Mr T-cell

TO DEFEAT the enemy, you must first know the enemy. In the immune system, that job is done by T-cells, which recognise the molecular signatures of threats to their owner’s well-being. This week, at the AAAS conference, researchers explained how turbocharging these cells can boost the immune system’s ability to fight cancer, and possibly other illnesses, too.

The technology they use merges gene therapy, synthetic biology and cell biology. First, a batch of T-cells is extracted from the blood. A custom-built virus is used to implant them with new genes. The modified cells are then returned to the body, where their new DNA gives them a fresh set of targets to attack.

Stanley Riddell, at the Fred Hutchinson Cancer Research Centre in Washington state, creates cells that target a molecule, called CD19, that is found on the surfaces of some cancers. A firm called Juno Therapeutics is exploring whether the technique can be used to treat cancers that affect B-cells, another part of the immune system.

Dr Riddell has meanwhile been refining the technology. He told the meeting of his attempts to isolate and modify certain types of T-cells that are known to respond best to a given disease. In a trial of 31 patients with acute lymphoblastic leukaemia (ALL), that approach brought about a complete remission in 93% of cases—something Dr Riddell described as unprecedented.

Another refinement has been dealing with the toxic effects that these treatments can trigger. Sometimes, boosted T-cells can prove too eager for their owner’s good. As their numbers double, roughly every 12 hours, they can trigger a runaway immune reaction called a cytokine storm. This can be fatal: two of the patients in the ALL trial died in that way.

The biggest cytokine storms, though, seem to come from the patients with the most advanced cancers. Dr Riddell’s solution is to give the sickest patients the lowest dose. This means that the T-cells multiply more slowly, reducing the chances of an immune-system overreaction.

Although the ALL results are impressive, it is difficult to expand the approach to other cancers. To prime a T-cell to attack, it needs to be given precise co-ordinates. Otherwise it may lock onto, and destroy, something else in the body. But besides CD19, which is found in only a few cancers, scientists know of no other chemical target that is specific to cancer alone.

In a paper published on January 28th in Cell, Kole Roybal and his colleagues at the University of California, San Francisco propose a solution: tweaking cells to attack when they sense two different target chemicals instead of one. In isolation, neither target may be unique to cancer cells—but the combination might be. That could allow the immune system to be unleashed on tumours whilst sparing healthy tissue.

It is a long way from the lab to the clinic. But the technology is moving fast, and researchers hope that, one day, engineered T-cells might be used to treat a wide range of diseases, including HIV, immune deficiencies, and autoimmune disorders. Besides the elegance of the idea of boosting the body’s own defences, the technology offers another big advantage over traditional drugs: once they have done their job, the engineered T-cells stick around in the body. That could offer protection against re-infection or the recurrence of a cancer. Chiara Bonini, of the San Raffaele Scientific Institute in Milan, told the meeting she had found that some modified cells were so durable that they might be able to protect their owners for a decade or more.