Therapeutic methods involving modulating inflammasome activation of myeloid-derived suppressor cells
Inventors
Blazar, Bruce R. • Koehn, Brent • Murray, Peter J. • Ting, Jenny P. Y. • Zeiser, Robert • Miller, Jeff S.
Assignees
Albert Ludwigs Universitaet Freiburg • University of North Carolina at Chapel Hill • St Jude Childrens Research Hospital • University of Minnesota System
Publication Number
US-12234480-B2
Publication Date
2025-02-25
Expiration Date
2036-08-05
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Abstract
In one aspect, a method of treating a subject having or at risk of having graft-versus-host disease (GvHD) generally includes administering to the subject a plurality of myeloid-derived suppressor cells (MDSCs) effective to ameliorate at least one symptom or clinical sign of graft-versus-host disease compared to a suitable control subject. In another aspect, a method of treating a tumor in a subject generally includes administering to the subject an anti-tumor therapy and co-administering to the subject an inflammasome inciting agent in an amount effective to increase inflammasome activation of MDSCs sufficiently to reduce suppressor function of the MDSCs.
Core Innovation
The invention addresses the therapeutic use of myeloid-derived suppressor cells (MDSCs) engineered or treated to resist inflammasome activation in order to enhance their suppressor function in inflammatory conditions such as graft-versus-host disease (GvHD). It describes methods involving the administration of MDSCs, including those genetically modified to lack apoptosis-associated speck-like protein containing a CARD (ASC) or otherwise capable of resisting inflammasome activation, for treating or reducing the risk of GvHD.
The problem identified is that transferred MDSCs, while capable of suppressing immune responses and reducing GvHD, lose their suppressor function in the pro-inflammatory environment of GvHD due to inflammasome activation. This loss of suppressor activity limits the therapeutic potential of MDSCs. The invention thus seeks to overcome this limitation by providing MDSCs that are genetically or chemically rendered resistant to inflammasome activation, or by co-administering agents that inhibit inflammasome activation, thereby maintaining MDSC efficacy.
Additionally, the disclosure describes a method of treating tumors by increasing inflammasome activation of MDSCs using inflammasome inciting agents to reduce their suppressor function, thereby potentially enhancing anti-tumor therapies. The overall approach leverages the modulation of inflammasome pathways in MDSCs—either inhibiting or promoting activation depending on the disease context—to improve therapeutic outcomes.
Claims Coverage
There is one independent claim that defines the main inventive feature of the patent.
Human myeloid-derived suppressor cell (MDSC) deficient in apoptosis-associated speck-like protein containing a CARD (ASC)
The inventive feature is a human MDSC that is deficient in ASC, where the deficiency is achieved by either: - A genetic modification of the ASC gene resulting in ASC deficiency, or - A genetic knockdown of ASC via shRNA targeting the ASC gene or siRNA targeting the ASC gene. This MDSC is characterized by its resistance to inflammasome activation.
The claims are focused on human MDSCs rendered ASC-deficient, through genetic modification or knockdown, to confer resistance to inflammasome activation for improved therapeutic use.
Stated Advantages
MDSCs deficient in ASC are capable of resisting inflammasome activation, maintaining suppressor function, and remaining viable and functional for a longer period compared to MDSCs without ASC deficiency.
Genetically altering MDSCs to disable inflammasome activation can increase survival in GvHD compared to conventional MDSC therapy.
Methods that limit in vivo MDSC inflammasome activation empower MDSCs to maintain their suppressive potential and increase their therapeutic benefit.
Documented Applications
Treating a subject having or at risk of having graft-versus-host disease (GvHD) by administering MDSCs resistant to inflammasome activation.
Treating a tumor in a subject by administering an anti-tumor therapy and co-administering an inflammasome inciting agent to increase inflammasome activation of MDSCs and reduce their suppressor function.
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