Chimeric GM-CSF-IL-18 Receptor for Solid Tumor Immunotherapy

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Solution Overview

Problem

The solid tumor microenvironment poses challenges to the efficacy and persistence of therapeutic immune cells in immunotherapy due to the lack of immune cell-supportive cytokines, limiting the effectiveness of treatments like CAR T cells.

Innovation Solution

Development of chimeric cytokine receptors, specifically combining the extracellular domain of the GM-CSF receptor with the intracellular domain of the IL-18 receptor, which can be activated in the tumor microenvironment to enhance the effector function of therapeutic immune cells, including expansion, persistence, and tumor killing activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR T cells are used for solid tumor immunotherapy, then antitumor activity is achieved, but efficacy and persistence are limited due to lack of supportive cytokines in the tumor microenvironment

Engineering Contradiction:

Improveefficacy of therapeutic immune cellsVSAvoidpersistence of therapeutic immune cells

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent combines the extracellular domain of the GM-CSF receptor with the intracellular domain of the IL-18 receptor to create a chimeric cytokine receptor. This merging allows the receptor to bind GM-CSF (which is present in the tumor microenvironment) while signaling through IL-18 pathways (which promote immune cell activation, proliferation, and persistence), thereby resolving the contradiction between achieving antitumor activity and maintaining persistence in the tumor microenvironment

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric cytokine receptor acts as an intermediary that translates the presence of GM-CSF in the tumor microenvironment into IL-18-like signaling effects. This intermediary mechanism allows therapeutic immune cells to respond to available cytokines (GM-CSF) while achieving the beneficial effects of supportive cytokines (IL-18) that promote persistence and efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If the tumor microenvironment is targeted for immunotherapy, then antitumor activity is enhanced, but the hostile environment lacks immune cell-supportive cytokines limiting treatment effectiveness

Engineering Contradiction:

Improveantitumor activityVSAvoidresponse to cytokine environment

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The patent changes the receptor's signaling parameters by creating a chimera that responds to GM-CSF (abundant in tumor microenvironment) through IL-18 signaling pathways. This parameter change allows the immune cell to adapt to the tumor microenvironment's cytokine profile while maintaining the ability to mount an effective antitumor response, resolving the contradiction between productivity and adaptability

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230030680A1Chimeric gmcsf-il18 receptor

Publication Date: 2023.02.02 ST JUDE CHILDRENS RES HOSPITAL INC

AI summary

The present invention provides chimeric cytokine receptors, particularly chimeric cytokine receptors that canbe activated in tumor microenvironment, and their uses in tumor immunotherapy (e.g., adoptive cell therapy). The present invention further provides methods of genetically modifying therapeutic cells resulting in an enhanced immune response against a target antigen. The application further provides therapeutic cells that express said chimeric cytokine receptors and methods for treating patients using the modified therapeutic cells.