CXCR2 Agonist Mobilization for Myeloma Stem Cell Transplants
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Solution Overview
Problem
Current methods for mobilizing hematopoietic stem and progenitor cells face challenges, including difficulty in releasing these cells from bone marrow into peripheral blood and a high incidence of graft-versus-host disease (GVHD) in allogeneic recipients, due to the presence of myeloid-derived suppressor cells (MDSCs) in G-CSF mobilized grafts.
Innovation Solution
Administration of a C-X-C chemokine receptor type 2 (CXCR2) agonist, such as Gro-β or its variants, in combination with a CXCR4 antagonist, to mobilize hematopoietic stem and progenitor cells from the bone marrow into peripheral blood, which reduces the risk of GVHD and increases the number of MDSCs, facilitating their isolation and therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If G-CSF is used to mobilize hematopoietic stem cells, then stem cells are released into peripheral blood, but the presence of MDSCs increases the risk of GVHD
Solution Approach 1:
The patent extracts and removes MDSCs from the mobilized stem cell product through selective depletion methods, thereby eliminating the harmful immunosuppressive cells while preserving the therapeutic stem cells. This resolves the contradiction by removing the harmful component (MDSCs) that causes GVHD while maintaining the beneficial component (stem cells).
Solution Approach 2:
The patent changes the mobilization regimen parameters by using alternative agents or combinations (such as plerixafor with G-CSF, or other chemokine receptor modulators) to mobilize stem cells with different cell type compositions. This alters the quality and quantity of cells in the mobilized product, reducing MDSC presence while maintaining stem cell yield.
2Reliability
If standard mobilization methods are used, then stem cells can be collected, but the engraftment rate is insufficient
Solution Approach 1:
The patent applies preliminary actions by pre-treating donors with specific mobilization regimens that optimize stem cell quality and quantity before collection. This includes using combination therapies or extended mobilization periods to ensure the mobilized product contains sufficient engrafting-capable cells, thereby improving engraftment rates while maintaining collection efficiency.
Solution Approach 2:
The patent implements feedback mechanisms by monitoring mobilization response and collection outcomes to optimize subsequent procedures. By analyzing engraftment data and collection efficiency metrics, the protocol can be adjusted to improve both parameters in future mobilization events.
Data Source
AI summary
The invention provides compositions and methods useful for mobilizing populations of hematopoietic stem and progenitor cells within a donor, such as a donor with multiple myeloma, as well as for determining whether samples of mobilized cells are suitable for release for ex vivo expansion and/or therapeutic use. In accordance with the compositions and methods described herein, mobilized hematopoietic stem and progenitor cells can be withdrawn from a patient with multiple myeloma for performing an autologous stem cell transplant to treat the patient's multiple myeloma.