A Novel, Universal Targeting Receptor-Adaptor CAR Platform Demonstrates Versatile, Flexible, and Controlled Tumor Inhibition in an Ipsc-Derived T-Cell

Despite positive outcomes in some hematological oncology patients, several barriers to current autologous CAR T-cell therapies exist that prevent broader clinical success. These include tumor antigen escape, on-target off-tumor toxicities, and limited patient access to treatment. To increase safety and efficacy of CAR T-cell therapies, we are developing a Universal CAR (UCAR) that is activated through a soluble tumor targeting protein that pairs specifically with the UCAR. The UCAR approach enables a single CAR T-cell to target many different antigens through alternative targeting proteins to address antigen escape and tumor heterogeneity. Additionally, greater control of the activity of the cells within a patient is possible since effector activity is regulated through the dosing of the soluble protein. UCAR platforms are particularly interesting for inclusion into allogeneic cell therapy products, as the combination of these technologies enables a fully universal and “off-the-shelf” cell therapy cell line.

Here, we describe the development and functional assessment of the Universal Targeting Receptor-Adaptor Platform (UTRAP), an adaptable, highly specific, and developable system comprised of a novel UCAR and a soluble Bispecific Anti-Idiotype Targeting (BAIT) protein. We demonstrate that T-cells engineered with UTRAP have tunable activity that elicits robust cytotoxicity and tumor control, equivalent to a conventional CAR T-cell in vitro and in vivo. Our results show the flexibility of the antibody-based platform including multi-specific targeting and antigen swapping. Finally, we demonstrate that UTRAP is fully functional in allogeneic iPSC-derived gamma delta T-cells. These results pave the way for UTRAP to be used in any cell type advancing towards a truly universal, off-the-shelf cell therapy product that can adapt to target any tumor type.

Devaney:Century Therapeutics: Current Employment. Carton:Century Therapeutics: Current Employment. Hoffman:Century Therapeutics: Current Employment. Millar:Century Therapeutics: Current Employment. Walker:Century Therapeutics: Current Employment. Wheeler:Century Therapeutics: Current Employment. Miller:Century Therapeutics: Current Employment. Dower:Century Therapeutics: Current Employment. Morse:Century Therapeutics: Current Employment. Levitsky:Century Therapeutics: Current Employment, Current equity holder in publicly-traded company. Naso:Century Therapeutics: Current Employment.