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Publication Number
US-10888618-B2
Publication Date
2021-01-12
Expiration Date
Abstract
The invention provides a method for treating cancer using a coadministration strategy that combines local codelivery of a therapeutic agent and an intracellular penetration enhancing agent, and optionally in further combination with local administration of an immunotherapeutic agent, such as a cancer vaccine or NKT agonist. The invention also provides a method for treating cancer using an intracellular penetration enhancing agent. The methods of the invention aim to substantially kill and/or destroy the target tumor cells, as well as those cancerous cells that have metastasized to other parts of the body.
Core Innovation
The invention concerns a method of treating cancer in a subject by intratumorally administering an aqueous pharmaceutical composition that comprises a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent. The therapeutic agent is selected from a chemotherapeutic agent, an interfering RNA, a therapeutic protein, or a therapeutic antibody, and is mixed with, and not covalently bound to, the intracellular permeation enhancing agent.
The intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, or related functional derivatives, including multiple N-substituted oxo-containing acids and 2-ethylhexyl 2-hydroxybenzoate. The description further encompasses functionally effective salt forms of the listed permeation enhancing agents and combinations thereof, and frames the approach as increasing tumor-cell permeability for local treatment of solid tumors.
The described treatment may further comprise administering a therapeutically effective amount of an immunotherapeutic agent in addition to the intratumoral coadministration with the intracellular permeation enhancing agent. The immunotherapeutic agent is described in the context of cancer vaccines and immune response enhancement, including α-Gal glycolipid (α-GalCer) and β-ManCer (β-mannosylceramide) as NKT agonists, and CD4 cell stimulation via an α-Gal epitope. The document reports substantial tumor shrinkage/destruction and immune memory after regression and rechallenge in tumor models.
Claims Coverage
The document provides two independent claims that share a core structure: intratumoral administration of an aqueous pharmaceutical composition containing a therapeutically effective amount of a therapeutic agent and a specified intracellular permeation enhancing agent, with the therapeutic agent mixed and not covalently bound to the permeation enhancing agent. One independent claim further requires addition of an immunotherapeutic agent.
Intratumoral aqueous composition with mixed, not covalently bound permeation enhancer
Intratumorally administering a pharmaceutical composition comprising an aqueous solution containing a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent, wherein the therapeutic agent is mixed with and not covalently bound to the intracellular permeation enhancing agent; wherein the therapeutic agent is a chemotherapeutic agent, an interfering RNA, a therapeutic protein or a therapeutic antibody.
Specified intracellular permeation enhancing agent identity set
The intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino1 butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic acid, 7-Cyclohexyl-7-oxoheptanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, 4-Cyclopentyl-4-oxobutyric acid, 5-Cyclopentyl-5-oxovaleric acid, 6-Cyclopentyl-6-oxohexanoic acid, 7-Cyclopentyl-7-oxoheptanoic acid, 8-Cyclopentyl-8-oxooctanoic acid, 4-Cyclobutyl-4-oxobutyric acid, 5-Cyclobutyl-5-oxovaleric acid, 6-Cyclobutyl-6-oxohexanoic acid, 7-Cyclobutyl-7-oxoheptanoic acid, 8-Cyclobutyl-8-oxooctanoic acid, 4-Cyclopropyl-4-oxobutyric acid, 5-Cyclopropyl-5-oxovaleric acid, 6-Cyclopropyl-6-oxohexanoic acid, 7-Cyclopropyl-7-oxoheptanoic acid, 8-Cyclopropyl-8-oxooctanoic acid, a functionally effective salt of any of the foregoing, or any combination thereof.
Immunotherapeutic agent administered in addition to intratumoral coadministration
Further comprising administering a therapeutically effective amount of an immunotherapeutic agent.
Across the independent claims, the inventive concept centers on intratumoral delivery of an aqueous pharmaceutical composition that combines a therapeutic agent with a specified intracellular permeation enhancing agent, with the therapeutic agent mixed and not covalently bound to the permeation enhancing agent. One independent claim additionally requires coadministration of an immunotherapeutic agent.
Stated Advantages
Substantial tumor shrinkage/destruction.
Evidence supporting immune memory after regression and rechallenge.
Prevention of recurrence/metastasis is described as a goal in connection with immunotherapy.
Documented Applications
Treating cancer in a subject, including solid tumors such as carcinomas and sarcomas, using intratumoral coadministration of a therapeutic anticancer agent with an intracellular permeation enhancing agent.
Local immunotherapy following/combined with intratumoral treatment, including cancer vaccines using α-Gal glycolipids (α-GalCer) or NKT agonists such as β-ManCer (β-mannosylceramide).
Use of tumor models with cisplatin plus enhancer in mouse tumor models with bioluminescence/volume readouts, survival benefit, and evidence of immune memory after regression/rechallenge.
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