β-mannosylceramide and stimulation of NKT cell anti-tumor immunity
Inventors
Berzofsky, Jay A. • O'Konek, Jessica J. • Terabe, Masaki • Illarionov, Petr A. • Besra, Gurdyal S.
Assignees
University of Birmingham • US Department of Health and Human Services
Publication Number
US-9168291-B2
Publication Date
2015-10-27
Expiration Date
2031-03-11
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Abstract
β-mannosylceramides or salts or solvates thereof in a pharmaceutically acceptable carrier, for use as a Type I NKT cell agonist in conjunction with a therapeutically effective amount of α-galactosylceramide or a salt or a solvate thereof, and/or at least one or more T-cell co-stimulatory molecules, disclosed. Compositions comprising β-mannosylceramide, as well as methods of treatment of tumors are also provided.
Core Innovation
The invention provides compositions and methods for activating Type I natural killer T (iNKT) cells in mammals by using β-mannosylceramides (β-ManCer), or their salts or solvates, in pharmaceutically acceptable carriers. These β-ManCer compounds include a β-mannosyl moiety linked to a ceramide moiety composed of a sphingosine moiety and a fatty acid moiety with a linear or branched, saturated or unsaturated, aliphatic hydrocarbon chain ranging in length from about 8 to 49 carbon atoms. The compositions may also include additional immunostimulatory compounds such as cytokines (e.g., IL-2, GM-CSF, IL-12, IL-15), α-glycosylceramides (including α-galactosylceramide), T-cell co-stimulatory molecules, Toll-like receptor ligands, chemotherapeutic agents, vaccines, or antibodies.
The invention addresses the problem presented in the background that while α-galactosylceramide (α-GalCer) is known for its potent stimulation of iNKT cells and induction of anti-tumor immunity, there is a need to develop alternative methods for NKT cell activation that may provide different mechanisms and potentially improved or complementary effects against tumors and cancers. β-mannosylceramide was unexpectedly found to induce tumor protection via a mechanism distinct from and synergistic with that of α-GalCer, involving nitric oxide and TNF-α rather than IFN-γ, and without inducing strong cytokine production or anergy of NKT cells, thereby overcoming limitations of existing NKT cell activators.
Claims Coverage
The patent includes seven independent claims focusing on novel methods involving β-mannosylceramide compositions to activate NKT cells and treat cancers or induce immune responses.
Activation of mammalian NKT cells in vitro using β-mannosylceramide compositions
Culturing a mononuclear cell fraction comprising one or more mammalian NKT cells in vitro with a β-mannosylceramide or its salt or solvate in a pharmaceutically acceptable carrier, wherein the β-ManCer consists of a β-mannosyl moiety linked to a ceramide moiety that includes a sphingosine moiety and a fatty acid moiety with a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group of about 8 to about 49 carbon atoms.
Inducing immune response and treating cancer or inhibiting tumor growth using β-mannosylceramide compositions
Administering to a subject an effective amount of a composition comprising β-mannosylceramide or its salt or solvate in a pharmaceutically acceptable carrier, with the β-ManCer consisting of a β-mannosyl moiety linked to a ceramide moiety containing a sphingosine moiety and a fatty acid moiety as described, to induce an immune response or treat cancers (specifically lung, colon, skin cancers including melanoma) or inhibit growth of corresponding tumors.
Combining β-mannosylceramide compositions with chemotherapeutic agents for cancer treatment
Using compositions comprising β-mannosylceramide together with therapeutically effective amounts of one or more chemotherapeutic agents to treat cancer or inhibit tumor growth.
Treating cancer by activating NKT cells in vitro and administering activated cells to subjects
Culturing mononuclear cell fractions containing NKT cells in vitro with β-mannosylceramide compositions to activate them, then administering the activated NKT cells to subjects to treat cancer or inhibit tumor growth, where cancers and tumors include lung, colon, and skin cancers such as melanoma.
Use of autologous activated NKT cells for cancer treatment
Employing activated mammalian NKT cells that are autologous to the subject being treated for administration in methods treating cancer or inhibiting tumor growth.
Use of β-mannosylceramide compounds with defined chemical structures
Specifying the β-mannosylceramide compounds in the claimed methods as having defined chemical structures depicted in the claims, encompassing the β-mannosyl moiety linked to a ceramide moiety with described sphingosine and fatty acid characteristics.
Enhancement of vaccine efficacy by administering β-mannosylceramide compositions
Administering β-mannosylceramide compositions to subjects along with vaccines to increase vaccine efficacy in inducing immune responses against cancer.
The claims cover methods of activating mammalian NKT cells using β-mannosylceramide compositions both in vitro and in vivo, methods of treating cancers including melanoma, lung, and colon cancers, and inhibiting tumor growth by administering β-mannosylceramide compositions or activated NKT cells derived from such compositions. The claims also encompass combination therapies with chemotherapeutic agents and vaccines, as well as defined chemical structures of the β-mannosylceramide compounds.
Stated Advantages
β-ManCer induces potent anti-tumor immunity through mechanisms distinct from α-GalCer, involving nitric oxide and TNF-α rather than IFN-γ.
β-ManCer does not induce strong cytokine production or anergy in iNKT cells, allowing repeated activation without loss of efficacy.
Simultaneous use of β-ManCer with α-GalCer results in synergistic tumor protection, enhancing therapeutic potential.
β-ManCer compositions are effective at low doses and across different cancer types and mouse strains.
The compositions enhance vaccine efficacy and can be combined with chemotherapeutic agents and immune checkpoint antibodies for improved treatment outcomes.
Documented Applications
Treatment and inhibition of growth of tumors and cancers including melanoma, lung cancer, colon cancer, skin cancer, breast cancer, kidney cancer, stomach cancer, prostate cancer, ovarian cancer, brain, neck, liver, and lymphoid tumors in mammals.
Activation of NKT cells in mammals to induce immune responses against tumors or cancers.
In vitro activation of NKT cells with β-ManCer for adoptive cell therapy in cancer treatment.
Use in combination with vaccines, including prostate cancer vaccines such as TARP 29-37-9V, to enhance vaccine efficacy.
Use in combination with antibodies targeting immune checkpoints such as CTLA-4 or PD-1 or TGF-beta to overcome negative regulation and boost immune responses.
Combination with chemotherapeutic agents and other cancer immunotherapies including Ontak and rituximab.
Parenteral administration of β-ManCer compositions (e.g., intravenous, intraperitoneal, subcutaneous) for therapeutic uses.
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