Codon-Optimized c-Jun Sequences for CAR T Cell Persistence
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Solution Overview
Problem
Cancer immunotherapy with CAR T cells faces challenges such as limited CAR T expansion, exhaustion, and loss of persistence, leading to reduced clinical efficacy and potential relapse, necessitating improved treatment options with a better safety profile and higher efficacy.
Innovation Solution
Development of codon-optimized nucleotide sequences encoding an AP-1 transcription factor, which can be integrated into immune cells to enhance their anti-tumor activity by increasing the expression of c-Jun polypeptide, thereby improving the persistence and efficacy of CAR T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used for cancer immunotherapy, then tumor cells can be targeted and killed, but CAR T expansion is limited and cells become exhausted leading to loss of persistence and clinical efficacy
Solution Approach 1:
The patent applies codon optimization to the c-Jun gene sequence to modify nucleotide parameters while maintaining amino acid sequence. This changes the codon usage frequency to match host cell preferences, thereby improving translation efficiency and protein expression levels. The codon-optimized c-Jun sequence enables sustained expression of the transcription factor, which in turn maintains CAR T cell persistence and clinical efficacy over time by preventing exhaustion
2Productivity
If CAR T cells are infused to treat cancer, then immune attack on tumor cells is enhanced, but exhaustion and loss of persistence occur reducing long-term efficacy
Solution Approach 1:
The patent implements preliminary action by pre-optimizing the c-Jun gene sequence through codon optimization before introducing it into CAR T cells. This preparatory modification ensures that the transcription factor is efficiently expressed from the outset, establishing a foundation for sustained anti-tumor activity and preventing early exhaustion. The codon-optimized sequence is designed in advance to maximize protein production and maintain cellular functionality throughout treatment
Data Source
AI summary
Disclosed herein are polynucleotides comprising a nucleotide sequence encoding an AP-1 transcription factor (i.e., c-Jun). In some aspects, the nucleotide sequence is codon-optimized. In some aspects, the polynucleotides comprise one or more additional nucleotide sequences encoding a linker, signal peptide, antigen-binding domain, spacer, transmembrane domain, costimulatory domain, intracellular signaling domain, truncated EGFR, and combinations thereof. Also disclosed herein are cells, vectors, and pharmaceutical compositions comprising such polynucleotides. The use of such polynucleotides, cells, vectors, and pharmaceutical compositions to treat a disease or disorder (e.g., cancer) is also provided.