Membrane-Bound IL-15-IL-15Rα Chimeric Receptor for T-Cell Persistence
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Solution Overview
Problem
Certain cancers induce an immunosuppressive microenvironment that reduces the robustness of antitumor immune responses, posing challenges for cellular immunotherapies such as CAR T cell therapy and NK cell-based treatments.
Innovation Solution
Development of a membrane-bound IL-15-IL-15Rα sushi domain chimeric receptor to enhance cytokine signaling in T cells and NK cells, comprising specific amino acid sequences and linkers, which can be expressed in immune cells to improve their function and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cytokines are used to expand T cells, then T cell quantity increases, but T cell exhaustion and diminished persistence occur
Solution Approach 1:
The patent combines multiple cytokine functions (IL-15 for survival/proliferation and IL-21 for differentiation) into a single chimeric receptor construct. This merging allows simultaneous delivery of multiple cytokine signals through one receptor, achieving T cell expansion and persistence without the harmful effects of individual cytokine overstimulation
Solution Approach 2:
The chimeric receptor acts as an intermediary between cytokines and their native receptors. By fusing IL-15 and IL-21 signaling domains into a single receptor that can be engineered into T cells, the patent creates a controlled mediator that delivers cytokine signals in a regulated manner, avoiding the uncontrolled stimulation that leads to exhaustion
2Reliability
If multiple cytokines are used together to improve CAR-T potency, then immune response quality improves, but system complexity increases
Solution Approach 1:
The patent merges IL-15 and IL-21 signaling capabilities into a single chimeric receptor molecule. This consolidation reduces the complexity of delivering and coordinating multiple separate cytokine treatments while maintaining the synergistic effects needed for improved CAR-T potency and persistence
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
The chimeric receptor enhances the potency and persistence of T cells and NK cells, improving the effectiveness of immunotherapies against cancer by inducing a robust immune response.
Implementation Method 1
Since overall T cell function and proliferation are dependent on cytokine signaling, it is theorized that the use of cytokines may improve the overall quality and potency of T cell based therapies
Data Source
AI summary
The present disclosure relates to the field of cell therapy, and more specifically, to improving CAR and/or TCR function through improvement of cytokine signaling. Disclosed are embodiments of a membrane bound interleukin 15 (IL-15)-IL-15Ralpha sushi domain chimeric receptor. The chimeric receptor may comprise a FAS transmembrane domain or an IL-7 transmembrane domain. Different embodiments of the chimeric receptor have different polypeptide lengths between the IL-15 region and the transmembrane domain.