Hung Trinh, Senior VP of Operations at Seneca Therapeutics and CMC/MFG Consultant and Managing Director at Vertex Biopharm Consulting, shared a post on LinkedIn:
“BACH2 regulates T cell lineage state to enhance CAR T cell function
- BACH2 redirects lineage states to enhance CAR T cell function
Based on BACH2’s known function, we hypothesized that BACH2 was responsible for the enhanced function of 22/BB-S and could enhance the function of 22/28-S. - Tuning BACH2 enhances long-term CAR T cell function
We hypothesized that this lineage restriction was a result of maintained BACH2 expression throughout long-term engagement with tumor. To test this, we linked transgenic BACH2 to a degradation domain (DD) derived from Escherichia coli dihydrofolate reductase (ecDHFR - High expression of BACH2 during manufacture alone is sufficient to limit long-term T cell function and that low-level expression of BACH2 compels similar efficacy driven by 22/BB-S.
Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as ‘tonic signaling’. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs.
Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.”
Title: BACH2 regulates T cell lineage state to enhance CAR T cell function
Authors: Tien-Ching Chang, Amanda Heard, John Lattin, John M. Warrington, Amanda Barrett, Jack H. Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, Haorui Song, A. J. Federico, Avery Horn, Michael P. Meers, Evan W. Weber, Thomas J. Wandless, Jeremy Chase Crawford, Paul G. Thomas, John F. DiPersio, Nathan Singh
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