Chimeric TGFβ Receptors for Converting Tumor Immunosuppression
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Solution Overview
Problem
Current immunotherapy approaches for cancer, particularly those targeting TGFβ signaling, have shown limited success due to the immunosuppressive tumor microenvironment and the inability of T cells to effectively combat cancer cells, despite the potential of engineered T cells and chimeric antigen receptors.
Innovation Solution
Development of chimeric TGFβ receptors (CTBRs) that convert immunosuppressive TGFβ signals into immunostimulatory signals by linking TGFβR1 and TGFβR2 domains with intracellular signaling domains from immune receptors, such as IL-12Rβ, IL-7R, IL-2R, and TLRs, to enhance T cell function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are used for cancer immunotherapy, then selective recognition and powerful effector mechanisms are achieved, but T cell function is suppressed by the immunosuppressive tumor microenvironment
Solution Approach 1:
The patent converts the immunosuppressive TGFβ signal into an immunostimulatory signal by engineering chimeric TGFβ receptors that redirect TGFβ binding to activate activating transcription factor (ATF) signaling pathways, thereby transforming the harmful suppressive effect into a beneficial activating effect on T cell function
Solution Approach 2:
The patent introduces chimeric TGFβ receptors as intermediary molecules that mediate between TGFβ ligand binding and intracellular signaling pathways. These engineered receptors contain TGFβ binding domains coupled to intracellular domains that recruit and activate ATF signaling components, serving as a bridge to convert external TGFβ signals into internal activation cues
2Reliability
If T cells are exposed to TGFβ in the tumor microenvironment, then TGFβ signaling occurs, but T cells differentiate into exhausted T cells and lose effector function
Solution Approach 1:
The patent converts the harmful TGFβ-mediated exhaustion signal into a beneficial activation signal by engineering receptors that interpret TGFβ binding as a cue to activate ATF signaling pathways, thereby preventing differentiation into exhausted T cells and maintaining effector function
3Reliability
If monoclonal antibodies targeting CTLA-4 or PD-1 are used, then substantial anti-tumor effect is achieved, but substantial toxicity occurs due to systemic immune activation
Solution Approach 1:
The patent applies local quality by engineering T cells to express chimeric TGFβ receptors that are specific to the tumor microenvironment where TGFβ is present. This creates localized TGFβ signal conversion only at the tumor site, avoiding systemic immune activation and its associated toxicities while maintaining effective anti-tumor responses
Solution Approach 2:
The patent converts the locally harmful TGFβ signal in the tumor microenvironment into a beneficial activation signal through engineered chimeric receptors, achieving tumor-specific immune activation without the systemic toxicity associated with checkpoint inhibitor antibodies
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.