ILC1 Cell Therapy Targeting Leukemia Stem Cells in AML

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Acute myeloid leukemia (AML) has a high mortality rate due to the persistence of leukemia stem cells (LSCs) despite standard chemotherapy, and current treatments are ineffective in targeting these cells, leading to certain relapse and limited overall survival, especially in older adult patients who are ineligible for hematopoietic stem cell transplantation.

Innovation Solution

Type I innate lymphoid cells (ILC1s) are used to induce apoptosis and block differentiation of LSCs, promoting their transformation into non-leukemic cells, thereby suppressing leukemogenesis through the production of interferon-γ and interaction with specific signaling pathways, offering a novel strategy for AML treatment and relapse prevention.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If standard chemotherapy is used to treat AML, then leukemic blasts are killed, but leukemia stem cells persist and cause relapse

Engineering Contradiction:

Improvekilling efficiency of leukemic blastsVSAvoidprevention of relapse

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent segments the leukemic cell population by targeting leukemia stem cells (LSCs) specifically through ILC1 cell therapy, distinguishing them from differentiated leukemic blasts. This segmentation allows for selective elimination of the relapse-causing LSC population while preserving normal hematopoietic stem cells, thereby addressing the relapse problem without compromising overall treatment efficacy

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces type I innate lymphoid cells (ILC1s) as an intermediary therapeutic agent that mediates the elimination of leukemia stem cells. These ILC1s produce interferon-γ which directly targets and kills LSCs, serving as a bridge between the immune system and the resistant LSC population, thereby overcoming the limitation of chemotherapy that cannot effectively target these cells

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If hematopoietic stem cell transplantation is used to treat AML, then relapse-free survival is improved, but older adult patients are ineligible due to co-morbid conditions

Engineering Contradiction:

Improverelapse-free survivalVSAvoidapplicability to older adult patients

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs a more accessible and less resource-intensive cell therapy approach using type I innate lymphoid cells compared to hematopoietic stem cell transplantation. This ILC1-based therapy has lower procedural complexity and fewer stringent eligibility requirements, making it a viable option for older adult patients with co-morbid conditions who cannot undergo HSCT, while still achieving effective LSC elimination

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent changes the therapeutic parameter from complex stem cell transplantation to a simpler cell therapy approach using ILC1s. This parameter change reduces the physiological burden and procedural complexity, thereby expanding treatment eligibility to include older adult patients who were previously excluded due to their co-morbid conditions

Inventive Principle:

Principle #35Parameter changes

3Reliability

If ILC1s are used to target LSCs, then LSC apoptosis is induced and differentiation is blocked, but the mechanism involves complex signaling pathways

Engineering Contradiction:

Improveanti-leukemic effectVSAvoidsignaling pathway complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent utilizes the natural feedback mechanism where ILC1s detect leukemia stem cells and respond by producing interferon-γ, which then acts back on the LSCs to induce apoptosis and block differentiation. This feedback loop creates a self-regulating therapeutic system that automatically targets LSCs based on their presence, simplifying the clinical application despite the underlying molecular complexity

Inventive Principle:

Principle #23Feedback

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

ILC1s effectively target and reduce LSCs, preventing their differentiation into leukemia progenitor cells and terminal myeloid blasts, thereby prolonging relapse-free survival and reducing the risk of AML relapse, even in patients ineligible for traditional therapies.

Implementation Method 1

ILC1s induce leukemia stem cell (LSC; Lin−Sca-1+c-Kit+) apoptosis

Methodology Applied

Scientific EffectApoptosis:

Implementation Method 2

IFN-γ mediates ILC1-induced effects on LSCs via both the JAK-STAT and PI3K-AKT signaling pathways

Methodology Applied

Scientific EffectJAK-STAT signaling pathway:

Implementation Method 3

IFN-γ mediates ILC1-induced effects on LSCs via both the JAK-STAT and PI3K-AKT signaling pathways

Methodology Applied

Scientific EffectPI3K-AKT signaling pathway:

Data Source

PatentUS20240082398A1Methods of preparing and expanding type i innate lymphoid cells and therapeutic uses thereof

Publication Date: 2024.03.14 CITY OF HOPE

AI summary

Provided herein are, inter alia, compositions comprising ex vivo expanded ILC1 cells, methods of preparing the compositions, and methods useful for treating cancer and leukemia.