The synNotch solution: UCSF scientists engineer a next-gen T-cell immunotherapy

CAR-T has been all the rage in cancer R&D for several years now as a slate of biotech upstarts pursue highly promising work reengineering T cells into attack weapons by adding a chimeric antigen receptor that can zero in on particular cancer cells. The approach has been highly effective in acute lymphoblastic leukemia, triggering an attack on B cells by homing in on the CD19 antigen, a breakthrough that has inspired a race to the regulatory finish line with the first CAR-Ts.

That approach, though, has run into some major obstacles when researchers move from the blood cancer to solid tumors. But now a group of scientists working with UC San Francisco's Wendell Lim say they've come up with a new therapeutic model for T-cell engineering that promises to overcome that hurdle and make it a more precise weapon that can tackle solid tumors while avoiding off-target reactions that threaten patients.

The key to this new approach is a new receptor: synNotch. Taking a cue from nature, which relies on a sensor called Notch to perform key functions, the synthetic biology engineers say they can add a receptor that includes one section that sticks out from the cell with one that lies inside. By tinkering with synNotch they can reengineer the immune cell to run down a particular cancer cell target and then issue instructions to turn genes on or off to set up the other half of the therapeutic equation.

In a project described in Cell, the team says they created a synNotch that recognized an antigen on the surface of the cancer cell while the internal mechanism contributed a chimeric antigen receptor that recognized a different antigen. They then tested it on a mouse model that included two different tumor cells: one with both targets recognized by the external synNotch sensor and the CAR and one with just the CAR target. 

The newly programmed attack weapon zeroed in on the two targets (which required synNotch activation for it to work) while leaving the other alone, providing preclinical proof-of-concept evidence that they could create a much more efficient tumor cell killing vehicle.

"The kinds of engineered T cells that we can now construct give us the exciting potential to create precision cancer therapeutics that take advantage of all the genomic and proteomic information we are currently gathering on disease," said Lim, the senior author of the study. "This genomic information now becomes actionable." 

The team was led by Leonardo Morsut and Kole Roybal. 

Lim added that it is possible to reengineer a T cell with multiple synNotches to make it even more precise. And there are added applications for autoimmune disease, regenerative medicine, and more.

- here's the piece from UCSF
- read the journal abstract

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