Chimeric Cytokine Receptors Convert Immunosuppressive Signals
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Cancer treatments face challenges due to immune evasion mechanisms employed by tumors, such as downregulation of antigen expression and secretion of immunosuppressive cytokines that convert cytotoxic Th1 cells to an ineffective Th2 phenotype, limiting the efficacy of adoptive transfer therapies like CTL infusion.
Innovation Solution
Engineering tumor-specific T cells with a chimeric cytokine receptor comprising a cytokine-binding exodomain and a signal transducing endodomain, specifically combining IL-13 receptor exodomain with IL-2, IL-7, or IL-15 receptor endodomains, to render them resistant to immunosuppressive cytokines and maintain Th1 signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive transfer of TAA-specific CTL is used to treat tumors, then therapeutic benefit is achieved, but tumor immune evasion mechanisms (including secretion of immunosuppressive cytokines) limit the efficacy
Solution Approach 1:
The patent converts the harmful immunosuppressive cytokines (IL-4, IL-13) secreted by tumors into beneficial signals by engineering chimeric receptors that bind these cytokines and trigger Th1-stimulatory intracellular signaling pathways. This transforms the tumor's immune evasion mechanism into a tool for enhancing CTL activation and proliferation, directly addressing the efficacy limitation caused by immunosuppressive cytokines
Solution Approach 2:
The invention creates composite receptor structures by fusing the extracellular domain of immunosuppressive cytokine receptors (IL-4Rα or IL-13Rα1) with the intracellular signaling domain of Th1-stimulatory cytokine receptors (IL-2Rγ, IL-7Rα, or IL-15Rα). This composite chimeric receptor combines the ligand-binding specificity for immunosuppressive cytokines with the signaling capability to activate Th1 responses, resolving the contradiction between tumor cytokine secretion and therapeutic efficacy
2Adaptability or versatility
If immunosuppressive cytokines are secreted by tumors, then Th1 cells are converted to Th2 phenotype, but this limits the cytotoxic immune response needed to destroy cancer cells
Solution Approach 1:
The patent inverts the normal cytokine signaling pathway by engineering receptors that bind immunosuppressive Th2-polarizing cytokines (IL-4, IL-13) but trigger Th1-stimulatory signaling instead of Th2 differentiation. This inversion causes T cells exposed to tumor-secreted cytokines to maintain or adopt a cytotoxic Th1 phenotype rather than converting to Th2, directly counteracting the harmful repolarization effect
Solution Approach 2:
The invention changes the signaling parameter (intracellular pathway activation) triggered by immunosuppressive cytokine binding. By fusing the extracellular domain of IL-4Rα or IL-13Rα1 with the intracellular domain of IL-2Rγ, IL-7Rα, or IL-15Rα, the receptor changes the output signal from Th2-differentiating to Th1-stimulatory, thereby maintaining T cell cytotoxicity despite exposure to tumor cytokines
Data Source
Figure 1
Figure 2A~2B
Figure 2C~2D
AI summary
Disclosed are compositions and methods related to rendering ineffective Thl T cells resistant to the inhibitory cytokine milieu present in a cancer microenvironment. Tumor-specific T cells are modified to employ a chimeric receptor that binds inhibitory/suppressive cytokines and converts their intracellular consequences to a Thl immunostimulatory/activating signal. The T cells employ a chimeric antigen receptor having exodomains for IE 10, IE 13 and/or IL4 fused with the signal transducing endodomains for IL2 and/or IL7.