CAR-T Cell Genetic Modification for Persistent Antitumor Function
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Solution Overview
Problem
Existing CAR-T cell therapies face challenges in enhancing the persistence, proliferation, and function of T cells, particularly under hostile conditions, leading to tumor relapse and suboptimal therapeutic efficacy.
Innovation Solution
Introduce a genomic editing construct, such as a function-booster gene, into modified T cells to enhance persistence, proliferation, and cytotoxicity, and combine it with a CAR expression, using transposons and transposases for efficient genetic delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If electroporation is used to deliver large DNA molecules into T cells, then genetic modification can be achieved, but the process becomes inefficient and cellular viability is compromised
Solution Approach 1:
The patent extracts the harmful effect of electroporation by separating the DNA delivery function from the electroporation process. Instead of using electroporation to deliver large DNA molecules directly, the invention uses viral vectors (lentivirus, retrovirus) that naturally package and deliver genetic material efficiently without compromising cell viability through electrical shock.
Solution Approach 2:
The patent introduces viral vectors as intermediary carriers between the DNA and T cells. These viral vectors serve as mediators that efficiently transfer genetic material into T cells without requiring electroporation, thus resolving the contradiction between delivery efficiency and cell viability.
2Adaptability or versatility
If T cells are engineered with anti-CD19 CAR, then tumor targeting capability is improved, but persistence and efficacy are reduced in heavily pre-treated patients
Solution Approach 1:
The patent combines multiple therapeutic functions into a single CAR construct. The multi-functional CAR integrates tumor targeting (anti-CD19), costimulatory signals (4-1BB, CD28), and survival signals (Bcl-xL, survivin) into one engineered receptor, allowing T cells to simultaneously achieve tumor targeting, persistence, and enhanced efficacy even in pre-treated patients.
Solution Approach 2:
The patent creates a composite CAR structure combining multiple functional domains: antigen recognition domain (anti-CD19), costimulatory domains (4-1BB, CD28), and survival domains (Bcl-xL, survivin). This composite design allows the single CAR construct to provide multiple beneficial functions that resolve the contradiction between targeting capability and in vivo persistence.
3Productivity
If ex vivo culture conditions are optimized for T cell expansion, then proliferation is improved, but persistence under hostile in vivo conditions deteriorates
Solution Approach 1:
The patent applies local quality by providing different functional capabilities in different contexts. The CAR-T cells are engineered with specific domains that activate or function appropriately in different environments: costimulatory domains for ex vivo expansion and survival domains (Bcl-xL, survivin) for in vivo persistence under hostile conditions. This localized functional optimization resolves the contradiction between expansion and persistence.
Solution Approach 2:
The patent creates dynamic adaptability in CAR-T cells through engineered responsiveness to different environmental cues. The CAR construct with multiple signaling domains allows cells to dynamically adjust their behavior - proliferating under favorable ex vivo conditions and activating survival pathways under hostile in vivo conditions, thus resolving the contradiction between expansion and persistence.
Data Source
AI summary
Modified immune cells are provided, the modified immune cells expressing a heterologous polynucleotide comprising a nucleotide sequence encoding a function (e.g., at least one of persistence, proliferation, or cytotoxicity) booster, e.g., an apoptosis inhibitor. In one aspect, the modified T cells further comprise a chimeric antigen receptor. Methods, kits, and components for making and using the modified immune cells are also provided.