T-cells that have been genetically edited to boost their anticancer activity have destroyed solid tumours in mice.
Human tumours in mice have been eradicated by human immune cells that were genetically engineered to boost their anticancer activity.
So far, engineered immune cells have proved ineffective against solid tumours in human trials, but these cells could prove more potent.
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| Illustration of modified spiky viruses entering and altering a T-cell as part of the gene-editing process Science Photo Library/Alamy |
The tests in the mice, which were also engineered so that their immune systems were made of human cells, are “as close as you can get to the human system”, says Stephen Hatfield at Northeastern University in Massachusetts. “We’ve found in this paper, and we’re continuing to find in subsequent studies, that we can use far, far fewer T-cells to get complete tumour remission in animals.”
Our immune systems sometimes fail to recognise and target cancerous cells. But it is possible to remove immune cells from the body, genetically modify them to target a cancer and then return them.
These engineered T-cells, known as CAR T-cells, can be effective against cancers that involve cells circulating in the blood, such as leukaemia, and several treatments have now been approved. However, so far CAR T-cells haven’t proved effective against tumours that grow as solid lumps.
There are other issues, too. CAR T-cells can trigger serious reactions and having to modify each individual’s own cells makes the treatments very expensive.
One approach to solving these problems is to use gene editing to make additional changes to CAR T-cells.
In 2015, gene-edited CAR T-cells were used for the first time, to treat a girl with leukaemia called Layla. The gene editing was used to make T-cells from a donor into “off-the-shelf” cells safe for treating anyone.
But the scope for improving CAR T-cells further has been limited. This is because the more cuts that are made in DNA in the editing process, the greater the risk of the wrong ends being joined back together and causing dangerous mutations.
But a newer form of CRISPR gene editing called base editing can be used to change one DNA letter to another without cutting the DNA, allowing numerous changes to be made without extra risk. Last year, a teenager called Alyssa was treated with CAR T-cells that had four base edits as well as the added targeting protein.
Now, Hatfield and his colleagues have used base editing to make CAR T-cells with six edits. “Six, I think, is the most that we’ve ever seen, and it seems to have no negative impact,” says team member Ryan Murray, also at Northeastern University.
Three of the edits help turn donor cells into off-the-shelf cells. The other three edits are intended to enable the CAR T-cells to attack solid tumours.
Inside solid tumours, there are typically high levels of chemicals called TGF-beta and adenosine, which suppress immune activity. Many tumour cells also have a protein called PD-L1 on their surface that tells T-cells to leave them alone.
So the team used base editing to knock out the receptors on the CAR T-cells for adenosine and PD-L1. To shut down the TGF-beta receptor, a conventional DNA-cutting gene editor was used, as the base editor wasn’t effective against this target.
In the mouse tests, solid human tumours were allowed to grow for up to a month before the CAR T-cells were injected, says Hatfield. “Those tumours are reasonably large, larger than a lot of the other studies that that you may see on CAR T.”
In eight mice treated with the six-edit CAR T-cells, the tumours shrank and disappeared within a few weeks, whereas in untreated mice or those given CAR T-cells without the three edits designed to target solid tumours, the tumours kept growing.
The team has also found that the six-edit CAR T-cells are effective at much lower doses than standard CAR T-cells. Giving smaller doses should reduce side effects, says Hatfield. “That right there is an additional safety component.”
The team thinks fewer CAR T-cells are needed because fewer of them are being suppressed by factors such as TGF-beta.
Murray says the results have persuaded gene-editing company Beam Therapeutics, which was involved in the work, to explore how to apply this to people. “I think this paper really shows the power of base editing for solid tumours.”
The successful mouse trials don’t guarantee effectiveness in people, however. “Humanised mouse experiments provide some helpful information, but cannot fully recapitulate the human disease, especially the micro-environment issues relevant to solid tumours,” says Waseem Qasim at University College London, whose team created the cells used to treat Layla and Alyssa.
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