T Cell Modification via TCR Transfer for Solid Tumors
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Solution Overview
Problem
Current approaches to treating solid tumors with adoptive transfer of polyclonal tumor-infiltrating T cells are hindered by the variability in tumor-specificity of T cell products and the dysfunctional state of tumor-infiltrating T cells, leading to inconsistent robustness and limited efficacy.
Innovation Solution
A method involving the identification of expanded T cell clonotype families with exhaustion markers through single-cell TCR sequencing and transcriptome analysis, followed by modifying non-exhausted T cells with TCR sequences from exhausted T cells to enhance antitumor reactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If polyclonal tumor-infiltrating T cells are used for adoptive transfer, then tumor-specificity coverage is improved, but functional robustness deteriorates due to variable exhaustion states
Solution Approach 1:
The patent segments the T cell population by identifying and isolating specific clonotype families with exhaustion markers through single-cell TCR sequencing and transcriptome analysis. This segmentation allows selection of T cell clones with desired tumor-reactivity while excluding exhausted dysfunctional clones, thereby resolving the contradiction between coverage and robustness.
Solution Approach 2:
The patent applies local quality by modifying only the TCR specificity of selected T cell clones rather than treating the entire polyclonal population uniformly. Through TCR gene transfer into allogeneic or autologous T cells, the invention confers tumor-reactivity specifically to selected clones, ensuring functional robustness while maintaining tumor-specificity coverage.
2Adaptability or versatility
If exhausted T cells are directly transferred, then tumor-reactivity is improved, but functional activity deteriorates due to dysfunctional state
Solution Approach 1:
The patent extracts the beneficial TCR sequences from exhausted tumor-reactive T cells through single-cell sequencing, separating the tumor-reactivity capability from the dysfunctional exhausted state. The extracted TCR genes are then transferred to healthy, non-exhausted T cells, achieving tumor-reactivity without the functional limitations of exhaustion.
Solution Approach 2:
The patent creates copies of the TCR genes identified in exhausted tumor-reactive T cells and transfers them into healthy T cell hosts. This copying approach preserves the tumor-reactivity specificity while eliminating the dysfunctional exhausted phenotype, as the TCR is expressed in a functionally competent T cell background.
3Measurement precision
If single-cell sequencing methods are used to identify TCR sequences, then identification precision is improved, but process complexity increases
Solution Approach 1:
The patent applies preliminary action by performing single-cell TCR sequencing and transcriptome analysis upfront to identify and characterize TCR sequences and their associated exhaustion markers before T cell modification. This preliminary identification precision enables subsequent targeted TCR gene transfer, avoiding the need for complex iterative screening processes.
Data Source
AI summary
Disclosed are methods for identifying expanded, exhausted, and tumor-specific T-cell clonotypes for adoptive cell transfer, and methods of cancer treatment and modified T cells with anti-tumor T cell receptors (TCRs).