Switch Molecule Engineering for T Cell Activation
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Solution Overview
Problem
Current T cell-based adoptive immunotherapies for cancer, particularly solid cancers, face challenges due to immunological obstacles such as tumor-induced tolerant microenvironments and immunosuppressive mechanisms that counteract effective immune responses.
Innovation Solution
Modified T cells are engineered to express a switch molecule comprising an extracellular domain like a cytokine receptor and an intracellular domain like a signaling receptor, allowing them to secrete an activation factor when interacting with specific ligands at tumor sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are modified with CARs alone, then T cell-based adoptive immunotherapy can be implemented, but the therapy is insufficient for efficiently treating cancers especially solid cancers due to immunological obstacles
Solution Approach 1:
The patent combines multiple functional domains into a single switch molecule: an extracellular domain for ligand binding (e.g., TGF-beta receptor), a transmembrane domain for cell membrane anchoring, and an intracellular domain for signal transduction (e.g., IL-12 receptor signaling). This merged structure enables T cells to simultaneously recognize tumor-specific ligands and receive activation signals, overcoming the limitation of CAR-only modifications that cannot effectively penetrate immunosuppressive tumor microenvironments.
Solution Approach 2:
The switch molecule acts as an intermediary that translates extracellular ligand binding events into intracellular activation signals. The extracellular domain specifically binds to ligands in the tumor microenvironment (such as TGF-beta), and this binding event triggers conformational changes that activate the intracellular signaling domain, thereby mediating the conversion of environmental cues into T cell activation without requiring direct CAR engagement.
2Reliability
If T cells are engineered to overcome immunosuppressive barriers, then immune activation at tumor sites is enhanced, but the complexity of T cell modification increases
Solution Approach 1:
The switch molecule is designed with universal functionality that can respond to multiple types of ligands depending on the extracellular domain configuration. The same basic architecture (extracellular domain-transmembrane domain-intracellular domain) can be adapted to bind different tumor-associated ligands while maintaining the same signaling mechanism, thereby providing a universal platform for overcoming various immunosuppressive mechanisms without requiring entirely different modification strategies for each cancer type.
Data Source
AI summary
The present invention includes compositions and methods for modifying a T cell with a nucleic acid encoding a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof and an intracellular domain comprising a signaling receptor or fragment thereof. In one aspect, a method comprises introducing a nucleic acid encoding a switch molecule and a nucleic acid encoding a soluble fusion protein and/or a nucleic acid encoding a bispecific antibody into a population of cells comprising T cells, wherein the T cells transiently expresses the switch molecule and soluble fusion protein or bispecific antibody. In other aspect, compositions of T cells and methods of treating a disease or condition, such as cancer or an autoimmune disease, are also included.