Materials and methods for treating cancer
Inventors
DURRANT, Cameron • Chappell, Dale • KENDERIAN, SAAD J. • STERNER, ROSALIE M. • COX, MICHELLE J. • SAKEMURA, REONA
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Assignees
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624086-B2
Publication Date
2026-05-12
Expiration Date
Abstract
This document provides methods and materials involved in treating cancer. For example, chimeric antigen receptor T cells having reduced levels of GM-CSF are provided. Also provided as methods for making and using chimeric antigen receptor T cells having reduced levels of GM-CSF.
Core Innovation
The invention provides a method for enhancing anti-tumor efficacy of chimeric antigen receptor-expressing T19-cell (CAR T19-cell) therapy in a subject having cancer by administering GM-CSF gene knockout (GM-CSF k/o) CAR-T19 cells. The method is based on the administration of CAR-T19 cells having a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene knockout, such that tumor burden is reduced compared to tumor burden reduction by administration of CAR-T19 cells lacking the GM-CSF gene knockout.
The document further describes reduction of tumor burden alongside reduction of CAR-T associated toxicity, including cytokine release syndrome (CRS) and neurotoxicity (NT). It links GM-CSF depletion/neutralization to changes in immune cell trafficking, including reduced CD14+ myeloid trafficking to the central nervous system (CNS), which is described as associated with improved clinical endpoints.
In addition to GM-CSF gene knockout in CAR-T19 cells, the document describes adjunct administration of a recombinant anti-human GM-CSF neutralizing antibody, including lenzilumab, and in xenograft contexts an anti-mouse GM-CSF antibody. The document positions neutralization of GM-CSF with the recombinant anti-GM-CSF antibody as contributing to reduced tumor burden and reduced toxicity, including reductions described for cytokine cascades and CNS-related abnormalities and myeloid/macrophage infiltration.
Claims Coverage
The independent claim covers a method of enhancing anti-tumor efficacy of CAR T19-cell therapy by administering GM-CSF gene knockout (GM-CSF k/o) CAR-T19 cells, with a comparative tumor burden reduction outcome versus CAR-T19 cells lacking the GM-CSF gene knockout. The dependent claim set further adds inventive features related to optional recombinant anti-hGM-CSF antibody neutralization, CNS/neurotoxicity-associated CD14+ myeloid trafficking, and comparative clinical endpoints such as objective response rate, progression-free response, and/or survival, including antibody administration sequence after GM-CSF k/o CAR-T19 cells.
GM-CSF gene knockout in CAR T19 cells to reduce tumor burden
Administering to the subject CAR-T19 cells having a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene knockout (GM-CSF k/o), wherein administration of the GM-CSF k/o CAR-T19 cells reduces tumor burden compared to tumor burden reduction by administration of CAR-T19 cells lacking said GM-CSF gene knockout.
Recombinant anti-hGM-CSF antibody that binds and neutralizes human GM-CSF
Further administering a recombinant anti-hGM-CSF antibody that binds to and neutralizes human GM-CSF.
Decreased or prevented CD14+ myeloid cell trafficking to the CNS
Decreasing or preventing CD14+ myeloid cell trafficking to the central nervous system (CNS), where high CD14+ myeloid cell levels in the CNS indicate neurotoxicity.
Improved objective response rate with the anti-hGM-CSF antibody
An objective response rate of the subject receiving the anti-hGM-CSF antibody is improved compared to a subject not receiving the antibody.
Improved progression-free response and/or survival with the anti-hGM-CSF antibody
Administering an anti-hGM-CSF antibody improves progression free response and/or survival compared to a subject not administered the antibody.
Administering the anti-hGM-CSF antibody after GM-CSF k/o CAR-T19 cells
The anti-hGM-CSF antibody is administered after administration of the GM-CSF k/o CAR-T19 cells.
Overall, the claim coverage centers on administering GM-CSF k/o CAR-T19 cells to reduce tumor burden versus CAR-T19 cells lacking the GM-CSF gene knockout, optionally combined with a recombinant anti-hGM-CSF neutralizing antibody (including lenzilumab). Additional inventive coverage ties treatment to decreased CD14+ myeloid trafficking to the CNS and improved clinical endpoints, including objective response rate and progression-free response and/or survival, with an ordering requirement to administer the antibody after GM-CSF k/o CAR-T19 cells.
Stated Advantages
Reduces tumor burden compared to administration of CAR-T19 cells lacking the GM-CSF gene knockout.
Improved objective response rate compared to a subject not receiving the anti-hGM-CSF antibody.
Improved progression-free response and/or survival compared to a subject not administered the antibody.
Decreases or prevents CD14+ myeloid cell trafficking to the CNS, associated with neurotoxicity-related reduction.
Documented Applications
Enhancing anti-tumor efficacy of CAR T19-cell therapy in a subject having cancer, including administration of GM-CSF k/o CAR-T19 cells.
Adjunct therapy for CAR T19-cell treatment involving administration of a recombinant anti-hGM-CSF antibody (including lenzilumab).
Use in contexts described as reducing CAR-T associated CRS and neurotoxicity/NT and improving CNS-related outcomes tied to CD14+ myeloid trafficking.
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