Written by Charlotte Harrison, Science Writer.
Chimeric antigen receptor (CAR)-T cell therapies are highly successful, but they are currently engineered to recognise just one specific protein on cancer cells. This means they need to be re-designed and re-administered if the protein mutates or is downregulated.
Now, researchers from the University of Pittsburgh have developed a universal receptor system that allows T cells to recognize any, and more than one, cell-surface target. The technology was also used to create a therapeutically relevant synthetic Notch receptor.
SNAPpy CAR-T cells
To expand the targeting capabilities of CARs, the researchers developed a system in which receptor specificity could be directed post-translationally.
A SNAPtag — a self-labelling protein — was genetically fused to the receptor. This tag enabled the receptor to covalently attach to an antibody bearing a benzylguanine motif that was given to mice or cells at the same time as the receptor. In this way, the antibody was used to programme antigen recognition, and was strongly attached to the receptor that mediates the immune response.
The authors showed that in mice, the antibodies attached to the SNAP–CAR-T cells in the blood. Of note, the SNAP–CAR-T cells together with the antibody shrank tumours and prolonged the survival of mice, and these effects were comparable to those of traditional CAR-T cells.
Excitingly, the SNAP–CAR-T technology has the potential to enter clinical studies, as it has already been licenced.
Synthetic Notch (synNotch) receptors are another class of antigen receptors with therapeutic potential. They can be engineered to target cell-surface antigens to regulate any gene of interest.
The researchers created a SNAP–synNotch receptor that was activated by an antibody in cell-based assays, where it activated cytokine-response genes.
The covalent bond between the synNotch receptor and the SNAPtag was found to be key to creating active SNAP-SynNotch cells. An advantage of this tight bond is that SNAP–synNotch cells should be active even when the interaction between the antibody and tumour cells is weak, giving greater scope to the type of cancer proteins that can be targeted.
“This SNAP-SynNotch system is super programmable because you can have both designer input and designer gene output,” said author Jason Lohmueller in a press release. “Our hope is that we can use this approach to make cell therapies and deliver genes for cancer, autoimmune disorders, organ transplantation tolerance and more.”