CAR-T Cell Transduction Timing for Persistence
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Solution Overview
Problem
Current CAR-T cell immunotherapies face limitations due to poor T cell expansion and persistence in vivo, primarily due to rapid differentiation and exhaustion, which restricts their clinical efficacy.
Innovation Solution
Co-expressing a Chimeric Antigen Receptor (CAR) with specific transcription factors such as FOXO1, EOMES, Runx3, and BACH2 in T cells to prevent or reduce differentiation and exhaustion, thereby maintaining a higher proportion of naïve and central memory T cells, enhancing persistence and expansion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If T cells are activated and expanded ex vivo prior to transduction, then a clinically effective therapeutic dose of T cells is generated, but the T cells undergo substantial differentiation resulting in short-lived survival and lack of persistence in vivo
Solution Approach 1:
The patent applies preliminary action by transducing T cells with CAR-encoding vectors before activation and expansion, rather than after. This ensures that the T cells are already genetically modified with the desired CAR sequence before they undergo differentiation during expansion, allowing the modified cells to persist longer in vivo while still achieving the required therapeutic dose
Solution Approach 2:
The patent changes the temporal parameter of the process by reversing the conventional sequence: instead of activating/expanding first then transducing, the T cells are transduced first and then activated/expanded. This parameter change in the process sequence resolves the contradiction between achieving sufficient cell numbers and maintaining cell persistence
2Productivity
If T cells are activated and expanded prior to transduction, then sufficient T cells are available for therapy, but the T cells exhaust and differentiate rapidly limiting clinical efficacy
Solution Approach 1:
The invention performs the transduction action preliminarily before activation and expansion, ensuring that T cells acquire the CAR phenotype before undergoing proliferation. This preliminary genetic modification allows the expanded cell population to maintain therapeutic functionality and persistence, thereby preserving clinical efficacy while achieving the necessary productivity
3Ease of manufacture
If conventional CAR-T cell therapy is used, then T cells are generated for immunotherapy, but the T cells show poor expansion and persistence after infusion into patients
Solution Approach 1:
The patent implements preliminary transduction of T cells with CAR-encoding vectors before activation and expansion, ensuring that the T cells are pre-modified with the therapeutic CAR sequence. This preliminary action maintains ease of manufacture while fundamentally improving in vivo persistence, as the cells are already genetically equipped for long-term survival before entering the patient
Data Source
AI summary
The present invention provides a cell which comprises a first exogenous nucleic acid molecule encoding a Chimeric Antigen Receptor (CAR) and a second exogenous nucleic acid molecule encoding a transcription factor.