T Cell iPSC Reprogramming for Antigen-Specific Production
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Solution Overview
Problem
Current methods for producing cancer-reactive T cells for adoptive cell therapy are time-consuming and inefficient, often requiring prediction algorithms and extensive sequencing to identify appropriate T cell receptors (TCRs) for tumor antigens, limiting their availability for patients.
Innovation Solution
A method involving the isolation and culturing of T cells from patient samples to produce T cell-induced pluripotent stem cells (iPSCs), which are then differentiated into CD4−CD8− double negative T cells, allowing for the identification and expansion of T cells with specific TCR alpha-chain and beta-chain pairs for antigenic specificity, thereby bypassing the need for predictive algorithms and extensive sequencing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods are used to produce cancer-reactive T cells, then T cells with specific antigenic specificity can be obtained, but the process is time-consuming and requires extensive sequencing and prediction algorithms
Solution Approach 1:
The patent uses induced pluripotent stem cells (iPSCs) as copies of the original T cells. The iPSCs are generated by reprogramming T cells and then differentiated back into T cells with the same TCR specificity, allowing rapid production without extensive sequencing. This copying approach preserves antigenic specificity while dramatically reducing production time.
Solution Approach 2:
The patent changes the developmental parameters of T cells by regressing them to a pluripotent state and then re-differentiating them. This parameter change allows the T cells to be produced through a standardized protocol rather than requiring identification of specific TCR sequences, thus reducing time while maintaining specificity.
2Measurement precision
If current methods are used to produce cancer-reactive T cells, then T cells with specific antigenic specificity can be obtained, but the process is complex and requires prediction algorithms
Solution Approach 1:
By creating iPSC copies of the original T cells, the patent eliminates the need for complex prediction algorithms and extensive sequencing. The iPSC approach provides a direct pathway to generate T cells with desired specificity through a simpler, more standardized process.
Solution Approach 2:
The iPSCs serve as an intermediary between the original T cells and the final T cell product. This intermediary allows the complex task of generating specific T cells to be broken down into simpler steps: reprogramming to iPSC state, then differentiating to desired T cell type, thereby reducing overall process complexity.
3Reliability
If current methods are used to produce T cells for ACT, then T cells with desired TCRs can be identified, but the process is inefficient and limits availability for patients
Solution Approach 1:
The iPSC copying method allows for efficient T cell production by creating multiple copies of the original T cell through differential cloning. This approach dramatically increases productivity while maintaining reliable TCR identification, as the iPSCs inherit the TCR specificity from the original T cells.
Solution Approach 2:
By changing the cellular state parameter from mature T cell to pluripotent stem cell and back, the patent enables efficient scaling of T cell production. This parameter change allows for batch processing and standardization, improving both productivity and reliability of TCR identification.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces the time and cost of producing T cells with specific antigenic specificity, enabling more efficient and rapid generation of T cells for adoptive cell therapy, applicable for cancer, infections, and autoimmune conditions, with enhanced tumor-antigen specific reactivity.
Implementation Method 1
culturing the separated T cells of b) to produce T cell induced pluripotent stem cells (iPSCs)
Implementation Method 2
culturing the T cell iPSCs of c) to produce CD4−CD8−(double negative) T cells
Implementation Method 3
screening the CD4−CD8−(double negative) T cells to identify one or more CD4−CD8−(double negative) T cells that comprise a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest
Data Source
AI summary
Provided are methods of producing an isolated population of T cells for adoptive cell therapy. Also provided are related isolated populations of cells, pharmaceutical compositions, and methods of treating or preventing cancer, infections, and autoimmune conditions in a patient.