also appreciate that rheological characterization can vary with ambient conditions, such as temperature and / or pH.

[0160] As will be understood by those of skill in the art upon reading this disclosure, the useful biomaterial preparations described herein are generally biocompatible. In some embodiments, the useful biomaterial preparations described herein are biodegradable in vivo. In some embodiments, at least one polymer component in a biomaterial preparation used in accordance with the present disclosure may be biodegradable in vivo. In some embodiments, at least one polymer component in a suitable biomaterial preparation may exhibit resistance to biodegradation (e.g., by enzymatic and / or oxidative mechanisms). In some embodiments, at least one polymer component in a suitable biomaterial preparation may be chemically oxidized. Thus, in some embodiments, the biomaterial preparation is capable of being chemically and / or biologically degraded within a physiological environment, e.g., within the subject's body, e.g., at the subject's target site. Those of skill in the art upon reading this disclosure will understand that the degradation rate of a biomaterial preparation used in accordance with the present disclosure may vary based on, for example, the selection of the polymer component(s) and their material properties and / or their concentrations (e.g., as described herein). For example, the half-life of a suitable biomaterial preparation (the time it takes for 50% of the biomaterial preparation to degrade into monomers and / or other non-polymeric moieties) may be on the order of days, weeks, months, or years. In some embodiments, the biomaterial preparations described herein may be biologically degraded, for example, by enzymatic activity or cellular mechanisms, for example, by exposure to lysozyme (e.g., having a relatively low pH), or by simple hydrolysis. In some instances, a suitable biomaterial preparation may be degraded into monomers (e.g., monomers of a polymer) and / or non-polymeric moieties that are non-toxic to cells. As will be appreciated by those skilled in the art, a suitable biomaterial preparation will have a longer residence time at a target site (e.g., a target site at and / or near a lymphadenectomy site) when administered if such a suitable biomaterial preparation has a slower degradation rate in vivo.

[0161] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) (e.g., a target site at and / or near a lymphadenectomy site), at least 10% or more (including, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo two or more days after administration. In some embodiments, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, or less than or equal to the above remain at the target site in vivo two or more days after administration. Combinations of the above are also possible. For example, in some embodiments, biomaterial preparations used in accordance with the present disclosure, when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) (e.g., a target site at and / or near a lymphadenectomy site), are characterized in that 30%-80%, or 40%-70% of a suitable biomaterial preparation in such polymer network state remains at the target site in vivo 2 or more days after administration.

[0162] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site (e.g., a target site at and / or near a lymphadenectomy site) of a test subject (e.g., as described herein), at least 10% or more (including, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 3 days or more after administration. 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, or less of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 3 days or more after administration. Combinations of the above are also possible. For example, in some embodiments, a suitable biomaterial preparation is characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) at a target site at and / or near a lymphadenectomy site, 30%-80%, or 40%-70% of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 3 days or more after administration.

[0163] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site (e.g., a target site at and / or near a lymphadenectomy site) of a test subject (e.g., as described herein), at least 10% or more (including, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 5 days or more after administration. 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, or less of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 5 days or more after administration. Combinations of the above are also possible. For example, in some embodiments, a suitable biomaterial preparation is characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) at a target site at and / or near a lymphadenectomy site, 30%-80%, or 40%-70% of the suitable biomaterial preparation in such polymer network state remains at the target site in vivo 5 days or more after administration.

[0164] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site (e.g., a target site at and / or near a lymphadenectomy site) of a test subject (e.g., as described herein), at least 10% or more (including, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 7 days or more after administration. 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, or less of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 7 days or more after administration. Combinations of the above are also possible. For example, in some embodiments, a suitable biomaterial preparation is characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) at a target site at and / or near a lymphadenectomy site, 30%-80%, or 40%-70% of the suitable biomaterial preparation in such polymer network state remains at the target site in vivo 7 days or more after administration.

[0165] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site (e.g., a target site at and / or near a lymphadenectomy site) of a test subject (e.g., as described herein), at least 10% or more (including, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 14 days or more after administration. 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, or less of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 14 days or more after administration. Combinations of the above are also possible. For example, in some embodiments, a suitable biomaterial preparation is characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) at a target site at and / or near a lymphadenectomy site, 30%-80%, or 40%-70% of the suitable biomaterial preparation in such polymer network state remains at the target site in vivo 14 days or more after administration.

[0166] In some embodiments, biomaterial preparations used in accordance with the present disclosure are characterized in that when assessed in vivo by administration to a target site of a test subject (e.g., as described herein) (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site), no more than 10% or less (including, for example, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or no more) of such suitable biomaterial preparation in a polymer network state remains at the target site in vivo 10 days or more after administration.

[0167] In certain embodiments, compositions described herein include a biomaterial preparation forming a matrix or depot and an immunomodulatory payload present in the biomaterial preparation. In certain embodiments, the immunomodulatory payload is released from the biomaterial preparation by diffusion following administration to a target site (e.g., a target site at and / or near a lymphadenectomy site). For example, in certain embodiments, the polymer network state of the biomaterial preparation may be characterized in that less than 100% of the immunomodulatory payload (including, for example, less than 95%, less than 90%, less than 85%, less than 80%, less than 70%, less than 50%, or less) is released from the biomaterial preparation within 3 hours when tested in vitro by placing a composition comprising a biomaterial and an immunomodulatory payload in PBS (pH 7.4).

[0168] In certain embodiments, the polymer network state of a biomaterial preparation may be characterized in that when tested in vitro by placing a composition comprising a biomaterial and an immunomodulatory agent payload in PBS (pH 7.4), at least 30% (including, for example, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, or more) of the immunomodulatory agent payload is released from the biomaterial preparation within 12 hours.

[0169] In certain embodiments, the polymer network state of the biomaterial preparation may be characterized in that, when tested in vivo by administering a composition comprising the biomaterial and an immunomodulatory agent payload to the mammary fat pad of a mouse subject, 60% or less (including, e.g., 50% or less, 40% or less, etc.) of the immunomodulatory agent payload is released in vivo 8 hours after administration.

[0170] In some embodiments, the compositions provided herein are characterized in that a test animal group with spontaneous metastasis having such a composition at a target site (e.g., a target site at and / or near the lymphadenectomy site) has a higher survival rate when evaluated two months after administration than a comparable test animal group having a biomaterial preparation at the target site (e.g., a target site at and / or near the lymphadenectomy site) that does not contain an immunomodulatory agent payload. In some such embodiments, the increase in survival observed in a test animal group with spontaneous metastasis having an immunomodulatory composition at a target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) is at least 30% or more (including at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) compared to the survival rate of a comparable test animal group having a biomaterial preparation at the target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) that does not contain an immunomodulatory payload, when assessed two months after administration.

[0171] In some embodiments, the compositions provided herein are characterized in that a test animal group with spontaneous metastasis having such a composition at a target site (e.g., a target site at and / or near the lymphadenectomy site) has a higher survival rate when evaluated 3 months after administration than a comparable test animal group having a biomaterial preparation at the target site (e.g., a target site at and / or near the lymphadenectomy site) that does not contain an immunomodulatory agent payload. In some such embodiments, the increase in survival observed in a test animal group with spontaneous metastasis having an immunomodulatory composition at a target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) is at least 10% or more (at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) compared to the survival of a comparable test animal group having a biomaterial preparation at the target site (e.g., a target site at the lymphadenectomy site and / or a target site near the lymphadenectomy site) that does not contain an immunomodulatory payload, when assessed 3 months after administration.

[0172] In certain embodiments, the biomaterial preparations described herein may form a polymer network with or without the addition of a crosslinking agent. In certain embodiments, the polymer network is crosslinked. The polymer network (e.g., hydrogel) may be crosslinked using any method known in the art, such as chemical crosslinking (e.g., by using small molecule crosslinkers that may be derived from natural sources or may be synthesized), polyelectrolyte crosslinking (e.g., mixing a polymer with a second polymer that contains an opposite charge), thermally induced crosslinking, photoinduced crosslinking (e.g., using vinylsulfone, methacrylate, acrylic acid), pH induced crosslinking, and enzyme-catalyzed crosslinking. In some embodiments, one or more crosslinking methods described in Parhi, Adv Pharm Bull., Review 7(4):515-530 (2017), which is incorporated herein by reference for the purposes described herein, may be used to form the polymer network (e.g., hydrogel).

[0173] B. Exemplary Payloads As already mentioned herein, in some embodiments, a biomaterial preparation (e.g., a polymer preparation described herein, including a polymer combination preparation) may be administered without an additional payload. In some embodiments, such a preparation may have certain immunomodulatory properties in itself. Alternatively or additionally, in some embodiments, a biomaterial preparation (e.g., a polymer preparation described herein, including a polymer combination preparation) may include and / or be otherwise administered in combination with one or more therapeutic agents and / or payloads (e.g., an immunomodulatory agent payload, e.g., an immunomodulatory agent). That is, in some embodiments, an immunomodulatory composition may include or consist of a biomaterial (e.g., a polymer) and a payload.

[0174] In some embodiments, the immunomodulatory compositions described herein comprise one or more payloads. In some embodiments, the payload can be or can include a biologically active agent (e.g., the administration of which to a site as described herein has a biological (e.g., physiological) effect on the site). In some embodiments, the payload can be or can include a detectable agent (e.g., a detectable moiety).

[0175] In some embodiments, the payload is an immunomodulatory agent.

[0176] In some embodiments, the payload is not a toxic agent (e.g., a cytotoxic or cytostatic agent or other anti-proliferative agent), e.g., the payload is not a traditional chemotherapeutic agent that acts simply by killing cancer cells but does not promote clinically significant immunogenic cell death (see, e.g., Vacchelli et al., “Trial watch: Chemotherapy with immunogenic cell death inducers”, Oncoimmunology, March 1, 2013; Kepp et al., “Consensus guidelines for the detection of immunogenic cell death” Oncoimmunology, December 13, 2014; Bloy et al., “Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance” Immunology Reviews, November 2017; Michaud et al., “Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice”, Science, December 16, 2011; Galluzzi et al., “Cell death in mice: a novel mechanism of action of immunotherapy”, Science, December 16, 2011; al., “Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018”, Cell Death Differentiation, March 2018, Galluzzi et al., “Immunogenic cell death in cancer and infectious disease”, Nature Reviews Immunology, October 2016, Galluzzi et al.See, “Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors”, Nature Reviews Clinical Oncology, August 5, 2020 (the contents of each of which are incorporated herein by reference for purposes described herein). In some embodiments, whether such chemotherapeutic agents can promote a clinically meaningful degree of immunogenic cell death can be determined by, for example, evaluating the relative therapeutic efficacy of the chemotherapeutic agent after treatment of the same tumor model in immunocompromised versus healthy mice. Examples of conventional chemotherapeutic agents can be found within any of a variety of anti-cancer drug classes, including, but not limited to, alkylating agents, antimetabolites, topoisomerase inhibitors, and / or mitotic inhibitors. In some embodiments, the immunomodulatory compositions described herein are substantially free of any conventional chemotherapeutic agents. In some embodiments, the immunomodulatory compositions are substantially free of cytotoxic or cytostatic agents (or other anti-proliferative agents).

[0177] In some embodiments, the payload may be dispersed in a biomaterial preparation (e.g., a polymer preparation described herein, including a polymer combination preparation). In some embodiments, the present disclosure provides and / or utilizes, inter alia, a polymer preparation and / or a composition comprising one or more payloads, where at least a portion of the payload(s) is dispersed in the polymer preparation.

[0178] In some embodiments, the payload that may be included in the biomaterial preparation may be or include a therapeutic agent for the treatment and / or prevention of a disease, disorder, or condition. In some embodiments, the therapeutic agent that may be included in the biomaterial preparation may be or include an agent for immune regulation, wound healing, cancer treatment, and / or analgesia. In some embodiments, the therapeutic agent that may be included in the biomaterial preparation may be useful for the treatment of cancer. In some embodiments, the payload that may be included in the biomaterial preparation is or includes a chemotherapeutic agent, for example, in some embodiments, a chemotherapeutic agent that induces immunogenic cell death. As will be appreciated by those skilled in the art, such chemotherapeutic agents suitable for use according to the present disclosure may be synthetic or natural compounds; single molecules or complexes of different molecules. In some embodiments, suitable chemotherapeutic agents that induce immunogenic cell death may belong to any of a variety of classes of compounds, including, but not limited to, small molecules, peptides, saccharides, steroids, antibodies, fusion proteins, nucleic acid agents (such as, but not limited to, antisense polynucleotides, ribozymes, and small interfering RNAs), peptidomimetics, and the like.

[0179] In some embodiments, the payload that may be included in the biomaterial preparation is or includes one or more nucleic acid agents. Such nucleic acid agents may have enzymatic activity (e.g., ribozyme activity), gene expression inhibitory activity (e.g., antisense RNA agents or interfering RNA agents), polypeptide coding function, immunomodulatory activity, and / or other activity. In some embodiments, the nucleic acid agents that may be included in the biomaterial preparation may themselves act to regulate one or more aspects of the immune response or may encode modulators of one or more aspects of the immune response.

[0180] In some embodiments, the payload that may be included in the biomaterial preparation is or includes a photosensitizer used in photodynamic therapy (PDT). In PDT, the photosensitizer is administered locally or systemically to the patient, followed by irradiation of light that is absorbed by the photosensitizer in the tissue or organ to be treated. Light absorption by the photosensitizer produces reactive species (e.g., radicals) that are harmful to cells. For maximum efficacy, the photosensitizer must not only be in a form suitable for administration, but also in a form that can readily undergo cellular internalization at the target site, preferably with some selectivity compared to normal tissue.

[0181] In some embodiments, the payload is or includes a radiosensitizer. A radiosensitizer is typically a molecule, compound, or drug that makes target cells more sensitive to radiation therapy. Administering an immunomodulatory composition (e.g., an immunomodulatory composition that is or includes a biomaterial preparation) that includes a radiosensitizer to a patient undergoing radiation therapy can concentrate the function of the radiosensitizer to the target cells, thereby enhancing the effect of radiation therapy.

[0182] In some embodiments, the payload is or includes a radioisotope. Examples of suitable radioisotopes include any alpha-emitter, beta-emitter, or gamma-emitter that, when localized at a target site, results in cell destruction, including, for example, but not limited to, iodine-131, iodine-125, bismuth-212, bismuth-213, astatine-211, rhenium-186, rhenium-188, phosphorus-32, yttrium-90, samarium-153, and lutetium-177.

[0183] In some embodiments, the payload is or includes a prodrug activating enzyme, for example, for a directed enzyme prodrug therapy approach. For example, in some embodiments, a biomaterial preparation including a prodrug activating enzyme and a prodrug can be administered to a subject, where the biomaterial preparation is formed in situ at a target site and the prodrug activating enzyme contained therein converts the prodrug delivered to / around the target site into an active drug. The prodrug can be converted to an active drug in one step or in two or more steps (by the prodrug activating enzyme).

[0184] In some embodiments, the payload is or includes an antiangiogenic agent. Antiangiogenic agents suitable for use according to the present disclosure may include any molecule, compound, or factor that inhibits, suppresses, delays, or reduces the process of angiogenesis or the process by which new blood vessels are formed by developing from pre-existing blood vessels. Such molecules, compounds, or factors may inhibit angiogenesis by inhibiting, suppressing, delaying, or reducing any of the steps involved in angiogenesis, including: (1) dissolution of the membrane of the blood vessel of origin; (2) migration and proliferation of endothelial cells; and (3) formation of the tubular structure of new blood vessels by migratory cells. Examples of antiangiogenic agents include, but are not limited to, bevacizumab (Avastin®), celecoxib (Celebrex®), endostatin, anti-VEGF antibodies, interferon-alpha, squalamine, cisplatin, combretastatin A-4, and Neovastat.

[0185] In some embodiments, the payload is or includes an immunomodulatory payload. In some embodiments, the immunomodulatory payload is included in the biomaterial preparation as a monotherapy. In some embodiments, the immunomodulatory payload is or includes an inflammation modulator. As will be appreciated by those skilled in the art, inflammation can be immunostimulatory or immunosuppressive depending on the biological context. Thus, in some embodiments, the immunomodulatory payload is or includes an immunostimulatory inflammation modulator. In some embodiments, the immunomodulatory payload is or includes an immunosuppressive inflammation modulator. In some embodiments, the immunomodulatory payload is or includes an innate and / or adaptive immunity modulator. In some such embodiments, the innate and / or adaptive immunity modulator is or includes an innate and / or adaptive immunity agonist.

[0186] In some embodiments, the immunomodulatory payload is or includes a modulator of granulocytes. Granulocytes are a category of white blood cells in the innate immune system characterized by the presence of granules in the cytoplasm. Granulocytes may be referred to as polymorphonuclear leukocytes or polymorphonuclear neutrophils (PMN, PML, or PMNL) due to the variable shape of their nuclei, which are usually lobed into three segments. This distinguishes them from mononuclear agranulocytes. Examples of granulocytes include, but are not limited to, neutrophils, eosinophils, basophils, and / or mast cells.

[0187] In some embodiments, the immunomodulatory payload is or includes a modulator of agranulocytes. As will be appreciated by those skilled in the art, agranulocytes, also known as nongranulocytes or mononuclear leukocytes, are characterized by a lack of granules in their cytoplasm, which distinguishes them from granulocytes. Examples of agranulocytes include, but are not limited to, lymphocytes, monocytes, and / or macrophages. As will be appreciated by those skilled in the art, lymphocytes typically include, but are not limited to, B cells, T cells, natural killer T cells, and / or natural killer (NK) cells.

[0188] In some embodiments, the immunomodulatory payload is or comprises a modulator of myeloid and / or lymphoid cells. In some embodiments, the immunomodulatory payload is or comprises a modulator of neutrophils, eosinophils, basophils, lymphocytes, and / or monocytes. In some embodiments, the immunomodulatory payload is or comprises a modulator of hematopoietic stem cells, common myeloid progenitors, megakaryocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, monocytes, macrophages, dendritic cells, common lymphoid progenitors, natural killer cells, T lymphocytes, B lymphocytes, and / or plasma cells.

[0189] In some embodiments, the immunomodulatory payload is or includes an immunomodulatory agent as described in International Patent Publication Nos. WO2018 / 045058 (including, but not limited to, examples such as activators of the innate immune response, activators of the adaptive immune response, immunomodulatory cytokines, modulators of macrophage effector function, etc.) and WO2019 / 183216 (including, but not limited to, examples such as inhibitors of immunosuppressive inflammation, such as mediated by the p38-mitogen-activated protein kinase (MAPK) pathway), the contents of each of which are incorporated herein by reference for the purposes described herein. In some embodiments, the immunomodulatory payload is or includes an activator of the innate immune response, e.g., in some embodiments, the activator of the innate immune response can be or include a stimulator of interferon genes (STING) agonist, a Toll-like receptor (TLR) agonist, and / or an activator of the innate immune response as described in International Patent Publication No. WO2018 / 045058, the contents of which are incorporated herein by reference for purposes described herein. In some embodiments, the immunomodulatory payload is or includes an inhibitor of immunosuppressive inflammation, e.g., in some embodiments, the inhibitor of immunosuppressive inflammation can be or include a COX-2 inhibitor or an inhibitor of immunosuppressive inflammation mediated by the p38-mitogen-activated protein kinase (MAPS) pathway, as described in International Patent Publication No. WO2019 / 183216, the contents of which are incorporated herein by reference for purposes described herein.

[0190] In some embodiments, the immunomodulatory payload is or includes a Toll-like receptor 7 and 8 (TLR7 / 8) agonist (e.g., those described in International Patent Publication No. WO2018 / 045058). In some embodiments, an exemplary TLR7 / 8 agonist is or includes resiquimod (R848) or a variant thereof.

[0191] In some embodiments, the immunomodulatory payload is or includes an immunomodulatory cytokine (e.g., those described in International Patent Publication No. WO2018 / 045058). In some embodiments, exemplary immunomodulatory cytokines are or include interleukin-2 (IL-2), interleukin-12 (IL-12), or variants thereof.

[0192] In some embodiments, the immunomodulatory payload is or includes a nonsteroidal anti-inflammatory drug (NSAID) (e.g., those described in International Patent Publication No. WO2019 / 183216). In some embodiments, the NSAID is or includes ketorolac. Ketorolac is traditionally used for short-term pain management and is therefore not usually prescribed for longer than 5 days due to toxicity. Systemic exposure of ketorolac can cause nephrotoxicity and cardiotoxicity as well as bleeding in the gastrointestinal tract. In some embodiments, the present disclosure recognizes that local retention of ketorolac may be desirable. For example, in some embodiments, the ketorolac used in the present disclosure is released from the biomaterial preparation (e.g., from the polymer preparation, such as the polymer combination preparation described herein) for at least 3 hours or more, such as at least 6 hours, at least 12 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, or longer, so that the immune system is modulated (e.g., the immunosuppressive inflammation induced by tumor resection surgery is inhibited or reduced). Ketorolac can be administered as a racemic mixture or as an individual enantiomer, such as the S-enantiomer. In some embodiments, the NSAID comprises lornoxicam. In some embodiments, the NSAID comprises sodium meclofenamate.

[0193] In some embodiments, the immunomodulatory payload is or includes a resolvin (e.g., those described in International Patent Publication No. WO2019 / 183216). In some embodiments, an exemplary resolvin is or includes RvD2. RvD2 is a resolvin that acts as a specific inflammation-resolving mediator (SPM) involved in a coordinated resolution program that can prevent excessive inflammation and / or resolve acute inflammation.

[0194] In some embodiments, the immunomodulatory payload is or comprises a hematopoietic stem cell mobilizing agent and / or a CXCR4 receptor antagonist, hi some embodiments, the hematopoietic stem cell mobilizing agent and / or the CXCR4 receptor antagonist is plerixafor.

[0195] In some embodiments, the immunomodulatory payload is or includes a NOD1 and / or NOD2 agonist (e.g., as described in International Patent Publication No. WO2018 / 045058). In some embodiments, an exemplary NOD1 and / or NOD2 agonist can be or include L-Ala-γ-D-Glu-mDAP (TriDAP). Tri-DAP is typically present in the peptidoglycan (PGN) of Gram-negative and certain Gram-positive bacteria. In some embodiments, TriDAP is recognized by the intracellular sensor NOD1, which triggers a signaling cascade that leads to NF-κB activation and / or production of inflammatory cytokines. In some embodiments, an exemplary NOD1 and / or NOD2 agonist can be or include MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP). Similar to TriDAP, M-TriDAP is a peptidoglycan (PGN) degradation product found primarily in Gram-negative bacteria. M-TriDAP is normally recognized by the intracellular sensors NOD1 (CARD4) and, to a lesser extent, NOD2 (CARD15). Recognition of M-TriDAP by NOD1 / NOD2 induces a signaling cascade involving serine / threonine RIP2 (RICK, CARDIAK) kinase that interacts with IKK, thereby triggering activation of NF-κB and / or production of inflammatory cytokines, such as TNF-α and IL-6. In some embodiments, M-TriDAP induces activation of NF-κB at a similar level as Tri-DAP.

[0196] In some embodiments, the immunomodulatory payload is or comprises a modulator of immune cell effector function, survival, and / or recruitment. In some embodiments, the immunomodulatory payload is or comprises a modulator of monocyte effector function, survival, and / or recruitment. In some embodiments, the immunomodulatory payload is or comprises a modulator of macrophage effector function, survival, and / or recruitment. In some embodiments, the immunomodulatory payload is or comprises a modulator of myeloid-derived suppressor cell effector function, survival, and / or recruitment. In some embodiments, the immunomodulatory payload is or comprises a modulator of neutrophil function, survival, and / or recruitment. In some embodiments, the immunomodulatory payload is or comprises a modulator of natural killer cell effector function, survival, and / or recruitment. Examples of such modulators of immune cell effector function, survival, and / or recruitment include, but are not limited to, adenosine A2A receptor (A2AR) inhibitors, chemokines (e.g., CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CCL21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and / or CX3CL1), angiopoietin 2 (ANG2) inhibitors, arginase-1 (ARG1) inhibitors, colony-stimulating factor 1 (CSF1) inhibitors, granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors, colony-stimulating factor 1 receptor (CLR) inhibitors, and / or CX3CL1 inhibitors. receptor (CSF1R) inhibitors, ectonucleotide triphosphate diphosphohydrolase (ENTPD1, ​​also known as CD39) inhibitors, tumor necrosis factor receptor superfamily member 5 (CD40) agonists, OX40 agonists, 4-1BB agonists, CD160 agonists, DNAM agonists, NKG2D agonists, NKG2A inhibitors, TIGIT inhibitors, LILRB1 inhibitors, LILRB2 inhibitors, leukocyte surface antigen CD47 (CD47) inhibitors, signal regulatory protein α (SIRPα) inhibitors, 5'-nucleotidase (NT5E, also known as CD73) inhibitors, prostaglandin endoperoxide synthase 2 (PTGS2,Also known as cyclooxygenase-2 (COX-2) inhibitors, prostaglandin E2 (PGE2) inhibitors, PGE2 receptor 2 (EP2) inhibitors, PGE2 receptor 4 (EP4) inhibitors, inducible nitric oxide synthase (iNOS) inhibitors, fibroblast growth factor 1 (FGF) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, class II HDAC (e.g., HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10) inhibitors, Ig-like transcript 2 (ILT2) inhibitors, S100A8 / A9 inhibitors, RAGE inhibitors, interleukin-8 (IL-8, also known as CXCL8) inhibitors, CXC chemokine receptor type 1 (CXCR-1) inhibitors, CXC chemokine receptor type 2 (CXCR-2) inhibitors, interleukin-10 (IL-10) inhibitors, interleukin-2 (and variants thereof), interleukin-12 (IL-12) (including subunit alpha (IL-12a) and subunit beta (IL-12b)) (and variants thereof), interleukin-15 (and variants thereof), interleukin-18 (and barrier inhibitors thereof), nts), leukotriene B4 (LTB4) inhibitors, resolvin family (e.g., RvD1, RvD2, RvD3, RvD4, RvD5, RvD6, 17R-RvD1, 17R-RvD2, 17R-RvD3, 17R-RvD4, 17R-RvD5, 17RRvD6, RvEl, 18S-RvE1, RvE2, RvE3, RvTl, RvT2, RvT3, RvT4, RvT5, RvT6, RvT7, RvT8, RvT9, RvT10, RvT11, RvT22, RvT12, RvT13, RvT14, RvT15, RvT16, RvT17, RvT18, RvT19, RvT21, RvT22, RvT23, RvT24, RvT25, RvT26, RvT27, RvT28, RvT29, RvT31, RvT32, RvT33, RvT34, RvT35, RvT36, RvT37, RvT38, RvT39, RvT40, RvT41, RvT42, RvT43, RvT44, RvT45, RvT46, RvT47, RvT48, RvT49, RvT51, RvT52, RvT53, RvT54, RvT55, RvT56, RvT57, RvT58, RvT59, RvT61, RvT62, RvT63, RvT64, RvT65, RvT66, R vT4, RvDln-3, RvD2n-3, and / or RvD5n-3) specific inflammation-resolving mediators (SPMs), lipoxin family (e.g., LxA4, LxB4, 15-epi-LxA4, and / or 15-epi-LxB4) SPMs, protectin / neuroprotectant (e.g., DHA-derived protectin / neuroprotectin and / or n-3 DPA-derived protectin / neuroprotectin) SPMs, maresins (e.g., DHA-derived maresins and / or n-3 DPA-derived maresins) SPMs, phosphoinositide 3 kinase gamma (PI3Kγ) inhibitors, transforming growth factor beta (TGF-β) inhibitors, transforming growth factor beta receptor (TGF-βR family, e.g., ALK1, ALK2, ALK3, ALK4, TGF-βR1, ALK6,ALK7, TGF-βR2, TGF-βR3, BMPR2, ACVR2A, ACVR2B, and / or AMHR2), vascular endothelial growth factor family (VEGF, e.g., VEGF-A, VEGF-B, VEGF-C, and / or VEGF-D) inhibitors, vascular endothelial growth factor receptor family (VEGFR, e.g., VEGFR-1, VEGFR-2, and / or VEGFR-3) inhibitors, JAK / STAT inhibitors, angiotensin II receptor inhibitors (e.g., valsartan), and / or combinations thereof.

[0197] Those skilled in the art will appreciate that the human immune system is complex and that strict classification of a particular agent as one category of immunomodulator (e.g., as an agonist of innate immunity versus an agonist of adaptive immunity, and / or as a modulator of macrophage effector function, such as granulocytes, myeloid cells, and / or lymphoid cells) may not necessarily be useful, necessary, or even possible. Based on the description herein, those skilled in the art will appreciate the metes and bounds of relevant agents useful in the embodiments described herein in context. For example, in some embodiments, certain immunomodulators that may be useful in one context as activators of adaptive immune responses may also be effective in modulating survival, recruitment, and / or effector function of one or more immune cell types, including, for example, macrophages, monocytes, myeloid-derived suppressor cells, neutrophils, and / or natural killer cells.

[0198] In some embodiments, the immunomodulatory payload is released from the immunomodulatory composition and taken up by an immune cell, hi some embodiments, the immune cell that takes up the immunomodulatory payload exhibits at least one of the following biological activities: expressing an immunomodulatory polypeptide in response to the immunomodulatory payload, exhibiting increased expression of type 1 interferon in response to innate immune stimulation induced by the immunomodulatory payload, and / or exhibiting a change in the level and / or activity of the immunomodulatory polypeptide.

[0199] In some embodiments, the immunomodulatory payload is a polynucleotide drug. In some embodiments, the polynucleotide drug is a coding polynucleotide that can be translated into a polypeptide. In some embodiments, the biomaterial preparation in the immunomodulatory composition is characterized in that the polynucleotide drug is released from the biomaterial preparation and taken up by local cells, such that at least a subset of local immune cells express the immunomodulatory polypeptide encoded by the polynucleotide drug. In some embodiments, the biomaterial preparation in the immunomodulatory composition is characterized in that at least a subset of local immune cells have increased expression of type 1 interferon in response to innate immune stimulation elicited by the polynucleotide drug. In some embodiments, the biomaterial preparation in the immunomodulatory composition is characterized in that at least a subset of local immune cells have altered levels and / or activity of the immunomodulatory polypeptide in response to the polynucleotide drug.

[0200] In some embodiments, target cells may include myeloid cells and / or plasmacytoid dendritic cells. In some embodiments, target cells may include non-immune cells, such as fibroblasts and / or endothelial cells.

[0201] II. Pharmaceutical Compositions In some embodiments, the biomaterial preparations used in accordance with the present disclosure may be formulated in accordance with available techniques as pharmaceutical compositions (e.g., immunomodulatory compositions) for administration to a subject in need thereof (e.g., as described herein). In some embodiments, such pharmaceutical compositions may include pharma- ceutically acceptable carriers or excipients, as used herein, including any solvent, dispersion medium, diluent, or other liquid vehicle, dispersing or suspending aid, surface active agent, isotonicity agent, thickening or emulsifying agent, preservative, solid binder, lubricant, and the like, appropriate for the particular dosage form desired. Remington's The Science and Practice of Pharmacy, 21st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006, the contents of which are incorporated herein by reference for the purposes described herein) discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation. Suitable pharma- ceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), saline, buffered saline, glycerol, sugars such as mannitol, lactose, trehalose, sucrose, or others, dextrose, fatty acid esters, and the like, and combinations thereof.

[0202] Pharmaceutical compositions may, if desired, be mixed with auxiliary agents that do not adversely react with the active compounds or interfere with their activity (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, flavoring agents, and / or aromatic agents, etc.) In some embodiments, the pharmaceutical compositions may be sterile. Suitable pharmaceutical compositions can, if desired, contain minor amounts of wetting or emulsifying agents, or pH buffering agents.The pharmaceutical composition can be a liquid solution, suspension, or emulsion.

[0203] The pharmaceutical composition may be formulated according to routine procedures as a pharmaceutical composition adapted for administration to humans. The preparation of the pharmaceutical composition must be suitable for the mode of administration. For example, in some embodiments, a pharmaceutical composition for injection may usually include a sterile aqueous isotonic buffer. If necessary, the pharmaceutical composition may also include a local anesthetic to ease pain at the injection site. In some embodiments, the components of the pharmaceutical composition (e.g., as described herein) are supplied separately or mixed together in a single-use form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampoule or sachet, or in a sterile syringe indicating the amount of the composition containing the biomaterial preparation (e.g., as described herein). When the pharmaceutical composition is administered by injection, in some embodiments, a dry lyophilized powder composition containing the biomaterial preparation (e.g., as described herein) may be reconstituted with an aqueous buffer and then injected into the target site of the subject that needs to be injected. In some embodiments, a liquid composition including a biomaterial preparation (e.g., those described herein) may be provided in a syringe for injection and / or administration via a robotic surgery system (e.g., the da Vinci System).

[0204] In some embodiments, the liquid composition may be provided in a syringe for administration with or without a needle, cannula, or trocar.

[0205] In some embodiments, the liquid composition may be administered by nebulization.

[0206] In some embodiments, administration of the liquid composition may be gas-assisted for use in minimally invasive surgery.

[0207] In some embodiments, administration of the liquid composition may be accomplished by using a multi-barrel syringe, where each barrel contains a separate polymer component of the biomaterial preparation and the multiple polymer components are combined when a shared plunger is depressed.

[0208] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any type of animal or in vitro or ex vivo cell. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals or in vitro or ex vivo cells are well understood, and such modifications can be designed and / or performed by those skilled in the art, e.g., veterinary pharmacologists, with no more than routine experimentation, if any.

[0209] Formulations of the pharmaceutical compositions described herein may be prepared according to established pharmacological practices. For example, in some embodiments, such preparation methods may include mixing the components of a biomaterial preparation containing an immunomodulatory payload with a diluent or other excipient and / or one or more other auxiliary ingredients, and then forming and / or packaging the product into a desired single-use or multi-use unit, as needed and / or desired. Alternatively, such preparation methods may also include preforming a biomaterial preparation containing an immunomodulatory payload as described herein prior to forming and / or packaging the product into a desired single-use or multi-use unit.

[0210] In some embodiments, the pharmaceutical composition may be prepared, packaged, and / or sold in bulk as a single-use unit and / or as a plurality of single-use units. As used herein, a "single-use unit" is a discrete amount of a pharmaceutical composition described herein. For example, a single-use unit of a pharmaceutical composition comprises a predetermined amount of a composition described herein and / or a biomaterial preparation comprising an immunomodulatory payload, which in some embodiments may be or may include a preformed polymer network of a biomaterial preparation (e.g., as described herein) comprising an immunomodulatory payload, or in some embodiments may be or may include a liquid or colloidal mixture of individual components of a biomaterial preparation (e.g., as described herein).

[0211] The relative amounts of the individual components of the biomaterial preparations used in accordance with the present disclosure (e.g., as a preformed polymeric network biomaterial or as the precursor component(s) of such polymeric network biomaterials) in the pharmaceutical compositions described herein and, optionally, any additional agents, e.g., pharma- ceutically acceptable excipients and / or any additional components, can vary depending, for example, on the desired material properties of the polymeric biomaterial, the size of the target site, the injection volume, the health and medical condition of the subject being treated, and / or the type of cancer, and can also depend on the route by which such pharmaceutical composition is administered.

[0212] In some embodiments, an immunomodulatory composition (e.g., comprising a biomaterial, such as a polymeric biomaterial, alone or in combination with a payload and optionally one or more other agents) in an amount effective (e.g., established to do so when administered to an appropriate population) to achieve a desired therapeutic effect (e.g., but not limited to, induction of at least one or more aspects of anti-tumor immunity, e.g., induction of natural immunity).

[0213] In some embodiments, the effective amount is an amount useful for treating cancer. In some embodiments, the effective amount is an amount effective to inhibit or reduce the risk or incidence of tumor recurrence and / or metastasis. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0214] In certain embodiments, pharmaceutical compositions consist essentially of or consist of a biomaterial preparation comprising an immunomodulatory agent payload, such compositions may contain one or more substance(s) / agent(s) other than the biomaterial preparation comprising an immunomodulatory agent payload, to the extent that such other substance(s) / agent(s), individually or together, do not substantially alter the relevant immunomodulatory property(s) of the biomaterial preparation comprising an immunomodulatory agent payload.

[0215] In certain embodiments, the pharmaceutical composition utilized according to the present disclosure does not include cells. In certain embodiments, the pharmaceutical composition does not include adoptively transferred cells. In certain embodiments, the pharmaceutical composition does not include T cells. In certain embodiments, the pharmaceutical composition does not include tumor antigens. In certain embodiments, the pharmaceutical composition does not include ex vivo loaded tumor antigens.

[0216] In certain embodiments, the pharmaceutical composition is in a liquid form (e.g., a solution or colloid). In certain embodiments, the pharmaceutical composition is in a solid form (e.g., a gel form). In certain embodiments, the transition from the liquid form to the solid form can occur outside the subject's body by sufficient crosslinking, such that the resulting material has a storage modulus consistent with the solid form that allows it to be physically manipulated and implanted in a surgical procedure. Thus, in some embodiments, the solid form may be suitable for carrying out the intended use of the present disclosure (e.g., surgical implantation). In certain embodiments, the transition from the liquid form to the solid form can occur in situ (e.g., within the subject's body) by thermal crosslinking, such that the resulting material has a storage modulus consistent with the solid form. In certain embodiments, the pharmaceutical composition is a suspension.

[0217] III. Treatment Methods The techniques provided herein are useful for treating cancer. In some embodiments, the techniques provided herein are useful for delaying the onset, slowing the progression, and / or ameliorating one or more symptoms of cancer in a subject, particularly metastatic cancer, disseminated cancer, or cancer following tumor resection. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the growth or regrowth (e.g., following surgical resection) of a primary tumor. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the occurrence of tumor recurrence and / or metastasis in a subject. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the occurrence of secondary tumor development in a subject. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the occurrence of tumor dissemination in a subject. In some embodiments, the techniques provided herein are useful for eliciting anti-tumor immunity in a subject. In some embodiments, the techniques provided herein are useful for reducing the activation of metastases that would otherwise be observed upon lymph node resection or that would otherwise be associated with lymph node resection.

[0218] In some embodiments, the techniques provided are particularly useful for application to subjects who have undergone or will undergo tumor resection.

[0219] In some embodiments, the provided technology is particularly useful for application to subjects who have been or are receiving conventional chemotherapy.

[0220] In some embodiments, the provided technology involves a reduction in the incidence and / or severity of certain adverse events (e.g., skin rash, hepatitis, diarrhea, colitis, hypophysitis, thyroiditis, and adrenal insufficiency) that may be associated with systemic administration of immunotherapeutic agents. In particular, the provided technology may reduce or eliminate the exposure of non-tumor specific immune cells to systemically administered immunotherapeutic agent(s) and / or to the high doses of such drug(s) that are often required for systemic administration to achieve sufficient concentrations to induce a desired response at the tumor and / or metastatic site. In particular, the provided technology may achieve localized immunomodulation (e.g., local agonism of innate and / or adaptive immunity) at the site of the lymph node. Without wishing to be bound by any particular theory, it is proposed that the local administration described herein may, among other things, improve the efficacy of certain payload agents (e.g., immunomodulatory agent payloads) by, for example, concentrating the immunomodulatory effect where it is needed.

[0221] Additionally or alternatively, in some embodiments, the provided techniques resulting in local immune modulation (e.g., agonism of innate and / or adaptive immunity) before or after lymphadenectomy can, inter alia, break local immune tolerance to cancer and allow for the development of anti-tumor immunity systemically, which can result in, for example, in some embodiments, eradication of disseminated disease.

[0222] In some embodiments, the compositions described herein are administered as a liquid, hi some embodiments, the compositions described herein are administered as a gel.

[0223] In some embodiments, the compositions administered as described herein do not include polymer particles and / or do not include a payload encapsulated within or otherwise in particulate form.

[0224] Generally, the present disclosure provides techniques in which the immunomodulatory compositions described herein are administered to the site of such lymph node resection, typically in conjunction with such lymph node resection (eg, as part of the same surgical procedure).

[0225] In some embodiments, the lymph node resection site is near a tumor (e.g., a primary tumor, an established metastasis, etc.). In some embodiments, the resected tissue comprises tumor cells. In some embodiments, the resected tissue is substantially free of tumor cells. In some embodiments, the lymph node resection site is in immunological communication with the subject's tumor site. In some embodiments, the resected lymph node is or comprises a sentinel lymph node.

[0226] In some embodiments, the compositions described herein are administered by a method comprising injection. In some embodiments, administration can be or include injection using a hypodermic needle. In some embodiments, injection is or includes subcutaneous injection. In some embodiments, subcutaneous injection includes injection into the fat layer under the skin. In some embodiments, subcutaneous injection includes injection into a suitable target site (e.g., a target site at and / or near the lymphadenectomy site).

[0227] In some embodiments, the injection is or includes an injection into a space created by surgical intervention (eg, resection surgery).

[0228] In some embodiments, administering and / or delivering a biomaterial preparation (e.g., including a sustained release composition, e.g., as described herein) comprising a non-particulate immunomodulatory agent comprises administering one or more precursors of the biomaterial preparation such that the composition of the biomaterial preparation is formed in situ to constitute a sustained release composition. In some embodiments, such in situ formation comprises converting a precursor composition to a sustained release composition. In some embodiments, such precursor composition has a lower viscosity and / or storage modulus compared to the sustained release composition formed. In some embodiments, such sustained release compositions are constituted by a process comprising conversion of precursor components by gelation and / or crosslinking (e.g., gelation in response to temperature-induced crosslinking, pH-induced crosslinking, ionic crosslinking, etc.).

[0229] In some embodiments, the techniques provided herein include delivery of a biomaterial preparation to a target site. In some embodiments, the target site may be, but is not limited to, a site where at least one lymph node has been partially or fully resected. In some embodiments, the appropriate lymph node may be or may include a draining lymph node, a sentinel lymph node, a proximal lymph node, a lymph node in immunological communication with a tumor (e.g., a primary tumor and / or, in some embodiments, an established metastasis).

[0230] In some embodiments, administration occurs during or otherwise in conjunction with lymphadenectomy, which in some embodiments may be performed separately from tumor resection (usually but not necessarily before tumor resection), or in some embodiments, lymphadenectomy is performed simultaneously with tumor resection.

[0231] In some embodiments, the techniques provided herein may be particularly useful for treating subjects who have not undergone tumor resection, in other embodiments, for treating subjects who have undergone tumor resection, and in still other embodiments, for treating subjects who have undergone resection of at least a portion of their tumor. In some embodiments, the techniques provided herein may be particularly useful for treating subjects who are not candidates for tumor removal, e.g., subjects who are unable to undergo tumor resection (e.g., due to health constraints, technical constraints, religious constraints, etc.). In some embodiments, the technologies provided herein may be particularly useful for treating subjects having cancers characteristic of metastatic potential (e.g., cancers with mutations in tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), retinoblastoma (RB1), etc. (see, e.g., Fares et al., Molecular principles of metastasis: a hallmark of cancer revisited, Signal transduction and targeted therapy, March 12, 2020)).

[0232] In some embodiments, the techniques provided herein include providing a composition described herein to a site near (e.g., near) a lymph node resection site in a subject in need of being provided with a composition described herein. In some embodiments, "near" the resection site may be, for example, up to 10 cm, e.g., up to 1 cm, up to 2 cm, up to 3 cm, up to 4 cm, up to 5 cm, up to 6 cm, up to 7 cm, up to 8 cm, up to 9 cm, or up to 10 cm away from the location where the lymph node (or a portion thereof) was removed.

[0233] IV. Therapeutic Use The techniques provided herein are useful for treating cancer. In some embodiments, the techniques provided herein are useful for delaying the onset of cancer, slowing its progression, or ameliorating one or more symptoms thereof. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the occurrence, growth, and / or spread of lymph node tumors or metastases. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the growth or regrowth (after resection) of primary tumors. In some embodiments, the techniques provided herein are useful for reducing or inhibiting the occurrence of tumor recurrence and / or metastasis. In some embodiments, the techniques provided herein are useful for eliciting anti-tumor immunity. In some embodiments, the techniques provided herein are particularly useful when a subject suffers from or is susceptible to recurrent or disseminated cancer. In certain embodiments, the techniques provided herein are useful for inflammation and / or inflammatory diseases (e.g., autoimmune diseases and / or arthritis).

[0234] Accordingly, some aspects provided herein relate to methods of administering an immunomodulatory composition (e.g., comprising a biomaterial preparation) described herein to a target site in a subject in need of administration. In some embodiments, the subject to whom such a composition is administered may have undergone or may have undergone tumor removal (e.g., by surgical tumor resection). In some embodiments, the subject has not undergone tumor resection. In some embodiments, the subject to whom such a composition is administered may have tumor recurrence and / or metastasis. In some such embodiments, the method includes intraoperative administration of a composition comprising a biomaterial preparation described herein to a target site (e.g., a target site at and / or near a lymphadenectomy site), typically where the composition is administered during or otherwise in conjunction with lymphadenectomy. In some embodiments, such immunomodulatory compositions utilized in the methods of the present disclosure may be formulated as pharmaceutical compositions described herein.

[0235] In certain embodiments, the technology described herein includes methods that include administering an immunomodulatory composition to a target site in a subject in need of administration during or after removal of a tumor, for example, after removal of 50% or more of the subject's tumor weight (including, for example, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more of the subject's tumor weight). In certain embodiments, the methods provided herein include administering an immunomodulatory composition to a target site in a subject in need of administration after removal of 50% or more of the subject's tumor volume (including, for example, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more of the subject's tumor volume). In some embodiments, the methods provided herein include performing a tumor resection to remove the tumor in the subject prior to administration of the immunomodulatory composition.

[0236] In some embodiments, the compositions described and / or utilized herein are administered to a target site (e.g., a target site at and / or near the lymph node resection site) of a tumor resection subject immediately after the lymph nodes of the tumor resection subject have been removed, e.g., by surgical resection. In some embodiments, the compositions described and / or utilized herein are administered intraoperatively to a target site of a lymph node resection subject. In some embodiments, the compositions described and / or utilized herein are administered postoperatively to one or more target sites of the subject at one or more time points within 24 hours or less (including, e.g., within 18 hours, within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes, or less) after the tumor of the lymph node resection subject has been removed by surgical lymph node resection. In some embodiments, the compositions described and / or utilized herein are administered one or more times post-operatively to one or more target sites in a subject of lymphadenectomy at one or more time points within 12 months or less of the surgical intervention (including, for example, within 11 months, within 10 months, within 9 months, within 8 months, within 7 months, within 6 months, within 5 months, within 4 months, within 3 months, within 2 months, or within 1 month of the surgical intervention). In some embodiments, the compositions described and / or utilized herein are administered post-operatively at one or more target sites to a subject of lymphadenectomy at one or more time points within 31 days (including, for example, within 30 days, within 29 days, within 28 days, within 27 days, within 26 days, within 25 days, within 24 days, within 23 days, within 22 days, within 21 days, within 20 days, within 19 days, within 18 days, within 17 days, within 16 days, within 15 days, within 14 days, within 13 days, within 12 days, within 11 days, within 10 days, within 9 days, within 8 days, within 7 days, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, or within 1 day) of the surgical intervention.

[0237] In some embodiments, the target site of administration is or includes a tumor site (including, for example, a tumor resection site) and / or nearby lymph nodes and / or nearby sites. In some embodiments, such tumor sites may be characterized by a lack of total residual tumor antigen. In some embodiments, such tumor sites may be characterized by negative resection margins (i.e., no cancer cells are visible microscopically at the resection margins, for example, based on histological evaluation of tissue surrounding the tumor resection site). In some embodiments, such tumor sites may be characterized by positive resection margins (i.e., cancer cells are visible microscopically at the resection margins, for example, based on histological evaluation of tissue surrounding the tumor resection site). In some embodiments, such tumor sites may be characterized by the presence of total residual tumor antigen.

[0238] In some embodiments, the target site of administration is or includes a site in immunological communication with the tumor site. In some embodiments, the target site of administration is or includes a sentinel lymph node. In some embodiments, the target site of administration is or includes a draining lymph node.

[0239] As will be appreciated by those skilled in the art, compositions useful according to the present disclosure may be administered to a target site of a subject in need of administration using suitable delivery techniques known in the art. For example, in some embodiments, the provided techniques may be applicable for administration by injection. In some embodiments, the provided techniques may be suitable for administration, for example, by minimally invasive surgery (MIS), which typically involves one or more small incisions, such as robotic-assisted MIS, robotic surgery, and / or laparoscopic surgery. In some embodiments, the provided techniques may be suitable for administration in the context of accessible excision and / or skin resection. In some embodiments, the provided techniques may be suitable for administration (e.g., by injection) during surgery as part of a minimally invasive procedure, such as minimally invasive surgery (MIS), such as robotic-assisted MIS, robotic surgery, and / or laparoscopic surgery, and / or a procedure involving one or more accessible excision and / or skin resection. In some embodiments, the provided techniques may be suitable for administration (e.g., by injection), which, for example, in some embodiments, requires a robotic surgery system (e.g., da Vinci System) for minimally invasive administration. For example, in some embodiments, compositions that may be useful for injection and / or in the context of minimally invasive procedures, e.g., minimally invasive surgery (MIS), e.g., robotic-assisted MIS, robotic surgery, and / or laparoscopic surgery, and / or procedures involving one or more easily accessible excisions and / or skin resections, are liquid, and the biomaterial preparation provided in such compositions transitions from a liquid solution state to a polymer network state (e.g., a hydrogel) upon injection into a target site in a subject (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site), and in some embodiments is or includes a polymer solution (e.g., a viscous polymer solution) where such transition is triggered by exposure to the subject's body temperature.In some embodiments, biomaterial preparations in preformed polymer network biomaterials that are compressible without adversely affecting structural integrity can be injected, for example, via a minimally invasive procedure, e.g., minimally invasive surgery (MIS), e.g., robotic-assisted MIS, robotic surgery, and / or laparoscopic surgery and / or laparoscopic procedures.

[0240] In some embodiments, the techniques provided herein may be applicable for administration by implantation. For example, in some embodiments, the biomaterial preparation provided in the composition according to the present disclosure is a preformed polymer network biomaterial. An exemplary polymer network biomaterial is or includes a hydrogel. For example, in some embodiments, the immunomodulatory composition may be administered to a target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) by surgical implantation. In some embodiments, the immunomodulatory composition may be administered to a target site (e.g., a target site at a lymphadenectomy site and / or a target site near a lymphadenectomy site) by surgical implantation and may be secured by a bioadhesive. In some embodiments, administration may be performed intraoperatively (i.e., immediately after tumor resection).

[0241] In some embodiments, the amount of an immunomodulatory composition to achieve a desired therapeutic effect(s), such as, for example, anti-tumor immunity, may vary from subject to subject, depending on, for example, the subject's sex, age, and general condition, the type and / or severity of the cancer, the efficacy of the immunomodulatory composition, etc.

[0242] In some embodiments, the present disclosure provides techniques where administration of an immunomodulatory composition described herein is sufficient to provide anti-tumor immunity and thus does not necessarily require administration of a tumor antigen and / or adoptive transfer of immune cells (e.g., T cells) to a subject in need thereof (e.g., as described herein). Thus, in some embodiments, the techniques provided herein do not include administration of a tumor antigen to a subject within, e.g., within one month or less (including, e.g., within three weeks, within two weeks, within one week, within five days, within three days, within one day, within twelve hours, within six hours) after the subject has been administered a composition described and / or utilized herein. In certain embodiments, the techniques provided herein do not include adoptive transfer of immune cells (e.g., T cells) to a subject within, e.g., within one month or less (including, e.g., within three weeks, within two weeks, within one week, within five days, within three days, within one day, within twelve hours, within six hours) after the subject has been administered a composition described and / or utilized herein.

[0243] In some embodiments, the present disclosure provides techniques where administration of an immunomodulatory composition is particularly effective when administered to a subject in need thereof, e.g., as a combination therapy with tumor antigens and / or adoptive transfer of immune cells (e.g., T cells) (e.g., as described herein). Thus, in some embodiments, the techniques provided herein include administering a tumor antigen to a subject, e.g., within one month or less (e.g., within three weeks, within two weeks, within one week, within five days, within three days, within one day, within twelve hours, within six hours) after the subject has been administered a composition described and / or utilized herein. In certain embodiments, the techniques provided herein include adoptive transfer of immune cells (e.g., T cells) to a subject, e.g., within one month or less (e.g., within three weeks, within two weeks, within one week, within five days, within three days, within one day, within twelve hours, within six hours) after the subject has been administered a composition described and / or utilized herein.

[0244] In some embodiments, the techniques provided herein are useful for treating cancer in a subject. In some embodiments, the techniques provided herein are used to treat resectable tumors. In some embodiments, the techniques provided herein are used to treat solid tumors (such as, but not limited to, blastomas, carcinomas, germ cell tumors, and / or sarcomas). In some embodiments, the techniques provided herein are used to treat lymphomas present in tissues other than the spleen or lymphatic system, such as the thyroid or stomach.

[0245] In some embodiments, the technology provided herein is directed to treating cancers including, but not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bile duct carcinoma; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; notochord cancer. tumors;craniopharyngioma;colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma);connective tissue cancer;epithelial carcinoma;ductal intraepithelial carcinoma;ependymoma;endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma);endometrial cancer (e.g., uterine carcinoma, uterine sarcoma);esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma);Ewing's sarcoma;eye cancer (e.g., intraocular melanoma, retinoblastoma);familial hypereosinophilia;gallbladder cancer;gastric cancer (e.g., gastric adenocarcinoma);gastrointestinal stromal tumor (GIST);germ cell carcinoma;head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., pharyngeal ( laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic cancer (e.g., lymphoma, primary pulmonary lymphoma, bronchus-associated lymphoid tissue lymphoma, splenic lymphoma, nodal marginal zone lymphoma, childhood B-cell non-Hodgkin's lymphoma); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma (also known as Wilms' tumor), renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary adenocarcinoma);leiomyosarcoma (LMS);melanoma;midline carcinoma;multiple endocrine neoplasia syndrome;muscle carcinoma;mesothelioma;nasopharyngeal carcinoma;neuroblastoma;neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannoma);neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor);osteosarcoma (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;penile cancer (e.g., Paget's disease of the penis and scrotum);Pharyngeal cancer;Pinealoma;Pituitary carcinoma;Pleuropulmonary blastoma;Primitive neuroectodermal tumor (PNT);Plasma cell neoplasms;Paraneoplastic syndromes;Intraepithelial neoplasia;Prostate cancer (e.g., prostatic adenocarcinoma);Rectal cancer;Rhabdomyosarcoma;Retinoblastoma;Salivary gland cancer;Skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC));Small intestinal cancer (e.g., appendix cancer);Soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), lipoma) The compounds are useful for treating cancers including liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma; sebaceous gland carcinoma; gastric cancer; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thymic carcinoma; thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; vulvar cancer (e.g., Paget's disease of the vulva), or any combination thereof;

[0246] In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is kidney cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is thyroid cancer. In certain embodiments, the cancer is brain cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is esophageal cancer.

[0247] In some embodiments, the technology provided herein is directed to the treatment of adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, carcinoid tumor, cardiac tumor, cervical cancer, choriocarcinoma, chordoma, colorectal cancer, connective tissue cancer, craniopharyngioma, ductal carcinoma in situ, endothelial sarcoma, endometrial cancer, ependymoma, epithelial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, familial hypereosinophilia, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hemangioblastoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, inflammatory myofibroblastic tumor, supraspinal tumor, sarcoma ... Intradermal neoplasms, immune cell amyloidosis, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), melanoma, midline carcinoma, multiple endocrine neoplasia syndrome, muscle cancer, mesothelioma, myeloproliferative disorders (MPD), nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroendocrine carcinoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, paraneoplastic syndromes, parathyroid carcinoma, papillary adenocarcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pinealoma, pituitary cancer, pleuropulmonary blastoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasms, prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sebaceous gland cancer, skin cancer, small intestine cancer bowel cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, sweat gland cancer, synovial tumor, testicular cancer, thymic cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vascular cancer, vulvar cancer, or a combination thereof.

[0248] In some embodiments, the methods provided herein can include administering an immunomodulatory composition to a target site (e.g., as described herein) in a subject, and optionally monitoring the subject after administration, for example, every 3 months or longer (including, for example, every 6 months, every 9 months, every year, or longer) after administration, for risk or occurrence of tumor growth, tumor regrowth, and / or tumor outgrowth in the subject. If the subject is determined to have a risk or occurrence of tumor growth, tumor regrowth, tumor outgrowth, and / or tumor recurrence based on the monitoring report, in some embodiments, the subject can be administered a second composition (e.g., as described herein) and / or undergo a different treatment regimen (e.g., chemotherapy).

[0249] In some embodiments, the techniques provided herein can be useful for treating a subject suffering from metastatic cancer. For example, in some embodiments, the methods provided herein can include administering to a target site (e.g., as described herein) of a subject suffering from one or more metastases, optionally undergoing tumor resection (e.g., surgical resection of primary tumor), and optionally monitoring at least one metastatic site in the subject after administration, for example, every 3 months or longer (e.g., including every 6 months, every 9 months, every year, or longer) after administration. Based on the results of the monitoring report, in some embodiments, the subject can be administered a second composition (e.g., as described herein) and / or undergo a different treatment regimen (e.g., chemotherapy).

[0250] In certain embodiments, the techniques provided herein do not include administering an immunomodulatory composition in conjunction with tumor resection. In certain embodiments, the techniques provided herein include administering an immunomodulatory composition in conjunction with tumor resection. In certain embodiments, the techniques provided herein include administering an immunomodulatory composition to the tumor site after tumor resection.

[0251] It will also be understood that in some embodiments, the compositions described herein may be administered in combination with one or more additional pharmaceutical agents. For example, in some embodiments, the compositions may be administered in combination with additional pharmaceutical agents that reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution in the body. It will also be understood that in some embodiments, the additional therapeutic agents used may achieve the desired effect for the same disorder and / or may achieve a different effect. In certain embodiments, the additional pharmaceutical agent is not an adoptively transferred cell. In certain embodiments, the additional pharmaceutical agent is not a T cell. In certain embodiments, the additional pharmaceutical agent is administered multiple days or multiple weeks after administration of the compositions described herein.

[0252] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human subject undergoing tumor resection. In certain embodiments, the subject is a human subject not suitable for tumor resection surgery. In certain embodiments, the subject is a human patient undergoing (pre-operative) neoadjuvant therapy. In certain embodiments, the subject is a human patient not undergoing neoadjuvant therapy. In certain embodiments, the subject is a human patient undergoing (pre-operative) neoadjuvant chemotherapy. In certain embodiments, the subject is a human patient not undergoing (pre-operative) neoadjuvant chemotherapy. In certain embodiments, the subject is a human patient undergoing neoadjuvant radiation therapy. In certain embodiments, the subject is a human patient not undergoing neoadjuvant radiation therapy. In certain embodiments, the subject is a human patient undergoing neoadjuvant chemotherapy and radiation therapy. In certain embodiments, the subject is a human patient not undergoing neoadjuvant chemotherapy or radiation therapy. In certain embodiments, the subject is a human patient who has received and / or is receiving neoadjuvant molecular targeted therapy. In some embodiments, the subject is receiving, has received, or will receive immune checkpoint blockade therapy. In certain embodiments, the subject is receiving immune checkpoint blockade therapy. In certain embodiments, the subject is a human patient who has received and / or is receiving molecular targeted therapy (e.g., a therapy such as those described as neoadjuvant and / or adjuvant therapy) as the only therapeutic intervention (e.g., a subject in whom surgical resection is not a viable option). In some embodiments, the subject is receiving, has received, or will receive certain other cancer therapies (e.g., including but not limited to, costimulation, oncolytic viruses, CAR T cells, transgenic TCRs, TILs, vaccines, BiTEs, ADCs, cytokines, modulators of innate immunity, or any combination thereof).In certain embodiments, the subject is a human patient who has and / or is undergoing neoadjuvant immunotherapy including immune checkpoint blockade (e.g., anti-CTLA-4, anti-PD-1, and / or anti-PD-L1). In certain embodiments, the subject is a human patient who has not and / or will not undergo neoadjuvant immunotherapy including immune checkpoint blockade (e.g., anti-CTLA-4, anti-PD-1, and / or anti-PD-L1). In certain embodiments, the subject is a human patient whose tumor has not responded objectively to neoadjuvant therapy (as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or Immune Related Response Criteria (irRC)) and / or is objectively unresponsive (e.g., stable disease, progression). In certain embodiments, the subject is a human patient whose target lesions have responded objectively to neoadjuvant therapy and / or are objectively responding (e.g., partial response, complete response). Non-target lesions may show incomplete response, stable disease, or progression. In certain embodiments, the subject is a human patient suitable for receiving immunotherapy as a (post-operative) adjuvant therapy. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent, pig, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or a transgenic pig.

[0253] V.Kit The present disclosure provides kits that are useful for carrying out the techniques provided herein. In some embodiments, the kit includes a composition or pharmaceutical composition described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser container, or other suitable container). In some embodiments, one or more component(s) of the composition or pharmaceutical composition described herein are provided separately in one or more containers. For example, the individual components of the composition (e.g., those described herein) may be provided in separate containers in some embodiments. In some such embodiments, the individual components of the biomaterial (e.g., those described herein, such as, but not limited to, hyaluronic acid, chitosan, poloxamer, etc.) may each be provided independently as a dry lyophilized powder, dry particles, or liquid. In some embodiments, the individual components, such as the delivery agent and / or the delivery technology (e.g., a syringe, a bag, etc., or component(s) thereof), may be provided as a single-use and / or multi-use item in the container. In some embodiments, the individual components of the composition may be provided as a single mixture in the container. In some such embodiments, the single mixture may be provided as a dry lyophilized powder, dry particles, or a liquid (eg, a homogenous liquid).

[0254] In some embodiments, the compositions described herein may be provided as a preformed polymer network biomaterial (with a modulator of myeloid-derived suppressor cell function incorporated therein) in a container. In some embodiments, such a preformed polymer network biomaterial (e.g., a hydrogel) may be provided in a dry state. In some embodiments, such a preformed polymer network biomaterial (in the form of a viscous polymer solution) may be provided in a container.

[0255] In some embodiments, the provided kits may optionally include a container containing a pharmaceutical excipient for diluting or suspending the compositions or pharmaceutical compositions described herein. In some embodiments, the provided kits may include a container containing an aqueous solution. In some embodiments, the provided kits may include a container containing a buffer solution.

[0256] In some embodiments, the provided kits may include a payload, such as a therapeutic agent described herein. For example, in some embodiments, the payload may be provided in a separate container so that it can be added to a liquid mixture of a biomaterial preparation (e.g., as described herein) prior to administration to a subject. In some embodiments, the payload may be incorporated into a biomaterial preparation described herein.

[0257] In certain embodiments, the kits described herein further comprise instructions for carrying out the methods described herein. The kits described herein may also include information from regulatory agencies, such as the U.S. Food and Drug Administration (FDA), if necessary. In certain embodiments, the information included in the kits provided herein is, for example, prescription information for the treatment of cancer. Instructions may be present in the kit in various forms, one or more of which may be present in the kit. One form in which these instructions may be present is as information printed on a suitable medium or substrate, such as a paper or multiple papers on which the kit packaging, insert, and other information is printed. Yet another means may be a computer readable medium on which the instruction information is recorded, such as a diskette, CD, USB drive, and the like. Yet another means that may be present is a website address that may be used via the Internet to access the instruction information. Any convenient means may be present in the kit.

[0258] Other features of the present invention will become apparent through the following description of exemplary embodiments, which are provided for the purpose of illustrating the present invention and are not intended to limit the present invention. EXAMPLES

[0259] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

[0260] Example 1. Preparation and Use of Exemplary Compositions Described herein Containing TLR7 / 8 Agonists for In Vivo Cancer Treatment This example describes administration of a composition comprising an immunomodulatory composition to a target site that is or includes a lymph node resection site. In some embodiments, the target site additionally is or includes a primary tumor resection site. In some embodiments, the immunomodulatory composition comprises a biomaterial preparation and an immunomodulatory payload. In some embodiments, such an immunomodulatory payload is or includes a TLR7 / 8 agonist. In some embodiments, such a biomaterial preparation is a thermoresponsive polymer solution that forms a hydrogel at physiological temperatures.

[0261] In some embodiments, in vivo studies utilized in vitro grown breast cancer cell lines. In some embodiments, prior to implantation, breast cancer cells were cultured in medium containing fetal bovine serum and appropriate selection agents. In some embodiments, cells were cultured at physiological temperatures with known humidity, oxygen and CO2 concentrations.

[0262] In some embodiments, 4T1-Luc2 breast cancer cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. In some embodiments, cells were cultured at 37° C. and 5% CO in a humidified incubator.

[0263] In some embodiments, in vivo animal studies are performed in mice. In some embodiments, mice are orthotopically inoculated with breast cancer cells into the mammary fat pad. In some embodiments, surgery is performed at an appropriate time after inoculation (e.g., approximately 10 days after tumor inoculation). In some embodiments, a composition described herein comprising a biomaterial preparation and an immunomodulatory payload is administered to a target site that is or includes the lymphadenectomy site, simultaneously with lymphadenectomy and primary tumor resection. In some embodiments, a composition comprising a biomaterial preparation and no immunomodulatory payload is administered to a target site that is or includes the lymphadenectomy site to serve as a negative control. In some embodiments, a long-term survival benefit is observed due to the local sustained release of the immunomodulatory payload.

[0264] In one embodiment, an in vivo animal study was performed in 6-8 week old BALB / cJ female mice. 5 4T1-Luc2 breast cancer cells were orthotopically inoculated. Mice were size-matched and randomly assigned to treatment groups, and surgery was performed 10 days after tumor inoculation. For primary tumor resection and proximal inguinal lymph node resection, mice were anesthetized with 2% isoflurane, and the primary tumor and proximal inguinal lymph nodes were resected. Concurrently, a composition described herein comprising a biomaterial preparation (e.g., a biomaterial preparation comprising 9-11% w / w poloxamer and 2.0-2.5% w / w hyaluronic acid) containing a thermoresponsive polymer solution that forms a hydrogel at physiological temperature) with an immunomodulatory payload (e.g., a TLR7 / 8 agonist (e.g., resiquimod (R848) at a dose of 0.2 mg / mouse)) was implanted at the target site, which was or included the lymph node resection site. An empty biomaterial was used as a negative control. A long-term survival benefit was observed with localized sustained release of R848 (Figure 1). Kaplan-Meier survival analysis was used with the log-rank (Mantel-Cox) test to analyze survival curves. A significant difference was observed in animals treated with the composition containing R848 when compared to the negative control (p=0.0147).

[0265] Example 2. Preparation and Use of Exemplary Compositions Described herein Containing TLR7 / 8 Agonists for the Treatment of Cancer In Vivo This example describes administration of a composition comprising an immunomodulatory composition to a target site that is or includes a lymph node resection site. In some embodiments, the target site is not or does not include a primary tumor resection site. In some embodiments, the immunomodulatory composition comprises a biomaterial preparation and an immunomodulatory payload. In some embodiments, such an immunomodulatory payload is or includes a TLR7 / 8 agonist. In some embodiments, such a biomaterial preparation is a thermoresponsive polymer solution that forms a hydrogel at physiological temperatures.

[0266] In some embodiments, in vivo studies utilize breast cancer cell lines grown in vitro. In some embodiments, prior to implantation, breast cancer cells are cultured in medium containing fetal bovine serum and appropriate selection agents. In some embodiments, cells are cultured at physiological temperatures with known humidity, oxygen and CO2 concentrations.

[0267] In some embodiments, 4T1-Luc2 breast cancer cells are cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. In some embodiments, the cells are cultured at 37° C. and 5% CO in a humidified incubator.

[0268] In some embodiments, in vivo animal studies are performed in mice. In some embodiments, mice are orthotopically inoculated with breast cancer cells into the mammary fat pad. In some embodiments, surgery is performed at an appropriate time after inoculation (e.g., approximately 10 days after tumor inoculation). In some embodiments, a composition described herein comprising a biomaterial preparation and an immunomodulatory payload is administered to a target site that is or includes a lymphadenectomy site, simultaneously with lymphadenectomy and primary tumor resection. In some embodiments, the target site is not or does not include the primary tumor resection site. In some embodiments, a composition comprising a biomaterial preparation and no immunomodulatory payload is administered to a target site that is or includes a lymphadenectomy site to serve as a negative control. In some embodiments, a long-term survival benefit is observed due to the local sustained release of the immunomodulatory payload.

[0269] In one embodiment, the in vivo animal study is carried out in 6-8 week old BALB / cJ female mice. 5 4T1-Luc2 breast cancer cells are orthotopically inoculated. Mice are size-matched and randomly assigned to treatment groups, and surgery is performed 10 days after tumor inoculation. For primary tumor resection and proximal lymph node resection, mice are anesthetized with 2% isoflurane and the primary tumor and proximal lymph nodes are excised. Concurrently, a composition as described herein comprising a biomaterial preparation (e.g., containing a thermoresponsive polymer solution that forms a hydrogel at physiological temperature) with an immunomodulatory payload (e.g., a TLR7 / 8 agonist (e.g., resiquimod (R848)) is implanted into a target site that is or includes a lymph node resection site and is not or does not include a primary tumor resection site. An empty biomaterial is used as a negative control. It is expected that a long-term survival benefit will be observed due to the localized sustained release of R848. Survival curves are analyzed using Kaplan-Meier survival analysis with the log-rank (Mantel-Cox) test. It is expected that a significant difference will be observed in animals treated with the composition containing R848 when compared to the negative control.

[0270] Example 3. Preparation and Use of Exemplary Compositions Described Herein for In Vivo Cancer Treatment This example describes administration of a composition comprising an immunomodulatory composition to a target site that is or includes a lymph node resection site. In some embodiments, the target site is not or does not include a primary tumor resection site. In some embodiments, the immunomodulatory composition comprises a biomaterial preparation and an immunomodulatory agent payload. In some embodiments, such an immunomodulatory agent payload is or includes a modulator of innate immunity, a modulator of myeloid cell function, a modulator of adaptive immunity, a modulator of inflammation, a TLR7 / 8 agonist (e.g., resiquimod), a COX inhibitor (e.g., COX-1 inhibitor and / or COX-2 inhibitor), an NSAID (e.g., ketorolac), an angiotensin II receptor inhibitor (e.g., valsartan), a CXCR4 receptor antagonist (e.g., plerixafor), an immunomodulatory cytokine (e.g., IL-2 or IL-12), or a combination thereof. In some embodiments, such biomaterial preparations are or include thermoresponsive polymers (eg, poloxamers), carbohydrate polymers (eg, hyaluronic acid and / or chitosan or modified chitosan), or combinations thereof.

[0271] In some embodiments, in vivo studies utilize breast cancer cell lines grown in vitro. In some embodiments, prior to implantation, breast cancer cells are cultured in medium containing fetal bovine serum and appropriate selection agents. In some embodiments, cells are cultured at physiological temperatures with known humidity, oxygen and CO2 concentrations.

[0272] In some embodiments, 4T1-Luc2 breast cancer cells are cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. In some embodiments, the cells are cultured at 37° C. and 5% CO in a humidified incubator.

[0273] In some embodiments, in vivo animal studies are performed in mice. In some embodiments, mice are orthotopically inoculated with breast cancer cells into the mammary fat pad. In some embodiments, surgery is performed at an appropriate time after inoculation (e.g., approximately 10 days after tumor inoculation). In some embodiments, a composition described herein comprising a biomaterial preparation and an immunomodulatory payload is administered to a target site that is or includes a lymphadenectomy site, simultaneously with lymphadenectomy. In some embodiments, lymphadenectomy is performed during tumor resection surgery. In some embodiments, lymphadenectomy is performed without tumor resection surgery. In some embodiments, the target site is not or does not include a primary tumor resection site. In some embodiments, a composition comprising a biomaterial preparation and not an immunomodulatory payload is administered to a target site that is or includes a lymphadenectomy site, serving as a negative control. In some embodiments, a composition comprising an immunomodulatory payload and not a biomaterial preparation is administered to a target site that is or includes a lymphadenectomy site, serving as a negative control. In some embodiments, long-term survival benefits are observed due to localized sustained release of the immunomodulatory payload.

[0274] In one embodiment, the in vivo animal study is carried out in 6-8 week old BALB / cJ female mice. 54T1-Luc2 breast cancer cells are orthotopically inoculated. Mice are size-matched and randomly assigned to treatment groups, and surgery is performed 10 days after tumor inoculation. For lymphadenectomy, mice are anesthetized with 2% isoflurane and lymph nodes are excised. Lymphadenectomy can be performed during or without tumor resection surgery. Concurrently, a composition as described herein comprising a biomaterial preparation with an immunomodulatory payload was implanted at a target site that is or includes a lymphadenectomy site and is not or does not include a primary tumor resection site. Empty biomaterial and / or immunomodulatory payload alone are used as negative controls. It is expected that a long-term survival benefit will be observed due to the localized sustained release of the immunomodulatory payload. Survival curves are analyzed using Kaplan-Meier survival analysis with log-rank (Mantel-Cox) test. It is expected that significant differences will be observed in animals treated with a composition containing a biomaterial preparation and an immunomodulatory payload when compared to the negative control.

[0275] Equivalence and Scope In the claims, "a," "and," and "the" can mean one or more, unless specified to the contrary or otherwise clear from the context. A claim or description including "or" between one or more members of a group is deemed to apply when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless specified to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0276] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented enumerated, for example, in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, where the invention or aspects of the invention are described as comprising certain elements and / or features, it should be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For the sake of brevity, those embodiments have not been specifically described in these exact terms herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and permit the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Moreover, unless otherwise stated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges stated in different embodiments of the invention, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0277] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference for the purposes described herein. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed known to those of skill in the art, they may be excluded even if they are not expressly stated to be excluded herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0278] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the detailed description of the invention above, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to the detailed description of the invention can be made without departing from the spirit and scope of the invention as defined in the following claims.

[0279] The entire contents of International Patent Publication No. WO2018 / 045058 (e.g., compositions, devices, methods of preparation, methods of use, and kits) are hereby incorporated by reference for the purposes described herein.

Claims

1. A composition for use in a method of treating cancer, comprising an immunomodulatory composition, the method comprising the step of administering the composition to a target site in a cancer subject, the target site being or including a lymph node dissection site.

2. The composition of claim 1 , wherein the immunomodulatory composition is characterized by its ability to induce an innate immune response.

3. The composition of claim 1 , wherein the immunomodulatory composition is characterized by its ability to inhibit an immunosuppressive inflammatory response.

4. The composition of claim 1 , wherein the immunomodulatory composition is or comprises a biomaterial preparation.

5. The composition of claim 1 , wherein the immunomodulatory composition comprises a biomaterial preparation and at least one immunomodulatory payload.

6. The composition of claim 4 or 5, wherein the biomaterial preparation comprises at least one polymer (e.g., at least two polymers).

7. The composition of claim 5 , wherein the immunomodulatory payload is or comprises a modulator of innate immunity.

8. The composition of claim 5 , wherein the immunomodulatory payload is or comprises a modulator of myeloid cell function.

9. The composition of claim 5 , wherein the immunomodulatory payload is or comprises a modulator of adaptive immunity.

10. The composition of claim 5 , wherein the immunomodulatory payload is or comprises a modulator of inflammation.

11. The composition of any one of claims 5 to 7, wherein the immunomodulatory payload is or comprises a TLR7 / 8 agonist.

12. 12. The composition of claim 11, wherein the immunomodulatory agent payload is or comprises resiquimod.

13. The composition of claim 10, wherein the immunomodulatory agent payload is or comprises a COX inhibitor (e.g., a COX-1 inhibitor and / or a COX-2 inhibitor).

14. 11. The composition of claim 10, wherein the immunomodulatory agent payload is or comprises an NSAID, e.g., ketorolac.

15. 6. The composition of claim 5, wherein the immunomodulatory agent payload is or comprises an angiotensin II receptor inhibitor, e.g., valsartan.

16. 6. The composition of claim 5, wherein the immunomodulatory agent payload is or comprises a CXCR4 receptor antagonist, e.g., plerixafor.

17. The composition of claim 5, wherein the immunomodulatory payload is or comprises an immunomodulatory cytokine, such as IL-2 or IL-12.

18. The composition of any one of claims 1 to 17, wherein the cancer subject is a subject of tumor resection surgery.

19. A composition described in any one of claims 1 to 18, wherein the method includes removing at least one lymph node proximal to a tumor in the cancer subject prior to the administering step.

20. 20. The method of claim 19, wherein said removal of at least one lymph node is performed intraoperatively during tumor resection surgery.

21. 20. The method of claim 19, wherein said removal of at least one lymph node is performed in a separate operation from the tumor resection operation.

22. The composition described in claim 20 or 21, wherein the method further comprises administering a second immunomodulatory composition to the tumor resection site during surgery.

23. 23. The composition of claim 22, wherein the second immunomodulatory composition administered to the tumor resection site is the same as the immunomodulatory composition administered to the lymph node dissection site.

24. 23. The composition of claim 22, wherein the second immunomodulatory composition administered to the tumor resection site is different from the immunomodulatory composition administered to the lymph node dissection site.

25. The composition according to any one of claims 18 to 24, wherein the tumor resection surgery comprises removal of at least a part of an organ containing the tumor.

26. 26. The method of claim 25, wherein the tumor resection surgery further comprises anastomosis after the removal of at least a portion of the organ containing the tumor.

27. 27. The composition of any one of claims 1 to 26, wherein the lymph nodes are or comprise sentinel lymph nodes, draining lymph nodes, axillary lymph nodes, inguinal lymph nodes, femoral lymph nodes, facial lymph nodes, cervical lymph nodes, supraclavicular lymph nodes, inclavicular lymph nodes, pectoral lymph nodes, mediastinal lymph nodes, pelvic lymph nodes, mesenteric lymph nodes, and / or retroperitoneal lymph nodes.

28. 28. The composition of claim 27, wherein the lymph node is a sentinel lymph node.

29. 28. The composition of claim 27, wherein the lymph node is a draining lymph node.

30. A composition described in any one of claims 1 to 29, wherein the method comprises administering the composition intraoperatively to the target site in a cancer subject undergoing lymph node dissection surgery.

31. The composition according to any one of claims 1 to 30, wherein the lymph node dissection surgery further comprises anastomosis.

32. The cancer being treated is selected from the group consisting of carcinoma, sarcoma, germ cell tumor, blastoma, lymphoma, skin cancer, melanoma, laryngeal head and neck cancer, thyroid cancer, brain cancer, bladder cancer, gastrointestinal cancer (e.g., stomach cancer), breast cancer, lung cancer, breast cancer, colorectal cancer, genitourinary cancer, renal cancer, prostate cancer, gynecological cancer, testicular cancer, ovarian cancer, and ovarian cancer. The composition according to any one of claims 1 to 31, which is at least one of uterine cancer and / or uterine cancer.

33. The composition of any one of claims 4 to 32, wherein the biomaterial preparation comprises a thermoresponsive polymer.

34. 34. The composition of claim 33, wherein the thermoresponsive polymer is or comprises a poloxamer.

35. The composition of any one of claims 4 to 34, wherein the biomaterial preparation comprises a carbohydrate polymer.

36. The composition of claim 35 , wherein the carbohydrate polymer comprises hyaluronic acid and / or chitosan or modified chitosan.

37. 37. The composition of any one of claims 4 to 36, wherein the biomaterial preparation comprises 7-12.5% ​​(w / w) poloxamer, and one or both of 0.5-7% (w / w) hyaluronic acid and 0.5-7% (w / w) chitosan or modified chitosan.

38. 37. The composition of any one of claims 1 to 36, wherein the method reduces the likelihood of developing one or more symptoms associated with lymphedema and / or lymphocele compared to lymph node dissection without administration of an immunomodulatory composition.

39. The composition of any one of claims 1-37, wherein the method reduces the likelihood of developing one or more metastatic foci compared to lymph node dissection without administration of an immunomodulatory composition.

40. The composition according to any one of claims 1 to 38, characterized in that said administration to the lymph node dissection site is carried out by implantation.

41. The composition according to any one of claims 1 to 38, characterized in that said administration to the lymph node dissection site is carried out by injection.

42. 1. A combination comprising a biomaterial preparation and an immunomodulatory payload, said combination for use in a method of treating cancer by administering said combination intraoperatively to a subject suffering from cancer, said method comprising administering said combination to a lymph node dissection site rather than or in addition to a tumor resection site.

43. A composition comprising a biomaterial preparation, the composition being for use in a method of treating cancer by administering the composition in combination with an immunomodulatory payload to a subject suffering from cancer intraoperatively, the method comprising administering the composition and the immunomodulatory payload to a lymph node dissection site rather than or in addition to a tumor resection site.

44. A composition comprising an immunomodulatory payload, the composition for use in a method of treating cancer by administering the composition in combination with a biomaterial preparation to a subject suffering from cancer intraoperatively, the method comprising administering the composition and the biomaterial preparation to a lymph node dissection site rather than or in addition to a tumor resection site.

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