γδ T-Cell IL-15Rβ Armoring for Restored IL-15 Responsiveness
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Solution Overview
Problem
Traditional chimeric antigen receptor (CAR) armoring in γδ T cells reduces their responsiveness to IL-15, hindering their effectiveness in immunotherapies, necessitating new compositions and methods to reprogram these cells for enhanced IL-15 responsiveness.
Innovation Solution
Engineering γδ T cells to express recombinant IL-15 receptor β subunit (IL-15Rβ) without IL-15Rα, optionally with a tethered IL-15 or a cleavable peptide linker, and potentially co-expressing IL-15Rα, to establish a positive IL-15 signaling loop, enhancing cell persistence and proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If γδ T cells co-express IL-15 (secreted or membrane-bound) to improve cell persistence and growth, then cell persistence is improved, but responsiveness to IL-15 is reduced
Solution Approach 1:
The invention segments the IL-15 receptor complex by expressing only the IL-15Rβ subunit without the IL-15Rα subunit. This segmentation allows the cell to maintain IL-15 responsiveness while avoiding the feedback inhibition that occurs with full IL-15 co-expression, thereby resolving the contradiction between persistence improvement and responsiveness maintenance.
Solution Approach 2:
The invention applies local quality by selectively expressing the IL-15Rβ subunit with specific properties (without IL-15Rα) in the γδ T cells. This localized modification of receptor composition enables the cells to respond to IL-15 signals while maintaining enhanced persistence, addressing both requirements simultaneously.
2Productivity
If γδ T cells co-express IL-15 to enhance proliferation and survival, then cell growth is improved, but IL-15 responsiveness is reduced
Solution Approach 1:
By segmenting the receptor expression to include only IL-15Rβ without IL-15Rα, the invention enables sustained IL-15 responsiveness that continues to drive proliferation and survival without the diminishing returns caused by full receptor complex co-expression.
Solution Approach 2:
The invention changes the parameter of receptor composition by expressing only the IL-15Rβ subunit, which alters the signaling dynamics to maintain responsiveness while still achieving enhanced proliferation and survival outcomes.
3Duration of action of stationary object
If traditional CAR armoring is applied to γδ T cells, then cell persistence is improved, but therapeutic effectiveness is reduced due to reduced IL-15 responsiveness
Solution Approach 1:
The invention segments the armoring approach by using selective IL-15Rβ expression instead of full IL-15 co-expression, thereby maintaining therapeutic effectiveness through preserved IL-15 responsiveness while still achieving improved cell persistence for long-term therapy.
Solution Approach 2:
By applying local quality modification to the receptor expression profile (IL-15Rβ only), the invention optimizes the balance between persistence and therapeutic effectiveness, ensuring that γδ T cells remain responsive to IL-15 cues while maintaining enhanced durability in the therapeutic setting.
Data Source
AI summary
The present disclosure provides compositions and methods for engineering γδ T cells (e.g., vδ1 T cells and vδ2 T cells) with an IL-15 receptor β subunit (IL-15Rβ), e.g., by transduction with a viral vector, to restore IL-15 responsiveness. Further provided are populations of engineered γδ T cells and methods of using the same.