Transformative gene therapies

The approval of gene therapy for leukaemia, expected in the next few months, will open the door to a radically new class of cancer treatments. Companies and universities are racing to develop these new therapies, which re-engineer and turbocharge millions of a patient’s own immune cells, turning them into cancer killers that researchers call a ‘living drug’. One of the big goals is to get them to work for many other cancers, including those of the breast, prostate, ovary, lung and pancreas.

“This has been utterly transformative in blood cancers,” said Dr Stephan Grupp, director of the cancer immunotherapy programme at the Children’s Hospital of Philadelphia, USA. “If it can start to work in solid tumours, it will be utterly transformative for the whole field.”

But it will take time to find that out, Stephan said, at least five years. This type of treatment is also being studied in glioblastoma, an aggressive brain tumour. Results of a study at the University of Pennsylvania, published last month, were mixed. In the first 10 patients treated there, one has lived more than 18 months, with what the researchers called ‘stable disease’. Two other survivors have cancer that has progressed, and the rest have died.

Studies are forging ahead on many fronts. Researchers plan to try giving the cell treatment to children with earlier stages of leukaemia than in the past, combining it with other treatments and developing new types of cell therapy. One new version, with human trials just starting, uses immune cells extracted not from the patient, but from samples of umbilical-cord blood donated by mothers when they give birth. The products closest to approval have a limited focus — to treat blood cancers like leukaemia as opposed to the solid tumours that form in organs like the breasts and cause many more deaths.

For an effective treatment

The new treatments are expected to cost hundreds of thousands of dollars, and they come with risks. Patients in the earliest studies nearly died from side effects like raging fever, low blood pressure and lung congestion. Doctors have learned how to control those reactions, but experts also have concerns about possible long-term effects like second cancers that could, in theory, be caused by the disabled viruses used in genetic engineering. No such cancers have been seen so far, but it is too soon to rule them out.

The new leukaemia treatment involves removing millions of white blood cells called T-cells from the patient’s bloodstream, genetically engineering them to recognise and kill cancer, multiplying them and then infusing them back into the patient. The process is expensive because each treatment has to be made separately for each person.

Solid tumours are less amenable to treatment with these altered cells — which scientists call CAR-T cells — but studies at various centres are trying to find ways to use it against mesothelioma and cancers of the ovary, breast, prostate, pancreas and lung. “These solid tumours are like Fort Knox,” Stephan said. “They don’t want to let the T-cells in. We need combination approaches, CAR-T plus something else, but until the something else is defined we’re not doing to see the same kind of responses.” The T-cell therapy for leukaemia was created at the University of Pennsylvania, which licensed it to Novartis.

Some of the more promising work so far involves efforts to make the existing gene treatments even more effective in blood cancers. For lymphoma patients, the T-cells are being given along with a drug, ibrutinib, and the combination seems to work better than either treatment alone.

Studies underway

Stephan said that one encouraging avenue of research involved giving the T-cells at an earlier stage of the disease, instead of very late, as rules now require. He said a study was being planned at multiple centres that he hoped would start within the next six months or so.

The patients would be children with early signs that the usual chemotherapy — which cures many — is not working well for them. “We could deploy the treatment considerably earlier and before they get so sick,” he said. He added, “That is another big step in terms of trying to figure out how to use these cells appropriately.”

Earlier treatment, he said, might help some patients avoid bone-marrow transplant. Children with less advanced disease also tend to have milder side effects from the T-cell treatment.

Studies in children are also underway to combine T-cell treatment with the immunotherapy drugs called checkpoint inhibitors, which help unleash the cancer-killing power of T-cells. There will be many such studies, Stephan predicted, but, he said, “It’s early days.” The T-cells in the Novartis products, and in the earliest ones its competitors are developing, have been engineered to seek and destroy cells that display on their surfaces a protein called CD19 — a characteristic of many leukaemias and lymphomas.

Identifying other targets would be a boon, Stephan said, because sometimes leukaemic cells lacking CD19 proliferate, escape the treatment and cause relapse. Another target is being studied, and Stephan said the next step, which he called “super important,” would be to attack two cellular targets in the same patient. In the next year or so, he said, that approach will also be studied in both children and adults who have acute myeloid leukaemia, which he described as a “tough disease.”

Alternative path

Researchers at the University of Texas MD Anderson Cancer Centre, USA are trying a different approach to engineering cells, one that they hope might eventually yield an ‘off the shelf’ treatment that would not have to be tailored to each individual patient. Instead of using T-cells, the team uses natural killer cells, another component of the immune system, one that has a powerful ability to fight anything it recognises as foreign.

They use natural killer cells because T-cells from one person cannot be safely given to another, lest they attack the host’s tissue, causing graft-versus-host disease, which can be fatal. Natural killer cells do not cause that deadly reaction, so it is safe to use such cells from a newborn’s cord blood to treat patients. The natural killer cells are genetically engineered to attack CD19, and also to produce a substance that activates them.

They also have an ‘off switch’, a gene that will let the researchers shut down the cells if they cause dangerous side effects that cannot be controlled. One unit of cord blood yields enough cells to treat five patients, Katy said, and in two weeks the natural killer cells can be expanded 500-fold, to one billion cells.