Genetically Engineered Cells Combining CCL21 and IL-7 for Solid-Tumor Efficacy
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Solution Overview
Problem
CAR-T cells exhibit limited efficacy on solid tumors and often fail to translate in vivo effectiveness despite showing promise in vitro.
Innovation Solution
Genetically engineered immune effector cells expressing an exogenous receptor specifically binding to a target antigen, exogenous CCL21, and an IL-7R-binding protein or IL-7 are developed, enhancing cell survival and proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used for tumor immunotherapy, then they can specifically kill tumors in an MHC non-restrictive manner, but they exhibit poor efficacy on solid tumors
Solution Approach 1:
The patent combines multiple functional elements into a single CAR-T cell construct: the CAR receptor for antigen recognition, CCL21 for immune cell infiltration and homing to tumor sites, and IL-7 for sustained proliferation and survival. This merging of functions addresses the limitation of poor solid tumor efficacy by simultaneously enabling target recognition, tumor site infiltration, and long-term persistence in the challenging solid tumor microenvironment
Solution Approach 2:
The invention creates a composite functional system within the CAR-T cell by integrating multiple transgenic components (CAR, CCL21, IL-7) that work synergistically. The CAR provides specific tumor recognition, CCL21 creates a chemotactic gradient for immune cell recruitment to the tumor, and IL-7 sustains cell survival and proliferation. This composite approach overcomes the single-function limitation that causes poor solid tumor efficacy
2Reliability
If a candidate drug shows excellent effects in vitro, then it demonstrates strong anti-tumor activity, but it often fails to show corresponding effects in vivo
Solution Approach 1:
The patent incorporates CCL21 into the CAR-T cell construct before in vivo administration. This preliminary action creates a chemotactic gradient that actively guides immune cells to the tumor site in the living organism, addressing the gap between in vitro efficacy (where target cells are directly exposed) and in vivo efficacy (where cells must navigate through tissue to reach tumors). The pre-loaded CCL21 ensures the cells can find and infiltrate solid tumors in the complex in vivo environment
Solution Approach 2:
CCL21 acts as an intermediary substance that mediates the interaction between CAR-T cells and the tumor microenvironment. It creates a chemical signal that bridges the gap between cell injection and tumor engagement, enabling the cells to locate and infiltrate solid tumors in vivo. This intermediary function explains the translation from in vitro activity to in vivo efficacy by providing the missing navigation and infiltration capability in the living system
Data Source
AI summary
Disclosed in the present invention is a genetically engineered cell, expressing an exogenous receptor that specifically binds to a target antigen and exogenous CCL21, and capable of further expressing an IL-7R binding protein or exogenous IL-7 that promotes cell proliferation. Also disclosed are an expression construct comprising an exogenous CCL21 expression cassette, and a vector containing same, a virus, and a pharmaceutical composition comprising said cell. Also disclosed is an application for the cell, the expression construct, the vector, and the virus in the preparation of drugs for inhibiting tumours or inhibiting pathogens.