TCR-T Cell Isolation via Tumor Infiltrating Marker Selection
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Solution Overview
Problem
Current TCR-T cell therapies for tumor treatment are limited by the scarcity of shared tumor antigens among patients, requiring individualized TCR-T cells that recognize unique tumor antigens, which is complicated by the mixture of antigen-specific and non-specific T cells in tumor tissues, making it difficult to quickly and accurately identify and isolate tumor antigen-recognizing T cells.
Innovation Solution
The method involves identifying and isolating T cells expressing specific molecular markers such as TNFRSF18, CXCL13, and ENTPD1 in CD4 T cells and TNFRSF18, CXCR6 in CD8 T cells, using flow sorting and in-situ sequencing, to derive TCRs that recognize tumor antigens, and constructing TCR-T cells for individualized therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional TCR-T cell therapy targeting known tumor antigens is used, then treatment can be provided for patients expressing both tumor antigens and corresponding HLA subtypes, but the number of treatable patients is very limited due to scarcity of shared tumor antigens
Solution Approach 1:
The patent enables patients to generate their own therapeutic T cells by isolating tumor-infiltrating T cells from their own tumor tissue. These patient-specific T cells naturally recognize the patient's unique tumor antigens, eliminating the need for matching known antigens with patient HLA subtypes. This self-service approach allows any patient with tumor-infiltrating T cells to be treated, dramatically expanding applicability.
Solution Approach 2:
The patent changes the selection criterion from targeting known tumor antigens with specific HLA restrictions to targeting any T cell that has naturally infiltrated the tumor tissue. This parameter change from antigen-specific selection to location-based selection (tumor infiltration) allows treatment of patients with diverse tumor antigens and HLA types.
2Measurement precision
If T cells are isolated from tumor tissue to obtain tumor antigen-specific TCRs, then individualized TCR-T cells can be created, but the process is complicated by the mixture of antigen-specific and non-specific T cells
Solution Approach 1:
The patent uses fluorescent markers (color changes) to label and distinguish different T cell populations based on their gene expression profiles. By staining cells with fluorescent antibodies against specific genes and using flow cytometry to detect fluorescence, the system can precisely identify and isolate tumor antigen-specific T cells from the mixed population without complex manual sorting procedures.
Solution Approach 2:
The patent replaces manual or mechanical sorting methods with flow cytometry-based separation. Instead of physically sorting cells through complex mechanical processes, the system uses fluorescent labeling combined with flow cytometry to automatically identify and separate specific T cell populations based on their molecular markers, significantly simplifying the isolation process.
3Measurement precision
If comprehensive identification and analysis of tumor antigens in T cells is performed, then accurate TCR-T cells can be obtained, but the systematic identification remains impossible due to extremely complicated processes and high technical difficulty
Solution Approach 1:
The patent extracts only the essential identifying feature of tumor antigen-specific T cells—their location within tumor tissue and their specific gene expression profile—rather than attempting to comprehensively analyze all aspects of tumor antigens. By focusing on these key extracted features, the method achieves accurate identification without the need for exhaustive systematic analysis of all tumor antigens and T cell characteristics.
Solution Approach 2:
The patent segments the complex identification process into distinct steps: first isolating tumor-infiltrating T cells based on location, then analyzing their gene expression profiles to identify specific markers, and finally sorting them based on these markers. This segmentation breaks down the overwhelming task of comprehensive tumor antigen identification into manageable, sequential steps that can be performed with current technology.
Data Source
AI summary
The present disclosure provides a TCR-T cell for tumor-killing, wherein the TCR-T cell is a T cell carrying a TCR that recognizes a tumor antigen, and the TCR in the TCR-T cell is derived from any one or more of the following T cells: 1) a CD4 T cell expressing one or more of TNFRSF18, CXCL13, TNFRSF4, TNFSF8, ENTPD1, ACP5, LAYN, TNFRSF9, CTLA4, CD200 and TIGIT genes in the tumor; and 2) a CD8 T cell expressing one or more of TNFRSF18, CXCL13, CXCR6, GALNT2, ENTPD1, ACP5, HAVCR2, LAYN, TNFRSF9, CTLA4 and CD109 genes in the tumor. The TCR-T cell according to the present disclosure can be effectively applied to the treatment of a tumor, especially in an immunotherapy.