Chimeric Costimulatory Receptors for Solid Tumor TIL Activation
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Solution Overview
Problem
Current TIL therapies for solid tumor cancers lack improved efficacy, duration of response, and safety, particularly for patients with locally advanced or metastatic tumors, and there is a need for more effective cell therapies using chimeric costimulatory receptors (CCRs).
Innovation Solution
Genetically modify tumor infiltrating lymphocytes (TILs) to express chimeric costimulatory receptors (CCR) comprising extracellular, hinge, transmembrane, and intracellular domains, and utilize a closed system expansion process to enhance TILs for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TILs are expanded using conventional methods, then expansion can be achieved, but efficacy and duration of response are insufficient for solid tumor cancers
Solution Approach 1:
The patent modifies the receptor parameters of TILs by introducing chimeric costimulatory receptors with specific extracellular domains (CD28, CD134, CD278, CD137, CD27) and intracellular domains (CD3ζ, CD40, CD40L, CD40R, CD27L) to enhance activation signals, thereby improving therapeutic efficacy and extending response duration in solid tumor cancer treatments
2Reliability
If chimeric costimulatory receptors are introduced to enhance activation, then therapeutic efficacy improves, but cell therapy complexity increases
Solution Approach 1:
The chimeric costimulatory receptors are segmented into distinct functional domains: extracellular domains (CD28, CD134, CD278, CD137, CD27) responsible for ligand binding, transmembrane domains for structural stability, and intracellular domains (CD3ζ, CD40, CD40L, CD40R, CD27L) for signal transduction. This segmentation allows modular design and independent optimization of each functional element
Solution Approach 2:
The patent creates universal chimeric costimulatory receptors that can be applied across multiple solid tumor cancer types and combined with various CAR-T therapies, achieving multi-functionality in enhancing activation while maintaining a standardized therapeutic platform that reduces overall complexity
3Productivity
If TILs are expanded rapidly, then production speed increases, but control over expansion parameters becomes more difficult
Solution Approach 1:
The patent implements feedback mechanisms during TIL expansion by monitoring cell activation markers, cytokine levels, and proliferation rates, allowing real-time adjustment of expansion parameters such as cytokine concentrations, feeder cell ratios, and incubation conditions to maintain precise control over the rapid expansion process
Data Source
AI summary
The present invention provides compositions comprising chimeric receptors, including chimeric costimulatory receptors (CCRs), and/or chemokine receptors, methods for preparing CCRs and/or chemokine receptors, and therapeutic populations of tumor infiltrating lymphocytes, marrow infiltrating lymphocytes, and peripheral blood lymphocytes expressing CCRs and/or chemokine receptors with increased therapeutic performance and other advantages for the treatment of cancers, including solid tumor cancers.