An innovative immunotherapy combination has shown a stunning 99% response rate in children with relapsed leukemia. The phase 2 trial, run jointly between researchers at St. Jude Children’s Research Hospital in Memphis and Shanghai Children’s Hospital in China tested the therapy in 225 children who had relapsed after conventional treatment.

The work published in the Journal of Clinical Oncology found that almost all of the children went into remission, meaning their leukemia was undetectable.

Childhood leukemia is the most common childhood cancer and over 9 in 10 children live long-term after a diagnosis in the United States. The conventional treatment is typically a cocktail of chemotherapy drugs given in 2-3 year regimens, the timings and dosings tweaked over several decades of clinical trials, slowly inching up the survival rate.

However, the disease does come back in some children and relapsed leukemia is far harder to treat, as it often has a degree of resistance to chemotherapies. A stem cell transplant is one option for some of these patients, but in recent years, newer, targeted therapies have also been developed, giving hope of a cure for children who have relapsed and their families.

One of the most exciting of these is CAR T cells, which are immune cells taken from a patient and genetically programmed to attack cancer cells. In the case of B-cell leukemia, the most common type in children -this target is a protein present on the surface of the leukemia cells, called CD19. The CAR T cells go after only cells which have the protein on their surface, sparing other blood cells and healthy tissues.

Although CAR T cells targeting CD19 have successfully treated many children (and now adults with blood cancer too), the treatment still fails in some children. Sometimes this is because the B-cells evolve to simply shed the CD19 protein from the surface, making them invisible to the CAR T cells which previously would have killed them. For this reason, the new trial looked at CAR T cells which targeted both CD19 and another surface protein on the cells, called CD22.

It is thought to be much harder for the leukemia cells to lose both CD19 and CD22 and evade therapy.

“Our thought was if one type of CAR T cells cannot kill all the cancer cells, the other type of CAR T cells may kill those cancer cells that remain,” said Pui.

One drawback of CAR T cell therapy is that it generally takes over a month to make them after the patient donates T cells. As childhood leukemia is a fast-moving disease, many children simply can’t wait this long for therapy. But the new study was able to shorten this process and make the CAR T cells in just one week after the cells were taken from the patient.

“This faster approach offers a big advantage,” said Pui. “For other approaches, you need to give the patient additional chemotherapy to prevent the progression of the disease and try to keep the patient in good shape for 35 to 40 days to prepare the CAR T cells. The patient may become too sick or have too many leukemia cells before they receive CAR-T cell treatment,” he added.

Although the initial response to the combination CAR T cell therapy was almost perfect, a quarter of children did relapse within the first 12 months following the treatment. Some had lost one or both of the proteins that the CAR T cells targeted on their leukemia cells, but almost half of those who relapsed still had both proteins. Three patients also died due to toxicities associated with the treatment.

The researchers are still trying to figure out why some patients respond well to therapy and others relapse, despite having both of the target proteins on their cells still. However, the combination treatment worked well enough that the researchers are recommending that it be tried before some other approaches before relapsed disease, such as radiation, which often comes with a host of acute and long-term side effects.

“While this novel combined immunotherapy approach will not work in all patients with extra medullary relapse, you can spare a substantial proportion of them from damaging therapy. Physicians should give patients a trial of CAR T cells before radiating them,” said Pui.