Engineered T Cell Generation Without Expansion for Higher Potency
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing processes for generating genetically engineered T cells, such as those expressing a chimeric antigen receptor (CAR), are time-consuming and may result in cell populations with low potency or persistence, necessitating improved manufacturing methods for cell therapy applications.
Innovation Solution
A method involving exposing primary T cells to a stimulatory reagent, introducing a viral vector encoding a recombinant protein, and harvesting the transformed cells within specific time frames to achieve a composition of engineered T cells with enhanced potency and stability, characterized by high percentages of naïve-like and central memory T cells, and controlled integrated vector copy numbers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing processes for generating genetically engineered T cells are used, then the cells can be engineered with recombinant receptors, but the process is time-consuming and produces cell populations with low potency or persistence
Solution Approach 1:
The patent applies preliminary action by stimulating T cells with anti-CD3 and anti-CD28 antibodies before viral transduction to achieve optimal cellular state for receptor expression. This pre-stimulation phase prepares the cells to maximize CAR expression and functional potency while controlling the overall timeline through subsequent harvesting at specific time points (48-120 hours) when integrated vector copy number is stable but differentiation is limited.
2Stability of the object's composition
If T cells are harvested at later time points to increase vector integration stability, then integrated vector copy number increases, but cell differentiation and exhaustion increase reducing potency
Solution Approach 1:
The patent applies dynamics by establishing a dynamic harvesting window (48-120 hours) that captures the optimal balance between vector integration stability and cell potency. The process monitors integrated vector copy number over time and harvests when stability is achieved but before excessive differentiation occurs, creating a dynamic optimization point that balances these competing requirements.
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
The method generates engineered T cell compositions within a shortened timeframe, resulting in less differentiated, more potent, and persistent cell populations suitable for cell therapy, with improved efficiency and effectiveness.
Implementation Method 1
introducing into T cells of the stimulated population, a viral vector comprising a heterologous polynucleotide encoding a recombinant protein
Data Source
AI summary
The present disclosure provides processes for genetically engineering T cells, such as primary CD4+ T cells and/or CD8+ T cells, for use in cell therapy that does not involve expanding the cells. In particular aspects, the provided processes successfully generate compositions of engineered T cells, such as containing populations of engineered T cells, that express a chimeric antigen receptor (CAR) within a shortened amount of time as compared to alternative engineering processes, such as processes that involve expanding the cells. In certain aspects, the provided processes successfully generate a composition of engineered T cells suitable for use in cell therapy within 4 days from when the process to stimulate or activate the cells is initiated. In some aspects, the resulting engineered cell compositions are composed of cell population that are less differentiated, less exhausted, and more potent than engineered T cell compositions generated by other means, such as by processes that involve expanding the cells. Also provided are compositions of T cells generated by the provided methods and their uses for treating subjects.