Combination of a cell therapy and a gamma secretase inhibitor
Inventors
GREEN, Damian J. • Riddell, Stanley R. • WORKS, Melissa
Assignees
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Publication Number
US-12193994-B2
Publication Date
2025-01-14
Expiration Date
Abstract
Provided herein are combination therapies involving administration of an immunotherapy involving a cell therapy, such as a T cell therapy, and an inhibitor of gamma secretase. Also provided are methods for engineering, preparing, and producing the cells, compositions containing the cells and/or gamma secretase inhibitor, and kits and devices containing and for using, producing and administering the cells and/or gamma secretase inhibitor, such as in accord with the provided combination therapy methods.
Core Innovation
The invention describes a combination therapy for multiple myeloma in which a subject receives T cell therapy and also receives a gamma secretase inhibitor. The T cell therapy comprises T cells expressing a recombinant receptor that specifically binds BCMA, including BCMA-targeting CAR T therapy. The combination is presented to address the presence of soluble or shed BCMA that can interfere with CAR binding and function.
The gamma secretase inhibitor inhibits intramembrane cleavage and shedding to maintain or prevent loss of CAR binding and function in the presence of soluble or shed BCMA. The document links this approach to modulation of BCMA, including surface BCMA and shed or serum BCMA levels, while supporting CAR+ T cell expansion and persistence and maintaining functional activity.
The document further describes treatment in terms of administering a compound defined by a structure, including LY3039478 and Compound 1, to a subject receiving the BCMA-binding T cell therapy. The approach targets multiple myeloma using a gamma secretase inhibitor scaffold administered together with recombinant receptor-expressing T cells that specifically bind BCMA.
Claims Coverage
The consolidated claim coverage identifies one independent treatment claim. The claim centers on BCMA-binding recombinant receptor T cell therapy for multiple myeloma together with administration of a compound of a defined structure, with additional claim refinements for compound timing, dosing, and BCMA-binding receptor sequence characteristics.
Bcma-specific recombinant receptor t cell therapy for multiple myeloma
Administering a T cell therapy to a subject having multiple myeloma, the cell therapy comprising a dose of T cells expressing a recombinant receptor that specifically binds BCMA.
Co-administration of a compound of a defined gamma secretase inhibitor structure
Administering to the subject a compound of the structure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or hydrate of either of the foregoing, together with the BCMA-binding T cell therapy.
Timing of compound initiation relative to cell therapy
Initiation of administration of a compound occurs within 72 hours, within 96 hours or within 1 week before initiation of administration of cell therapy.
Compound dosing amount constraints
Administering the compound at an amount that is or is about 25 mg, and/or administering the compound at an amount ranging from 10 mg to 100 mg.
Bcma-binding chimeric antigen receptor sequence constraints
Using a recombinant chimeric antigen receptor containing an antigen-binding domain specific for BCMA, with specified VH and VL regions whose CDRH1–CDRH3 and CDRL1–CDRL3 sequences match particular SEQ ID assignments.
The claim coverage is centered on treating multiple myeloma by administering BCMA-specific recombinant receptor T cells together with a co-administered gamma secretase inhibitor defined by a specific chemical structure. The dependent scope further narrows the regimen by timing and dosing of the compound and by sequence-defined BCMA-binding CAR features.
Stated Advantages
enhances CAR-T intrinsic activity
increases expansion of CAR+ T cells
improves CAR-T survival
improves cytotoxicity
improves persistence
reinforces CAR-T after weak expansion or relapse
may enable lower CAR-T doses to achieve similar effects
Maintains or prevents diminishment of CAR binding and function in the presence of soluble or shed BCMA.
Improves CAR+ T cell expansion and persistence versus control.
Preserves functional activity of the CAR-T therapy alongside BCMA modulation.
Documented Applications
treatment of multiple myeloma using a subject receiving BCMA-targeted T cell therapy together with a gamma secretase inhibitor compound
Combination treatment for multiple myeloma using BCMA-targeting CAR T (recombinant receptor specifically binding BCMA) together with a gamma secretase inhibitor to inhibit intramembrane cleavage/shedding and modulate BCMA, including shed/serum BCMA levels.
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