Engineered T Cells Expressing IL-7 and CCL19 for Solid Tumors
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Solution Overview
Problem
Conventional immunotherapy methods using immunocompetent cells, such as T cells, do not adequately enhance the proliferative potential, survival capacity, or ability to accumulate and activate T cells, leading to insufficient antitumor effects, particularly in solid cancers.
Innovation Solution
Genetically modify immunocompetent cells to express an exogenous T cell receptor specifically recognizing a cancer antigen, along with interleukin 7 (IL-7) and CCL19, to improve their immune function and accumulation at tumor sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapy methods are used to collect and amplify T cells, then T cells are transferred to patients, but the proliferative potential, survival capacity, and ability to accumulate T cells at tumor sites are insufficient
Solution Approach 1:
The patent combines multiple regulatory factors (IL-7, CCL19, and other cytokines/chemokines) into a single immunocompetent cell construct. This merging approach allows the T cells to simultaneously receive survival signals (IL-7), chemotactic guidance (CCL19), and immune activation signals, thereby resolving the contradiction between reliability of antitumor effect and productivity of proliferative potential by integrating multiple functional elements into one unified system
Solution Approach 2:
The modified T cells are engineered to autonomously produce and respond to regulatory factors themselves. The cells express endogenous IL-7 and CCL19, creating a self-sustaining system where the immunocompetent cells generate their own survival and accumulation signals, eliminating the need for external support and thereby improving both survival capacity and proliferative potential simultaneously
2Reliability
If T cells are genetically modified to express regulatory factors, then survival capacity and proliferative potential improve, but the complexity of cell engineering increases
Solution Approach 1:
The patent employs universal promoter elements and standardized genetic constructs that can be applied across different T cell modification protocols. By using commonly available cytokine genes (IL-7, CCL19) and standard viral vector systems, the complexity of gene modification is reduced while maintaining multi-functional capabilities for survival, proliferation, and tumor targeting
Solution Approach 2:
The regulatory factors (IL-7, CCL19) are pre-integrated into the T cell genome before activation and expansion. This preliminary genetic modification ensures that the cells are pre-equipped with survival and chemotactic capabilities, eliminating the need for complex post-modification procedures and reducing overall engineering complexity while maintaining high survival capacity
3Adaptability or versatility
If T cells express only autologous cytokine signals, then membrane surface transduction occurs, but the ability to enhance function of unintroduced T cells is lost
Solution Approach 1:
The patent uses secreted cytokines (IL-7, CCL19) as intermediary molecules that diffuse from modified T cells to affect both autologous and neighboring unintroduced T cells. This intermediary approach allows the regulatory signals to act as mobile mediators that can enhance the function of unintroduced T cells in the microenvironment while maintaining autologous transduction capabilities
Solution Approach 2:
The invention transitions from membrane-bound autocrine signaling to secreted paracrine signaling by using soluble cytokines instead of membrane-bound forms. This dimensional change from surface-confined signals to freely diffusing molecules enables the regulatory factors to affect cells beyond the immediate autologous cell, thereby enhancing unintroduced T cells while preserving autologous transduction
Data Source
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AI summary
It is to provide an immunocompetent cell that expresses regulatory factors of immunocompetent cell immune function and possesses all of proliferative potential, viability, and the ability to accumulate a T cell, and an expression vector of regulatory factors of immune function for generating the immunocompetent cell. An immunocompetent cell expressing a cell surface molecule specifically recognizing a cancer antigen, interleukin 7 (IL-7), and CCL19 is generated. Preferably, the cell surface molecule specifically recognizing a cancer antigen is T cell receptor specifically recognizing the cancer antigen, and the immunocompetent cell is a T cell.