Chimeric TGF-beta Receptor Converts Inhibitory Signals
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Solution Overview
Problem
Cancer therapies face challenges in effectively targeting and overcoming the immunosuppressive tumor microenvironment, particularly where TGFβ is secreted, as it inhibits T cell proliferation and function, limiting the efficacy of adoptive cell therapy.
Innovation Solution
Genetically modified T cells expressing a chimeric TGFβ receptor with an extracellular domain linked to an immunostimulatory endodomain, such as TLR4, convert the inhibitory TGFβ signal into a stimulatory one, enhancing T cell proliferation and anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TGFβ signaling is present in the tumor microenvironment, then tumor cells are protected from immune attack, but T cell proliferation and function are inhibited
Solution Approach 1:
The patent converts the harmful TGFβ signal into a beneficial activation signal by engineering chimeric receptors that bind TGFβ and trigger stimulatory intracellular signaling pathways. The chimeric TGFβ receptor fuses the extracellular TGFβ-binding domain with intracellular domains from stimulatory receptors like TLR4, CD28, or 4-1BB, transforming TGFβ from an immunosuppressive factor into an activator of T cell proliferation and anti-tumor function.
Solution Approach 2:
The chimeric receptor serves as an intermediary molecule that intercepts the TGFβ signal and redirects it through a different signaling pathway. Instead of allowing TGFβ to bind native suppressive receptors, the engineered receptor captures TGFβ and transmits an activation signal through fused intracellular domains, mediating a signal transformation from suppressive to stimulatory.
2Productivity
If adoptive cell therapy is used to treat cancer, then T cell anti-tumor activity is enhanced, but TGFβ in the tumor microenvironment causes T cell exhaustion and apoptosis
Solution Approach 1:
The patent applies preliminary anti-action by pre-equipping T cells with chimeric receptors that provide constitutive or inducible protection against TGFβ-mediated suppression before the cells encounter the tumor microenvironment. This preemptive engineering ensures that when T cells are infused into the patient, they are already armed with the capability to resist TGFβ-induced exhaustion and apoptosis, extending their persistence and functional duration in the tumor site.
Solution Approach 2:
The chimeric receptor system introduces dynamic responsiveness to TGFβ, allowing T cells to adapt their behavior based on TGFβ presence. Rather than being statically suppressed, T cells dynamically switch from TGFβ-mediated inhibition to TGFβ-driven activation, enabling them to thrive and persist in the otherwise suppressive tumor microenvironment.
3Adaptability or versatility
If conventional T cells are used in therapy, then they can recognize tumor antigens, but they fail to proliferate and maintain function in TGFβ-rich environments
Solution Approach 1:
The patent merges multiple functional domains into a single chimeric receptor molecule. The extracellular domain retains TGFβ binding capability while the intracellular domain incorporates signaling motifs from stimulatory receptors. This fusion combines antigen recognition, signal transduction, and activation functions into one engineered component, enabling T cells to simultaneously recognize TGFβ and receive activation signals for proliferation.
Solution Approach 2:
The invention fundamentally changes the signaling parameter response to TGFβ. Instead of the natural suppressive signaling outcome, the engineered receptor alters the intracellular signaling parameters to produce activation. By modifying the intracellular domain composition and signaling pathway engagement, the system transforms TGFβ from a negative regulator into a positive regulator of T cell proliferation and function.
Data Source
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AI summary
Embodiments of the disclosure concern cell therapy methods and compositions utilizing cells expressing at least a chimeric TGFβ receptor including the exodomain of a TGFβII receptor and an endodomain that is not from TGFβ receptor, thereby converting the negative signal of TGFβ for T cell proliferation into a T cell activation signal. In at least certain aspects, cells harboring the chimeric TGFβ receptor also harbor one or more chimeric antigen receptors.