Tumor Labeling Polypeptides for CAR-T Targeting in Solid Tumors
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Solution Overview
Problem
Current CAR-T cell therapy faces challenges in treating solid tumors due to heterogeneous tumor antigens, difficulty in finding suitable targeted sites, off-target toxicity, poor tumor homing, and strong immunosuppressive tumor microenvironments, limiting its effectiveness.
Innovation Solution
A therapeutic agent combining a nucleic acid encoding a labeling polypeptide and a chimeric antigen receptor-modified immune cell, where the labeling polypeptide is expressed on tumor cells to enhance recognition and the CAR-modified immune cells target this polypeptide, aided by oncolytic viruses to disrupt the tumor microenvironment and improve homing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat solid tumors, then immune system activation occurs, but treatment effectiveness is limited due to heterogeneous tumor antigens and poor tumor homing
Solution Approach 1:
The therapy is divided into two distinct components: (1) nucleic acids encoding labeling polypeptides that are introduced into tumor cells to express uniform surface markers, and (2) CAR-modified immune cells that specifically recognize these labeled markers. This segmentation allows the system to overcome tumor antigen heterogeneity by creating a standardized target that all tumor cells express uniformly.
Solution Approach 2:
The labeling polypeptide acts as an intermediary between the tumor cells and the CAR-modified immune cells. By introducing this artificial marker through nucleic acid delivery, the system creates a reliable recognition target that mediates specific binding and killing of tumor cells, bypassing the problem of natural antigen heterogeneity.
2Measurement precision
If CAR-modified immune cells are used to target tumor cells, then specific recognition is achieved, but off-target toxicity occurs
Solution Approach 1:
The labeling polypeptide is specifically expressed only on tumor cells through targeted nucleic acid delivery, creating a localized quality difference between tumor and normal cells. The CAR-modified immune cells then specifically recognize this localized marker, ensuring precise targeting and avoiding off-target toxicity to healthy tissues that do not express the labeling polypeptide.
3Reliability
If CAR-T cells are administered to treat solid tumors, then immune surveillance is activated, but tumor homing is poor due to dense matrix barriers
Solution Approach 1:
The labeling polypeptide serves as a chemoattractant intermediary that guides CAR-modified immune cells toward tumor locations. By expressing this marker on tumor cells, the system creates a chemical gradient that mediates the homing process, enabling immune cells to navigate through dense matrix barriers more effectively than through passive diffusion alone.
Data Source
AI summary
Provided are therapeutic agent including nucleic acid and CAR-modified immune cell and the use thereof. The therapeutic agent comprises first composition and second composition, the first composition comprises a nucleic acid having a labeling polypeptide coding sequence for being introduced into a tumor cell and/or a cancer cell; the labeling polypeptide has an extracellular antigen determining region, a spacer portion, a transmembrane portion that are operatively linked, which can be expressed to form modification on the surface of the tumor cell and/or cancer cell; the extracellular antigen determining region comprises one or more epitope polypeptides; wherein, amino acid sequences of proteins on cell membrane or secreted proteins of mammal do not comprise the epitope polypeptide amino acid sequence in the natural state; the second composition comprises chimeric antigen receptor modified immune cell which specifically recognize and bind to the extracellular antigen determining region. The therapeutic agent achieves synergistic therapeutic effect.