FSHR-Targeted Chimeric T Cells for Ovarian Cancer Immunotherapy
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Solution Overview
Problem
Current immunotherapy technologies face challenges in targeting specific antigens on tumor cells without causing side effects and are hindered by the immunosuppressive tumor microenvironment, particularly in treating ovarian cancer.
Innovation Solution
Development of chimeric proteins and modified T cells that utilize the FSH receptor (FSHR) as a target, combining FSH ligands with T cell activating functions, such as extracellular hinge domains, transmembrane domains, co-stimulatory signaling regions, and signaling endodomains, to enhance T cell activation against FSHR-expressing cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR therapy is used to target specific antigens on tumor cells, then T cell activation against tumor cells is improved, but the paucity of specific antigens expressed on tumor cells that are not shared with healthy tissues prevents successful treatment of solid tumors including ovarian cancer
Solution Approach 1:
The patent uses FSHR, a hormone receptor that is universally expressed on ovarian cancer cells and other solid tumors, as a target antigen. This universal target allows the CAR T cell therapy to be applicable across multiple tumor types rather than requiring tumor-specific antigens, thereby resolving the limitation of antigen availability while maintaining reliable T cell activation against tumor cells
2Reliability
If T cell infiltration is increased to exert pressure against ovarian cancer progression, then antitumor immune response is improved, but the immunosuppressive effect of the tumor microenvironment heavily impairs antitumor T cell responses
Solution Approach 1:
The patent employs FSHR as an intermediary target that T cells can recognize and bind to on the surface of ovarian cancer cells. This intermediary approach allows T cells to overcome the immunosuppressive tumor microenvironment by directly engaging tumor cells through the FSHR-FSH interaction, thereby restoring effective antitumor immune responses despite the suppressive conditions
3Productivity
If conventional chemotherapy and surgical approaches are used to treat ovarian cancer, then tumor removal is achieved, but the 5 year survival rate has barely changed in the last 40 years
Solution Approach 1:
The patent replaces conventional mechanical surgical removal and chemical chemotherapy with an immunological mechanism where genetically modified T cells specifically recognize and eliminate FSHR-expressing ovarian cancer cells. This substitution of mechanical/chemical approaches with a targeted immunological system aims to improve long-term survival rates by providing sustained antitumor immunity rather than temporary tumor removal
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 approach effectively activates T cells to target and eliminate FSHR-expressing tumor cells, delaying tumor progression and increasing CD4/CD8 ratios, thus providing a promising immunotherapy for ovarian and other FSHR-positive cancers.
Implementation Method 1
a ligand that comprises a follicle stimulating hormone (FSH) sequence, which ligand binds to human FSHR
Data Source
AI summary
A nucleic acid sequence is provided that encodes a chimeric protein comprising a ligand that comprises a naturally occurring or modified follicle stimulating hormone sequence, e.g., an FSHβ sequence, or fragment thereof, which ligand binds to human follicle stimulating hormone (FSH) receptor, linked to either (a) a nucleic acid sequence that encodes an extracellular hinge domain, a transmembrane domain, a co-stimulatory signaling region, and a signaling endodomain; or (b) a nucleic acid sequence that encodes a ligand that binds to NKG2D. The vector containing the nucleic acid sequence, the chimeric proteins so encoded, and modified T cells expressing the chimeric protein, as well as method of using these compositions for the treatment of FSHR-expressing cancers or tumor cells are also provided.