Source: Nature

The first clinical trial to test the tumour-fighting power of a stem-cell-like class of long-lived immune cells suggests that they could be more potent and less toxic than the standard mix of cells used in therapies for cancer.

The study, published in Cell on 30 April¹, was small, and larger trials are needed to establish the treatment’s effectiveness. But the early results are promising: of 11 people with difficult-to-treat blood cancers, 5 entered remission after receiving a treatment called chimeric antigen receptor (CAR) T-cell therapy that contained an unusually high proportion of immune cells with properties similar to stem cells.

This formulation was effective at lower doses than normal CAR-T-cell therapy and produced milder side effects. “On a per-dose basis, these cells definitely seemed more potent,” says Christine Brown, who studies cancer immunotherapy at City of Hope, a cancer treatment centre and research institute in Duarte, California, who was not involved in the study. “It’s a first step, but an important one.”

Many flavours

CAR-T-cell therapies reprogram immune cells called T cells to target and kill cancer cells. To make these complex, living drugs, researchers usually isolate T cells from the recipient’s blood and then genetically engineer them to express a protein that binds to cancer cells. But T cells come in a variety of flavours, each with unique functions, and CAR-T-cell therapies normally contain a mixture of them.

   

How to supercharge cancer-fighting cells: give them stem cell skills

Previous research suggested that the presence of a subset of T cells called stem-cell memory T cells is correlated with the success of CAR-T-cell therapy². These cells have properties similar to those of stem cells, including an ability to generate many types of T cell.

Luca Gattinoni, a cancer researcher at the Leibniz Institute for Immunotherapy in Regensburg, Germany, and his colleagues decided to test whether an ‘enriched’ therapy consisting mainly of these cells might be more effective than the usual CAR-T-cell treatments.

Working with James Kochenderfer, a cancer researcher at the US National Cancer Institute in Bethesda, Maryland, the authors devised a procedure that increased the proportion of stem-cell memory T cells in a dose of CAR T cells nearly tenfold. They used the enriched mixture to treat people with blood cancers whose disease had either relapsed after a blood-stem-cell transplant or had failed to respond to therapy. The team compared those individuals’ responses to those of people who had previously been treated with standard CAR-T-cell therapy.

Powerful product

The authors found that their CAR T cells were more likely to evoke complete remission in the participants than were similar doses of conventional CAR T cells. Of the 10 people given conventional CAR-T-cell therapy, one entered a full remission. But of the 11 participants who received the new therapy, 5 had a full remission, and another experienced a partial remission. Only one participant in this arm of the trial saw their disease worsen soon after treatment.

“Pound for pound, this is a more powerful product,” says Susan Kaech, a cancer immunologist at the Allen Institute in Seattle, Washington. “It’s exciting.”

CAR T cells sometimes elicit a dangerous immune response called cytokine release syndrome, but this side effect was relatively mild in participants who received the enriched treatment.

Most people who receive CAR-T-cell therapy are first treated with harsh drugs to reduce their levels of non-engineered T cells, a step that has been shown to enhance the performance of conventional CAR-T-cell therapy. The participants in the latest trial did not undergo this pretreatment, but adding it could further enhance the effectiveness of the enriched therapy, Brown says.

Gattinoni and his colleagues are planning follow-up trials in people with other forms of cancer, including some with sarcoma, which typically affects the skin or eyes. This study will be particularly interesting, he says, because it will test the effects of enriched CAR-T-cell therapy against a solid tumour. Solid tumours have proved more difficult to treat with conventional CAR-T-cell therapy than have blood cancers.

Those future studies will help researchers to address lingering questions about the approach, Brown says. For example, Gattinoni’s CAR-T-cell therapy contains very low levels of another class of T cells, called CD4⁺ T cells, but these could be important for provoking immune responses against solid tumours, she says.