Donor-Batched CAR-T Cell Production for Consistency
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Solution Overview
Problem
Existing methods for producing engineered T cell compositions, such as those used in cell therapy, often result in inconsistent cell populations with low potency and persistence in vivo, particularly when using chimeric antigen receptors, necessitating improved manufacturing and engineering techniques.
Innovation Solution
A method involving the selection and genetic engineering of T cells from multiple donors to enrich for CD57 negative and/or CD27 positive T cells, followed by the introduction of a recombinant receptor, with steps including knocking out endogenous MHC or T cell receptor components and combining the engineered T cell compositions to enhance consistency and potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing methods for producing engineered T cell compositions are used, then the production process is simpler, but the cell population consistency and potency are low
Solution Approach 1:
The patent segments the T cell production process into distinct stages: donor selection based on specific criteria (CD57-, CD27+, naive T cell enrichment), individual donor processing, genetic engineering with recombinant receptors, and pooled combination. This segmentation allows each stage to be optimized independently, improving overall cell population consistency while maintaining manageable process complexity through standardized protocols at each step.
Solution Approach 2:
The patent applies parameter changes by selecting T cells based on specific surface marker expressions (CD57 negativity, CD27 positivity, naive T cell markers) and controlling genetic engineering parameters (recombinant receptor integration). These parameter specifications transform the production process from a general procedure to a precisely controlled manufacturing process, directly improving cell population consistency and potency.
2Reliability
If T cells are engineered with recombinant receptors from multiple donors, then the therapeutic efficacy is improved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent implements preliminary action by pre-selecting donors and pre-enriching naive T cells before genetic engineering. Donors are screened for specific characteristics (CD57-, CD27+, naive T cell markers) and T cells are expanded and activated in advance. This preliminary preparation simplifies the subsequent manufacturing steps and ensures high-quality starting material, improving therapeutic efficacy while making the overall process more manageable.
Solution Approach 2:
The patent merges individual engineered T cell compositions from multiple pre-screened donors into a pooled product. This combining approach diversifies the cell population source, improving therapeutic efficacy and consistency by averaging out donor-specific variations, while the standardized individual processing steps keep the manufacturing complexity controlled.
3Reliability
If CD57 negative and CD27 positive T cells are enriched, then the potency and persistence in vivo are improved, but the selection process becomes more difficult
Solution Approach 1:
The patent uses flow cytometry-based selection which detects surface markers through fluorescent labeling (analogous to color changes). T cells are stained with fluorescently labeled antibodies against specific markers (CD57, CD27, naive T cell markers) and sorted based on fluorescence intensity. This transforms the difficult task of selecting rare cell populations into a straightforward optical detection and sorting process, improving persistence in vivo while reducing selection difficulty.
Data Source
AI summary
Provided herein are methods of producing engineered T cell compositions enriched for CD57 negative and/or CD27 positive T cells, such as from a plurality of donors. In some embodiments, the T cells are engineered with a recombinant receptor, such as a chimeric antigen receptor (CAR). Also provided herein are engineered T cell compositions containing T cells enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of different donors, including compositions in which the T cells are engineered with or express a recombinant receptor (e.g. CAR). Also provided are methods of using the engineered T cell compositions in adoptive therapy, including in connection for cancer immunotherapy, such as for allogeneic therapies or for administration to one or more subjects in which the T cells are not derived from the subject(s) to whom the compositions are administered.