Method for obtaining globally activated monocytes
Inventors
Bauer, Günter • DUCKWORTH, Justin • TIGELAAR, Robert • EDELSON, Richard • Girardi, Michael • Henco, Karsten • Hayday, Adrian
Assignees
TRANSIMMUNE AG • Yale University
Publication Number
US-12364755-B2
Publication Date
2025-07-22
Expiration Date
2035-07-03
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Abstract
The present invention relates to methods for producing immuno-stimulatory autologous dendritic cells. The present invention further relates to the use of such cells for treating patients suffering from hyper-proliferative disease such as cancer.
Core Innovation
The invention relates to methods for producing globally activated monocytes (GAMs) from an extracorporeal quantity of a mammalian subject's blood sample by subjecting the sample to a physical force such as shear stress. These globally activated monocytes are characterized by increased expression of molecular markers including at least HLA-DR, PLAUR, and ICAM-1. The method may involve passing the blood sample through a flow chamber device, optionally pre-coated or sequentially coated with plasma components such as fibrinogen or fibronectin, which activate platelets. Monocytes subsequently interact with these activated platelets under physical force leading to their global activation.
The invention addresses limitations of prior extracorporeal photopheresis (ECP) methods used for generating dendritic cells (DCs), which produce mixtures of immuno-stimulatory and immuno-suppressive DCs, requiring large blood volumes obtained via apheresis and involving photoactivation agents like 8-methoxypsoralen (8-MOP) and UV-A irradiation. The methods described here enable preferential production of immuno-stimulatory monocytes and DCs outside the body without the need for exogenous cytokine cocktails or photoactivation, and with smaller volumes of blood, possibly bypassing the need for apheresis. The invention further recognizes that GAMs obtained by this method have phagocytosing activity making them suitable for therapeutic uses beyond DC differentiation, such as direct tumor killing, wound healing, and regenerative medicine.
The invention also elucidates mechanistic insights where monocyte activation and subsequent differentiation into immuno-stimulatory DCs require physical forces and interactions with activated platelets and plasma components under shear stress conditions. The expression of immuno-suppressive markers like GILZ is minimized when photoactivatable agents and UV-A irradiation are excluded, favoring the production of immuno-stimulatory cells. The methods thus allow controlled generation of globally activated monocytes and dendritic cells with tailored immunologic activity profiles depending on process parameters, device geometry, flow rates, and applied physical forces.
Claims Coverage
The patent includes 13 claims that mainly cover methods for treating cancer by utilizing globally activated monocytes obtained through specific extracorporeal blood processing steps involving physical forces and platelet interactions.
Method for treating cancer using globally activated monocytes
A method wherein tumor cells in a mammalian subject are subjected to phagocytosis by globally activated monocytes characterized by increased expression of at least HLA-DR, PLAUR, and ICAM-1, the globally activated monocytes being obtained by subjecting an extracorporeal blood sample comprising monocytes to a physical force.
Method of obtaining globally activated monocytes via flow chamber device and platelet interaction
Obtaining globally activated monocytes by applying an extracorporeal blood sample to a device with platelets (from blood or separately provided) and subjecting the blood to a physical force through flow chamber passage or movement in a plastic bag to activate monocytes, identified by marker expression.
Administration of globally activated monocytes to a subject undergoing cancer therapy
Administering globally activated monocytes obtained as per the methods to mammalian subjects in need thereof, especially those undergoing chemotherapy, radiation therapy, or combination therapies.
Combination with anti-tumor therapeutic antibodies
Treating cancer in combination with the administration of globally activated monocytes along with anti-tumor therapeutic antibodies.
Non-antigen-specific administration of globally activated monocytes
Use of globally activated monocytes obtained without prior antigen presentation before administration to the subject.
Alternative monocyte activation by shaking or moving blood sample in plastic bag
Activating monocytes by placing the blood sample in a plastic bag and moving or shaking it, as an alternative to passing through a flow chamber, to induce monocyte activation.
The claims cover methods of producing and using globally activated monocytes characterized by specific molecular markers through extracorporeal physical activation, using flow chambers or mechanical agitation. The methods are applied for cancer treatment via monocyte-mediated phagocytosis, optionally combined with other therapies, emphasizing reliable identification of the globally activated monocytes by marker expression.
Stated Advantages
Globally activated monocytes and dendritic cells can be produced in comparatively large amounts with minimal interference by other factors and are patient-specific.
The generation of immuno-stimulatory dendritic cells does not require complex and expensive cytokine cocktails, unlike common standard methods.
The methods enable using smaller volumes of blood without requiring apheresis, reducing the burden on patients.
Controlled physical activation by shear stress and platelet interactions allow preferential production of immuno-stimulatory rather than immuno-suppressive antigen-presenting cells.
Globally activated monocytes have phagocytizing activity enabling applications in anti-tumor therapy, wound healing, and regenerative medicine.
Documented Applications
Treating patients suffering from hyper-proliferative diseases such as cancer through administration of globally activated monocytes capable of phagocytosing tumor cells.
Use of globally activated monocytes or derived dendritic cells for immunotherapy during chemotherapy, radiation therapy, or combination treatments.
Applying globally activated monocytes for wound healing, including chronic wounds and diabetic wounds.
Use of globally activated monocytes in regenerative medicine such as treatment of degenerative joint disease, neurological diseases including Alzheimer's, and stimulation of hair growth or regrowth.
Treatment of inflammatory diseases by virtue of the phagocytizing activity of globally activated monocytes.
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