UM171 Stem Cell Expansion for GVHD Reduction

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Solution Overview

Problem

Current allogeneic hematopoietic stem cell transplantation methods face challenges such as graft rejection, tumor recurrence, and severe graft-versus-host disease (GVHD) due to insufficient stem cell doses and immune system reactions, leading to prolonged immunodeficiency and increased risks of infections and relapse.

Innovation Solution

The method involves culturing stem and progenitor cells with UM171 or its analogues to expand dendritic (DC) cells and natural killer (NK) cells in vivo, enhancing immune responses and reducing GVHD and viral infections by transplanting a graft of expanded stem and progenitor cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cord blood is used as donor source, then HLA mismatches are permitted and GVHD incidence is reduced, but cell dose is limited resulting in delayed engraftment and increased infections

Engineering Contradiction:

ImproveGVHD reduction and HLA match flexibilityVSAvoidcell dose

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies preliminary action by culturing cord blood stem cells with UM171 before transplantation to expand the cell population. This pre-expansion ensures sufficient cell dose is available for transplantation while maintaining the inherent advantages of cord blood such as HLA mismatch tolerance and reduced GVHD risk.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the chemical parameter by introducing UM171, a small molecule compound, to stimulate stem cell proliferation. This parameter change (adding UM171 to the culture system) enables exponential expansion of cord blood-derived stem cells and their progeny including NK cells and dendritic cells, thereby increasing the cell dose without compromising cord blood's unique properties.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If stem cell dose is increased, then engraftment is improved, but graft rejection and tumor recurrence risks increase due to immune reactions

Engineering Contradiction:

Improveengraftment speedVSAvoidimmune reactions causing graft rejection

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by selectively expanding specific immune cell types (NK cells and dendritic cells) within the stem cell graft through UM171 treatment. This creates a graft with non-uniform cell composition that is enriched in cells capable of providing antitumor activity and immune regulation, thereby improving engraftment while reducing harmful immune reactions against the graft.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses UM171 as an intermediary substance that mediates the expansion of beneficial immune cells. This small molecule acts as a signaling mediator that stimulates stem cells to differentiate and proliferate into NK cells and dendritic cells, which then mediate protection against graft rejection and tumor recurrence.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If NK cell stimulation is increased using IL-2 or IL-15, then cytotoxic functions are enhanced, but toxicity and side effects increase dampening efficacy

Engineering Contradiction:

ImproveNK cell cytotoxic functionVSAvoidtoxicity and side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the use of expensive and toxic cytokine therapies (IL-2, IL-15) with a small molecule compound UM171 that can be administered in a controlled manner during culture. This substitution eliminates the need for high-dose cytokine infusions that cause severe side effects, while still achieving enhanced NK cell cytotoxic function through in vitro expansion.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent substitutes the biological system of cytokine stimulation with a chemical system using UM171. Instead of using protein-based cytokines (IL-2, IL-15) that trigger complex signaling pathways and severe side effects, the patent employs a small molecule compound that achieves similar or superior NK cell activation through a different mechanism, thereby reducing toxicity.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

4Quantity of substance

If double cord transplants are performed, then cell dose is sufficient, but transplant complexity and immunosuppressive therapy requirements increase

Engineering Contradiction:

Improvecell doseVSAvoidtransplant procedure complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent performs preliminary expansion of a single cord blood unit using UM171 before transplantation. This pre-expansion step generates sufficient cell dose from one cord blood unit, eliminating the need for double cord transplants and the associated complexity of managing two grafts, coordinating two donors, and managing potential conflicts between grafts.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12011460B2Expansion of NK and DC cells in vivo mediating immune response

Publication Date: 2024.06.18 UNIV DE MONTREAL

AI summary

It is provided a method of expanding dendritic (DC) cells and/or natural killer (NK) cells in vivo in a patient comprising the steps of producing a graft of stem and progenitor cells cultured with UM171 or analogues therefrom and expanded before being administered to the patient. The expansion or increase in dendritic (DC) cells and/or natural killer (NK) cells population in the patient results in an increase immune response reducing transplant related mortality (TRM), severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections.