Chimeric TGFβ Receptors for Tumor-Activated T Cell Signaling
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Solution Overview
Problem
Current immunotherapy strategies, including monoclonal antibodies and adoptive cellular therapies, have limited success in combating cancer due to the immunosuppressive tumor microenvironment mediated by TGFβ signaling, which inhibits T cell function and leads to exhaustion, despite attempts to inhibit TGFβ signaling yielding disappointing results.
Innovation Solution
Development of genetically modified T cells expressing chimeric TGFβ receptors (CTBRs) that convert TGFβ signaling into pro-inflammatory signals through fusion polypeptides combining TGFβR2 and TGFβR1 domains with immune receptor intracellular signaling domains, such as IL-12Rβ1/2, IL-7Rα/γ, IL-2Rβ/γ, IL-21R, IL-18R1/RAP, IL-1R1/RAP, and TLR1-10, to enhance T cell function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TGFβ signaling is inhibited to overcome immunosuppression, then T cell function is improved, but systemic immune activation and toxicity occur
Solution Approach 1:
The patent applies local quality by engineering T cells to express chimeric TGFβ receptors that are specific to the tumor microenvironment. The CTBRs convert TGFβ signals locally within tumor-infiltrating T cells into activating signals through intracellular domains from immune receptors like IL-12Rβ1/2, IL-7Rα/γ, and TLR1-10, rather than systemically inhibiting TGFβ signaling throughout the body. This localized approach restores T cell function at the tumor site without causing widespread immune activation and toxicity
Solution Approach 2:
The patent converts the harmful TGFβ immunosuppressive signal into a beneficial activating signal through the chimeric receptor design. The extracellular domain of the CTBR recognizes and binds TGFβ (the harmful signal), while the intracellular domain from immune receptors transduces this binding event into an activating signal that promotes T cell proliferation, cytokine production, and anti-tumor activity. This transforms the detrimental TGFβ pathway into a therapeutic advantage
2Reliability
If TGFβ signaling is inhibited to restore T cell efficacy, then anti-tumor response is enhanced, but treatment success remains limited
Solution Approach 1:
The patent introduces chimeric TGFβ receptors as intermediary molecules that mediate between the TGFβ ligand and the T cell signaling pathway. The CTBRs serve as a bridge that captures TGFβ signals and redirects them through intracellular domains from proven immune activating receptors (IL-12Rβ1/2, IL-7Rα/γ, IL-2Rβ/γ, IL-21R, IL-18R1/RAP, IL-1R1/RAP, TLR1-10). This intermediary approach provides a more effective and specific mechanism than broad TGFβ inhibition, leading to improved treatment success rates in adoptive cellular therapies
Solution Approach 2:
The patent applies parameter changes by modifying the signaling parameters of T cells through genetic engineering. By introducing CTBRs with diverse intracellular signaling domains, the patent alters the signal transduction parameters within T cells, transforming them from TGFβ-responsive (suppressive) to TGFβ-reactive (activating). This parameter change in signal transduction fundamentally improves T cell efficacy and anti-tumor response productivity
Data Source
AI summary
The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.