CAR-T Cell Preparation With Antigen Depletion and CD4/CD8 Selection
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for producing genetically modified cells for adoptive cell therapy lack reproducibility, efficiency, and safety, leading to potential delays and risks due to the presence of cells expressing target antigens, particularly in cancer therapies.
Innovation Solution
A method involving depletion of cells expressing a target antigen followed by selection for CD4+ and CD8+ cells, combined with the introduction of a nucleic acid sequence encoding a CAR or transgenic TCR, to produce a more uniform and less differentiated population of genetically modified cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cells expressing target antigen are not depleted before genetic modification, then the manufacturing process is simpler and faster, but the safety and therapeutic efficacy are compromised due to presence of target antigen-positive cells
Solution Approach 1:
The patent applies preliminary action by depleting target antigen-positive cells from the starting population before introducing the CAR-encoding nucleic acid. This preemptive removal prevents the subsequent generation of antigen-positive genetically modified cells, ensuring safety while maintaining a streamlined process through targeted cell depletion followed by efficient transduction of the remaining cells
2Manufacturing precision
If a comprehensive cell depletion and selection method is used, then the uniformity and quality of genetically modified cells are improved, but the manufacturing time and process complexity increase
Solution Approach 1:
The patent performs preliminary depletion of target antigen-positive cells and preliminary selection for CD4+ and CD8+ cells before the transduction step. This ensures that only appropriate cell populations are genetically modified, achieving high uniformity and quality while the subsequent efficient transduction and expansion processes help mitigate time losses
Solution Approach 2:
The patent changes the parameters of the cell population by selecting for specific cell types (CD4+ and CD8+ cells) with defined characteristics. This parameter-based selection ensures uniformity and reproducibility of the genetically modified cell product, allowing for consistent quality across manufacturing batches
3Productivity
If target antigen-positive cells are present in the starting population, then more cells are available for genetic modification, but the resulting cell population has reduced therapeutic efficacy due to fratricide and off-target effects
Solution Approach 1:
The patent extracts and removes target antigen-positive cells from the starting population before genetic modification. This extraction eliminates the source of potential fratricide and off-target effects, ensuring that the resulting genetically modified cell population maintains high therapeutic efficacy while the remaining antigen-negative cells are efficiently transduced and expanded
Data Source
AI summary
The present invention provides a method of preparing a population of genetically modified cells which comprise a chimeric antigen receptor (CAR) or a transgenic T-cell receptor (TCR) comprising: (i) providing a starting population of cells; (ii) depleting said starting population of cells which express a target antigen to form a depleted starting population; (iii) selecting for CD4+ and CD8+ cells in the depleted starting population to form a selected population of cells; and (iv) introducing into a cell in the selected population a nucleic acid sequence which encodes a CAR or transgenic TCR against the target antigen.