Invented by Michael Solomon Goldberg, Chun Gwon Park, Dana Farber Cancer Institute Inc
The Dana Farber Cancer Institute Inc invention works as followsProvided is a drug delivery composition and device useful for the treatment or prevention of metastatic cancers. A drug delivery device, for example, is a biodegradable scaffold that contains anti-cancer therapeutic substances that activate the innate immune and/or adaptive immune systems. Some compositions and devices can include a cytokine, such as IL-15 superagonist. To prevent tumor metastasis and tumor regrowth, the drug delivery device may be placed in the tumor’s void. There are also methods for making drug delivery compositions, devices, and kits containing the materials to make them.
Background for Drug delivery compositions, and their uses
The entire body is affected by the systemic administration of medication, nutrition, and other substances to the circulatory systems. There are two types of systemic administration: enteral (e.g. oral dosage that results in the absorption of drug through the stomach tract) and parenteral. These are the most common routes for immunotherapeutics to be administered. Immunotherapeutics can cause toxicities in non-diseased tissue, so systemic administration may lead to undesirable side effects. Some promising therapeutics can be difficult to develop because of associated toxicities or the limitations of current systems and administration methods. Systemic administration of immunotherapeutic drugs for the treatment or prevention of cancer can often be associated with immune-related adverse reactions (e.g., skin eruptions, hepatitis and diarrhea, hypophysitis and thyroiditis), as well as skin rashes and hepatitis. These adverse reactions may be due to non-tumor-specific immune cell exposure to the drug and the higher doses required for systemic administration to reach sufficient concentrations in the tumor to cause a desired response. Localizing the delivery of immunotherapeutic drugs can increase safety and enhance efficacy by concentrating its action where it is needed.
Surgery is often used as the first line of treatment for solid tumors cancers. It is usually combined with systemic anti-cancer therapy. Surgery-induced immunosuppression has been linked to the development of postoperative complications and tumor metastasis. This is due to changes in metabolic and endocrine response, eventually leading to the death of many patients. (Smyth M. J. et. al. Nature Reviews Clinical Oncology 2016, 13, 143?158. To achieve antimetastatic efficacy, and decrease in tumor regrowth, it is important to safely and effectively administer immunotherapies with surgical approaches.
Systemic administration of immunotherapies may cause adverse side effects. Surgical resections of tumors may result in immunosuppression. The present invention offers targeted drug delivery systems that target specific tissues or cell types or to certain diseased tissues, but not normal tissue. This is particularly useful for treating cancer. It is important that the drug only be administered to the cancerous tissue and that it does not cause any side effects to surrounding healthy tissue. The drug delivery systems are able to deliver therapeutic agents that target the immune system and prevent tumor recurrence or metastasis. They also minimize side effects.
In one embodiment, drug delivery compositions or devices comprising a biomaterial, (e.g. a hydrogel), and an activator for innate immune reaction (e.g. a STING antagonist) are provided. The activator of innate immunity response can be a stimulator for interferon genes (STING), agonist or cytosolic DNA sensor agonist, and a Toll-like receiver (TLR), agonist, C-type lectin receptor agonist, and a NOD receptor (NLR), agonist. Antitumor responses can be triggered by activators of the innate immune response.
In another aspect, there are drug delivery compositions or devices that include a biomaterial, activator of innate immunity response and a cytokine (e.g. an IL-15 superagonist). Certain cytokines can act as immunomodulators and activate T cells, NK and T cells, and in turn induce their proliferation. They can also cause T cells, NK and T cells to secrete interferon?. This can give T cells, NK and T cells the ability to kill malignant cell without antigenic stimulation. Other aspects include drug delivery compositions and devices that contain a biomaterial (e.g., an IL-15 supraagonist) and a cytokine.
In some embodiments, drug delivery compositions and devices consisting of a biomaterial and an activator for innate immune reaction and a chemotherapy (e.g. CXCL9) are provided. Certain chemokines may be used to control immune system cells during immune surveillance processes and recruit immune cells to tumor sites. They may be used to guide cells in both the adaptive and innate immune systems. Other embodiments include drug delivery compositions and devices that contain a biomaterial (e.g. CXCL9).
In some embodiments, drug delivery compositions or devices also include an activator for adaptive immune response (e.g. anti-PD-1 antibody and anti-CTLA-4 antibodies, agonist anti?CD137 antibody). Activators of adaptive immunity can activate therapeutic antitumor immune response, which includes the activation or blockade immune checkpoints.
Another aspect is provided drug delivery compositions or devices comprising a biomaterial, an activator of adaptive immunity response (e.g. anti-PD-1 antibody and anti-CTLA-4 antibodies, agonist anti?CD137 antibody).
Some embodiments include one or more activators of adaptive immunity response in drug delivery compositions or devices. An antibody is used in certain embodiments to activate adaptive immune response. This could be an anti-PD-1 antibody or anti-PDL1 antibody, anti?CTLA-4 antibody, agonist anti?CD137 antibody), or a bispecific antibody (e.g. a bifunctional fusion protein targeting PDL1 and TGF). An antibody-drug conjugate, such as trastuzumab/emtansine or inotuzumab/ozogamicin, or a small molecule, such as celecoxib, Bortezomib.
In some embodiments, the biomaterial can be a hydrogel. Hydrogels are a scaffold that allows components of the device or composition to be combined in a way that creates a drug delivery system that can be implanted in a surgical setting. Hydrogels can be prepared from hyaluronic acids in certain instances. Hyaluronic Acid is a biocompatible material which biodegrades in vivo and allows for drug release from the drug delivery system.
In some embodiments, drug delivery compositions or devices also include an oncolytic virus (a radioactive isotope), a chemotherapeutic agents, or a combination thereof.” Certain embodiments include at least one excipient.
In some embodiments, drug delivery compositions or devices also comprise an oncolytic viral, a radioactive Iotope, an immunomodulatory chemotherapy agent, a targeted agent or a combination thereof.
In certain embodiments, drug delivery compositions or devices contain at least one excipient.
In some embodiments, the drug delivery compositions or devices’ biomaterial (e.g. hydrogel) is biodegradable in vivo. The storage modulus for drug delivery devices varies from 500 Pa to 3000 Pa in some embodiments.
Another aspect of the invention is a method for treating or preventing cancer by surgically implanting a drug delivery composition. The cancer may be a sarcoma or carcinoma, lymphoma or germ cell tumor. Another aspect of the invention is surgically implanting drug delivery compositions to prevent primary tumor growth. Another aspect of the invention is surgically implanting drug delivery compositions to prevent tumor recurrence or metastasis. Certain embodiments further include the surgical placement of the drug delivery compositions following a tumor removal. Certain embodiments also include the implanting of drug delivery compositions at tumor resection.
Also included are methods and uses for preparing drug delivery compositions or devices, and kits providing drug delivery compositions or devices.
The details of some embodiments of the invention can be found herein. Additional features, objects and benefits of the invention will be evident from the detailed description, figures, examples, and claims.
Salt” is used in this document. “Salt” can be used to refer to all salts, as well as pharmaceutically acceptable salts.
Pharmaceutically acceptable salt” is a term that refers to salts that are safe for use in human and animal tissues. The term “pharmaceutically acceptable salt” refers to salts that are safe for human and animal contact and have a reasonable risk/benefit ratio. The art is well-versed in the use of pharmaceutically acceptable salts. For example, Berge et al. In J., we describe the pharmaceutically acceptable salts in great detail. Pharmaceutical Sciences, 1977. 66, 1-19. This information is incorporated by reference. The pharmaceutically acceptable salts of the compounds described in this invention are those that are derived from suitable organic and inorganic acids and bases. Non-toxic, pharmaceutically acceptable salts of the compounds of this invention include salts of an amino groups formed with inorganic and organic acids and bases, such hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids or with organic acids such as acetic, tartaric, citric, succinic, or malonic acids or using other techniques such as ion exchanging. Other pharmaceutically 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, 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, valerate salts, and the like. Alkali metal, alkaline metal, ammonium and N+ (C1-C4alkyl)4 are all suitable bases. salts. Salts of alkali and alkaline earth metals such as sodium, lithium or potassium, calcium, magnesium, etc. are representative. Other pharmaceutically acceptable salts include nontoxic ammonium and quaternary ammonium.
A ?polymer? “Polymer” is used as an ordinary term in the art. It refers to a molecular structure that contains one or more repeat units (monomers) connected by covalent bonds. Each repeat unit may be identical or may contain multiple types of repeat units. A polymer can be defined as a compound that contains eleven or more covalently linked repeating units. A polymer can be naturally occurring in certain embodiments. “Some embodiments of a polymer are synthetic, meaning that it is not naturally occurring.Click here to view the patent on Google Patents.