Exogenous control of CAR-T performance with RNA-based gene regulation
Krista McNally*, Jay Danao*, Melissa Fardy, Joe Solvason, Anna Müeller, Ben Wang and Gus Zeiner
Chimera Bioengineering Inc., South San Francisco, CA, USA
*These authors contributed equally
Chimeric antigen receptor (CAR) technology holds promise as a universal modality for cancer treatment. To date, constitutively active CARs have demonstrated impressive clinical efficacy for the treatment of several B-cell malignancies in patients, but CARs have shown measured success for the treatment of other types of cancers. To improve CAR performance with B-cell malignancies, and to expand the application horizon of CAR technology to other types of cancers, we are developing extensible RNA-based gene regulation technologies that can be used in conjunction with all CAR transgenes. Here we describe our progress towards exogenous control of CAR-T cell (CAR-T) behaviors using two independent RNA-based gene regulatory technology platforms. The first platform, called ‘SynRib’, is comprised of customizable, ligand-responsive gene regulators that affect CAR-T behavior through modulation of CAR mRNA stability. The second platform, called ‘Gold’, amplifies CAR-T effector outputs by coupling CAR transgene expression to CAR-T activation. Our hypothesis is that RNA-based control platforms will yield persistent and potent CAR-T therapeutics that resist immunogenic clearance and enable real-time tuning of CAR-T performance.