Mutated T Cell Signaling Constructs for Solid Tumor Persistence
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Solution Overview
Problem
Adoptive T cell therapies, particularly CAR-T cell therapies, face limitations in treating solid tumors due to issues such as T cell exhaustion, poor in vivo persistence, and immunosuppressive environmental factors, leading to inadequate proliferative capacity and effector function, which have not been effectively addressed by current rational design or genome-wide alterations.
Innovation Solution
The use of recombinant nucleic acid constructs encoding polypeptides with specific mutations, such as CARD-containing proteins and SH2 domains, to enhance T cell signaling, decrease exhaustion, and improve in vivo persistence and fitness, including the expression of these polypeptides in T cells through vectors like retroviruses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat solid tumors, then T cell signaling and effector function are activated, but T cell exhaustion and poor in vivo persistence occur
Solution Approach 1:
The patent introduces mutations in polypeptides (such as CARD-containing proteins and SH2 domains) to alter T cell signaling parameters. These parameter changes enhance T cell persistence and fitness without compromising effector function, directly resolving the contradiction between therapeutic efficacy and in vivo persistence
Solution Approach 2:
The patent creates composite polypeptide structures by combining multiple functional domains (CARD domains, SH2 domains, signaling domains) into engineered constructs. These composite structures integrate multiple functions including enhanced signaling, improved persistence, and maintained cytotoxicity, thereby resolving the contradiction between activation and exhaustion
2Reliability
If genome-wide alterations are used to modify T cell function, then T cell fitness may be improved, but the complexity of the approach increases and rational design becomes less effective
Solution Approach 1:
The patent extracts and focuses on specific critical polypeptides (CARD-containing proteins and SH2 domains) that are key to T cell function and persistence. By targeting these specific elements rather than implementing genome-wide alterations, the patent reduces complexity while maintaining effectiveness in improving T cell fitness
Solution Approach 2:
The patent segments the T cell modification approach into discrete, modular polypeptide constructs with specific functions (signaling, persistence, cytotoxicity). This segmentation allows for rational design of each component and simplifies the overall genetic modification strategy compared to genome-wide approaches
Data Source
AI summary
The present disclosure relates generally to compositions and methods for improving T cell therapy. In particular, the disclosure provides polypeptides and recombinant nucleic acid constructs and/or recombinant nucleic acids encoding polypeptides having mutations capable of altering T cell signaling, cytokine production, and/or in vivo persistence in tumors of therapeutic T cells comprising the mutation. The T cell signaling can be by NFAT, NF-κB and/or AP-1 pathways. The disclosure also provides vectors and cells including the polypeptides and/or recombinant nucleic acid constructs and/or recombinant nucleic acids of the disclosure as well as methods of preparing a T cell for use in cell therapy, and methods of identifying a mutation useful for improving T cell therapy.