Membrane-Bound IL-15 Fusion for T Cell Persistence

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Solution Overview

Problem

Cells used in adoptive cell therapy often fail to persist in the tumor microenvironment and lose their ability to kill tumor cells quickly, necessitating the development of T cells and natural killer cells with enhanced persistence and cytotoxic activity.

Innovation Solution

The use of membrane-bound IL-15 polypeptides and IL-15/IL-15Rα fusion polypeptides, combined with CD8 polypeptides and T cell receptors, to enhance the persistence and cytotoxic activity of T cells and natural killer cells in the tumor microenvironment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If conventional T cells are used in adoptive cell therapy, then the treatment can be administered, but the cells fail to persist in the tumor microenvironment and quickly lose their cytotoxic ability

Engineering Contradiction:

Improvepersistence of T cells in tumor microenvironmentVSAvoidcytotoxic activity of T cells

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent combines IL-15 and IL-15Rα into a single membrane-bound fusion polypeptide on the T cell surface. This merging of the cytokine and its receptor into one integrated structure ensures that IL-15 is presented in a membrane-bound format that cannot diffuse away, thereby simultaneously achieving long-term persistence and sustained cytotoxic activity through continuous local signaling

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The membrane-bound IL-15/IL-15Rα fusion polypeptide acts as an intermediary that mediates continuous survival and activation signals to the T cell. By presenting IL-15 in a membrane-bound format, it creates a self-sustaining signaling loop that maintains both persistence and cytotoxic function without requiring external cytokine supplementation

Inventive Principle:

Principle #24Intermediary (Mediator)

2Duration of action of moving object

If T cells are modified to enhance persistence through membrane-bound IL-15, then the duration of action is improved, but the device complexity increases due to genetic modification requirements

Engineering Contradiction:

Improvepersistence of T cellsVSAvoidgenetic modification complexity

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

The membrane-bound IL-15/IL-15Rα fusion polypeptide performs multiple functions simultaneously: it provides constitutive IL-15 signaling for persistence, maintains cytotoxic activity, and serves as a self-regulating system. This multi-functionality reduces the need for separate genetic modifications for each function, thereby managing complexity while achieving enhanced persistence

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20230348548A1Membrane-bound il-15, CD8 polypeptides, cells, compositions, and methods of using thereof

Publication Date: 2023.11.02 IMMATICS US INC

AI summary

The present disclosure relates to cells capable of co-expressing T cell receptors (“TCR”) together with membrane-bound IL-15 polypeptides and/or CD8 polypeptides and the use thereof in adoptive cellular therapy. The present disclosure further provides for modified IL-15, IL-15Rα, IL-15/IL-15Rα fusion polypeptide, and IL-15Rα/IL-15 fusion polypeptide sequences, vectors, and associated methods of making and using the same. The present disclosure further provides for modified CD8 sequences, vectors, and associated methods of making and using the same.