caTCF1 - An Engineered Transcription Factor to Supplement CAR T-cell Therapy
An engineered, constitutively active TCF1 to promote expression of memory-associated traits in CAR T cells
Memory T cells feature high proliferative potential and persistence, two characteristics that are advantageous in adoptive T-cell products. Indeed, CAR T cells generated from central memory cells provide superior antitumor activity compared to CAR T cells generated from other T-cell subsets. Current approaches to regulate T-cell differentiation have focused on manipulating cell culture conditions and using transcription factors to differentiate T cells away from the exhausted condition. TCF1 is a transcription factor that plays a key role in the differentiation of memory T cells and can sustain T cell activity even after prolonged antigen exposure. Notably, analysis of CAR T cells from CLL patients with better clinical outcomes showed elevated TCF1 expression levels.
Dr. Jensen and colleagues have developed a novel approach to promote memory associated traits in CAR T cells. They have engineered a constitutively active version of TCF1 (caTCF1) by fusing TCF1 with the trans-activating domain of β catenin. caTCF1 activated reporter gene expression independent of β catenin in vitro, and CD8 T cells expressing caTCF1 demonstrated higher expression of memory associated markers.
- Promotion of memory T-cell differentiation and/or delay of terminal effector differentiation
- CAR T-cell retention of memory-associated traits
- β catenin association independent activation of TCF1 driven transcription
- An engineered transcription factor that co-opts an endogenous transcriptional program
- Small DNA footprint of ~1.1 kilobases
The global T-cell therapy market was worth USD $2.4 billion in 2018 and is expected to grow at a CAGR of 15.4% from 2018 to 2027. The value of the CAR T-cell therapy market is expected to reach USD $2.9 billion by 2023, growing at a CAGR of 44.1% from 2018 to 2023.
Engineered transcription factor
Preclinical in vivo
Michael Jensen, MD
To learn more about this technology, please email Kamya Rajaram.