Chimeric Receptors with TGFβ-Binding Domain
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Solution Overview
Problem
Current cancer immunotherapy approaches, such as CAR T cell therapy, face challenges in enhancing immune response within the tumor microenvironment due to inhibitory signals from transforming growth factor β (TGFβ), which can lead to autoimmune toxicities with systemic blockade and unpredictable efficacy when used in specific contexts.
Innovation Solution
Development of chimeric activation receptors (CARs) in immune cells that include a TGFβ-binding domain, a transmembrane domain, and a CD2 costimulatory domain, capable of competing with endogenous TGFβ receptors for binding, converting inhibitory TGFβ signals into stimulatory signals, thereby enhancing cytokine production and cytolytic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic TGFβ inhibitors are used to block TGFβ inhibition of T cells, then immune response is enhanced, but autoimmune toxicities develop due to pleiotropic effects of TGFβ blockade in other tissues
Solution Approach 1:
The patent applies local quality by engineering T cells with a dominant-negative TGFβRII receptor that specifically blocks TGFβ signaling only within the tumor microenvironment where T cells are actively engaged against tumor cells. This localized approach prevents systemic TGFβ blockade and avoids autoimmune toxicities while maintaining immune response enhancement at the tumor site.
Solution Approach 2:
The dominant-negative TGFβRII receptor acts as an intermediary element introduced into T cells to specifically intercept and block TGFβ signaling pathways. This intermediary mechanism allows selective inhibition of TGFβ's immunosuppressive effects on T cells without affecting TGFβ's physiological functions in other tissues, thereby resolving the contradiction between immune enhancement and toxicity avoidance.
2Reliability
If dominant-negative TGFβRII is expressed to block TGFβ signaling, then antitumor immunity is enhanced, but autoimmunity or lymphoproliferative disorder occurs when expressed at wrong time or by wrong promoter during T cell development
Solution Approach 1:
The patent employs dynamics by using an inducible promoter system that allows temporal and conditional control of dominant-negative TGFβRII expression. The receptor is expressed only after T cell development is complete and only under specific induction conditions, ensuring that TGFβ signaling remains intact during critical developmental stages while being blocked during antitumor immune responses, thus preventing autoimmunity and lymphoproliferative disorders.
Solution Approach 2:
The patent applies preliminary action by establishing proper T cell development and differentiation before inducing expression of the dominant-negative TGFβRII receptor. This ensures that T cells are fully mature and have appropriate regulatory mechanisms in place before the receptor is activated, preventing developmental abnormalities and ensuring safe therapeutic intervention.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The CARs significantly increase IL-2 and IFNγ production and cytolytic activity in immune cells, providing enhanced antitumor immunity with reduced risk of autoimmune toxicity by localized action within the tumor microenvironment.
Implementation Method 1
the chimeric activation receptor comprises (i) a transforming growth factor β (TGFβ)-binding domain
Implementation Method 2
the chimeric activation receptor comprises (i) a transforming growth factor β (TGFβ)-binding domain; (ii) a transmembrane domain; (iii) and a CD2 costimulatory domain
Implementation Method 3
Upon interaction of the chimeric activation receptor with TGFβ, the cell produces one or more cytokines
Data Source
AI summary
The preset disclosure provides chimeric activation receptors comprising (i) a TGFβ-binding domain and (ii) a CD2 costimulatory domain. In some aspects, the TGFβ-binding domain comprises an extracellular domain of a TGFβ receptor. Other aspects of the disclosure are directed to nucleic acid molecules encoding a chimeric activation receptor, cells comprising the chimeric activation receptor and/or a nucleic acid molecule encoding the same, and methods of use thereof in the treatment of a disease or condition (e.g., a tumor) in a subject in need thereof.