Short hairpin RNA (shRNA) technology offers a differentiated strategy to future development of CAR T-cell therapies
Manipulating protein expression to generate cells with a specific desired feature is one of the central goals of engineered cell therapy. Short hairpin RNA (shRNA) is a well-established approach to reduce protein expression by silencing genes in a process called RNA interference.
Celyad Oncology’s shRNA technology allows for the modulation of gene expression in our CAR constructs without the need for gene-editing. We are currently engineering T-cells with specific desired features, including the reduced alloreactivity, increased persistence and enhanced anti-tumor activity or potentially improved tolerability. We have validated the utility, versatility and safety of our shRNA platform through our clinical pipeline candidates. Our next-generation NKG2D-based CAR T-cell clinical candidate, CYAD-02, incorporates a single shRNA hairpin targeting the NKG2D ligands MICA/MICB within the construct, and our BCMA-targeting CAR T-cell candidate, CYAD-211, incorporates a single shRNA hairpin targeting the CD3ζ component of the TCR complex.
Innovative multiplexing technology goes beyond allogeneic CAR T-cell therapy
The shRNA technology was first validated by creating off-the-shelf allogeneic CAR T-cells where the expression of CD3ζ was modulated in the CYAD-211 product candidate.
The shRNA technology can be further adapted through multiplexing: shRNA multiplexing is a unique capability where multiple genes can be modulated simultaneously, whether cell source is of autologous or allogeneic origin.
Our shRNA platform provides a versatile approach to control gene expression and optimize function of T-cells.
Thereby multiplexing allows to:
- Optimize CAR T-cell features, e.g. persistence, efficacy, or ability to evade complex or immunosuppressive tumor microenvironments, by modulating genes involved in alloreactivity, allorejection, fratricide, T-cell persistence and/or immunosuppression,
- Provide potential for broad therapeutic functionality, which is especially important in the context of solid tumors,
- Be complementary to our All-in-One Vector approach to express multiple shRNAs in a single construct within a single transduction step.