The Race to Supercharge Cancer-Fighting T Cells

Crystal Mackall remembers her scepticism the first time she heard a talk about a way to engineer T cells to recognize and kill cancer. Sitting in the audience at a 1996 meeting in Germany, the paediatric oncologist turned to the person next to her and said: “No way. That’s too crazy.”

Today, things are different. “I’ve been humbled,” says Mackall, who now works at Stanford University in California developing such cells to treat brain tumours. The US Food and Drug Administration approved the first modified T cells, called chimeric antigen receptor (CAR)-T cells, to treat a form of leukaemia in 2017. The treatments have become game changers for several cancers. Five similar products have been approved, and more than 20,000 people have received them. A field once driven by a handful of dogged researchers now boasts hundreds of laboratory groups in academia and industry. More than 500 clinical trials are under way, and other approaches are gearing up to jump from lab to clinic as researchers race to refine T-cell designs and extend their capabilities. “This field is going to go way beyond cancer in the years to come,” Mackall predicts.

Advances in genome editing through processes such as CRISPR, and the ability to rewire cells through synthetic biology, have led to increasingly elaborate approaches for modifying and supercharging T cells for therapy. Such techniques are providing tools to counter some of the limitations of current CAR-T therapies, which are expensive to make, can have dangerous side effects, and have so far been successful only against blood cancers. “These techniques have expanded what we’re able to do with CAR strategies,” says Avery Posey, a cancer immunology researcher at the University of Pennsylvania in Philadelphia. “It will really take this type of technology forward.”

Even so, the challenge of making such a ‘living drug’ from a person’s cells extends beyond complicated designs. Safety and manufacturing problems remain to be addressed for many of the newest candidates. “There’s an explosion of very fancy things, and I think that’s great,” says immunologist Michel Sadelain at the Memorial Sloan Kettering Cancer Center in New York City. “But the complexity cannot always be brought as described into a clinical setting.”

Revved up and ready to go

CAR-T therapies capitalize on the activities of T cells, the immune system’s natural hunters that prowl through the body looking for things that don’t belong. Foreign cells, or those infected with a virus, express unusual proteins that serve as a beacon to T cells, some of which release a toxic stew of molecules to destroy the abnormal cells. This search-and-destroy function can also target cancer cells for elimination, but tumours often have ways of disarming the immune system, such as by cloaking abnormal proteins or suppressing T-cell function.

CAR-T cells carry synthetic proteins — the chimeric antigen receptors — that span the cell membrane. On the outside is a structure that functions like an antibody, binding to specific molecules on the surface of some cancer cells. Once that has bound, the portion of the protein inside the cell stimulates T-cell activity, hot-wiring it into action. The result is a tiny, revved-up, cancer-fighting machine.

by Heidi Ledford, Nature | Read more:
Image: Steve Gschmeissner/SPL

[ed. See also: Engineering T cells (GT).]