Tumor-Reactive T Cell Identification Using Biomarkers Before Expansion
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Solution Overview
Problem
Current methods for identifying tumor-reactive T cells are inefficient and can exhaust the cells during expansion, compromising their efficacy, particularly in non-melanoma cancers where the baseline fraction of tumor-reactive CD8+ T cells is low.
Innovation Solution
A method involving the determination of expression of specific biomarkers such as MAGEH1, HMGB2, TMSB10, and others in T cells to identify reactive T cells, enabling their identification and potential therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If T cells are expanded to enrich tumor-reactive T cells, then the fraction of tumor-reactive T cells is increased, but the T cells become exhausted and their tumor killing efficacy is compromised
Solution Approach 1:
The patent applies preliminary action by identifying tumor-reactive T cells using biomarker expression profiles (such as TOX, INFF1, and other transcription factors) before expansion occurs. This allows selection of cells with high tumor-reactive potential prior to the exhaustion-prone expansion process, thereby maintaining efficacy while still achieving enrichment of the desired cell population.
2Quantity of substance
If T cells are expanded to increase the number of reactive T cells, then the available T cells for therapy are increased, but clones are lost during the expansion process
Solution Approach 1:
The patent performs preliminary identification of tumor-reactive T cells through biomarker profiling (including surface markers and intracellular transcription factors) before expansion. This pre-selection ensures that the expansion process starts with a well-characterized population, allowing for controlled expansion that maintains clone diversity while achieving sufficient cell numbers for therapy.
3Ease of operation
If conventional biomarkers (CD69, Nur77) are used to identify tumor-reactive T cells, then the identification process is simple, but the value and accuracy of identified TCRs is limited
Solution Approach 1:
The patent transitions from using conventional surface biomarkers (CD69, Nur77) to a multi-parameter approach that includes intracellular transcription factors (TOX, INFF1, BACH2, etc.) and other markers. This parameter expansion provides more precise identification of tumor-reactive T cells and their TCRs, overcoming the limitations of simple surface marker-based methods.
Data Source
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Figure 3A~3B
AI summary
The present invention relates to a method of identifying a T cell reactive to target cells of a subject presenting a T cell activating epitope (reactive T cell), comprising (a) determining expression of at least one biomarker selected from the group consisting of MAGEH1, HMGB2, TMSB10, MGAT4A, C12orf57, GIMAP7, HSPE1, STMN1, IL32, TPT1, MIF, PALM2-AKAP2, ISCU, CCR8, UGP2, EEF1B2, SETD7, MESD, LINC02099, IFT52, AKIRIN2, RIOK3, ANKRD12, CALR, DDX5, CNST, GNPDA1, MALAT1, RGL4, B2M, IFITM2, PTPN11, BTG1, ITSN2, RAD21, FYB1, DDX21, HSPD1, JAK1, ADAM19, TM2D3, CASP8, CARS1, PTPN7, HAPLN3, CSTB, TLE5, ACTG2, IL2RA, CD99, TMSB4X, CCR4, and PCM1 in T cells from a sample of said subject; and (b) identifying a reactive T cell based on the determination of step (a). The present invention also relates to further methods, reactive T cells, and polynucleotides related thereto.