Engineered T Cells With Chimeric TGFβ Receptors for Solid Tumors
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Solution Overview
Problem
T cell receptor (TCR)-expressing T cells exhibit limited efficacy in solid tumor indications due to the immunosuppressive tumor microenvironment, primarily caused by overproduction of immunosuppressive cytokines like TGFβ, which inhibits their function and contributes to tumor progression.
Innovation Solution
Engineering immune effector cells to express a MAGEA4 TCR and chimeric TGFβ receptors (CTBRs) that convert the immunosuppressive TGFβ signal into an immunostimulatory signal by linking TGFβ binding domains of TGFβR1 and TGFβR2 with immunostimulatory intracellular domains of immune receptors, such as cytokine, interleukin, pattern recognition, or toll-like receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are engineered to express TCR for tumor recognition, then tumor targeting capability is improved, but T cell function is inhibited by TGFβ in the tumor microenvironment
Solution Approach 1:
The patent converts the harmful TGFβ signal into a beneficial immunostimulatory signal by engineering chimeric TGFβ receptors that replace the suppressive intracellular domain with stimulatory domains from cytokine receptors, pattern recognition receptors, or toll-like receptors. This allows the TGFβ binding event to trigger activation rather than suppression, directly resolving the contradiction between tumor targeting and TGFβ-mediated inhibition
Solution Approach 2:
The chimeric TGFβ receptor constructs combine the extracellular TGFβ binding domain with intracellular signaling domains from other receptor types, creating a composite receptor that maintains TGFβ specificity while gaining new signaling capabilities. This composite structure enables T cells to respond to TGFβ with activation instead of suppression
2Ease of operation
If TGFβ binding is blocked to prevent immunosuppression, then T cell function is preserved, but TGFβ signaling pathways are disrupted
Solution Approach 1:
The chimeric TGFβ receptor acts as an intermediary that intercepts the TGFβ signal and redirects it through alternative signaling pathways. Instead of allowing TGFβ to bind native suppressive receptors, the engineered receptor mediates the interaction and converts it into an activating signal, preserving T cell function while maintaining controlled TGFβ signaling
3Reliability
If chimeric TGFβ receptors are engineered with multiple signaling domains, then immunostimulatory response is enhanced, but receptor structure complexity increases
Solution Approach 1:
The chimeric TGFβ receptor is segmented into distinct functional modules: the extracellular TGFβ binding domain, the transmembrane domain, and the intracellular signaling domain. This modular segmentation allows for systematic construction and optimization of the receptor while maintaining clarity in function-to-structure relationships, managing complexity through organized modularity
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.