Trained Immune Cells Destroy Cancer More Effectively in Acute Myeloid Leukemia

Natural killer cells ‘trained’ to more effectively attack cancer cells in patients with AML.

A different type of immunotherapy shows promise in acute myeloid leukemia (AML) patients experienced disease recurrence after treatment, or those who never responded to therapy to begin with.

In a study published in Science Translational Medicine, researchers found that 5 out of 9 participants responded to treatment, 4 of which achieved complete remission. One patient achieved a partial remission, with some abnormal cells reappearing at the 1-month mark, while the remaining 4 patients were unresponsive to treatment.

Researchers stated that the longest complete remission lasted approximately 6 months, compared with the average life expectancy for patients with active AML who do not respond to treatment, which is about 3 months.

“This is a small study, but a 50% response rate is promising since these are patients with very poor prognoses and very few options,” said senior study author and co-principal investigator Todd A. Fehniger, MD, PhD. “Many of these patients are older and are not candidates for traditional bone marrow transplants because of the side effects associated with such an aggressive treatment.”

The responses in the phase 1 trial indicate an improvement over results from 2 similar clinical trials that tested highly purified natural killer (NK) cells in patients with AML that was detectable at the time of treatment. In the previous trials, the NK cells were not activated in the same way as in the current study, and only 1 out of 15 patients responded to the treatment; however, the authors noted that the 2 trials still helped establish the safety of NK cells in patients with AML.

In the current trial, 4 additional patients received NK cells; however, the efficacy of the therapy could not be evaluated in those cases. Three of those patients died of bloodstream infections before the end of the trial, and 1 patient was not given a full dose of NK cells because researchers could not obtain a sufficient amount of cells from the donor.

It is known that AML patients have an increased risk of developing chemotherapy-induced infections. The patients in the current trial were especially ill after having exhausted treatment options, and were choosing between hospice care or enrolling in a clinical trial.

“We are cautiously optimistic about these results,” Fehniger said. “There’s so much variability in how an individual patient responds to treatment, but this particular immunotherapy does seem to be inducing remissions in patients for whom other therapies, including similar investigational immune therapies, have a small chance of working.”

In some cases, NK cells have been shown to attack leukemia cells on their own with no special modifications. Previous studies found that by exposing NK cells in the lab to a combination of 3 chemical signals, called interleukins, 12, 15, and 18, it activated them to morph into cytokine-induced memory-like NK cells that become more potent in fighting cancer after being injected into the patient.

“Soldiers are never sent into combat without basic training,” said first study author and co-principal investigator Rizwan Romee, MD. “You can think of the activation period in the laboratory as a sort of boot camp, exposing the cells to some of the conditions and signals they will encounter in the patient’s body. So when the NK cells see the real cancer for the first time, they remember their training and respond more effectively than cells that don’t have this exposure.”

For this particular form of immunotherapy, the NK cells are extracted from a donor who is closely related to the patient. Once the donor’s NK cells are separate from the rest of the blood, the cells are incubated overnight in a mixture of interleukins 12, 15, and 18. The chemical signals activate the NK cells, and train them to attack the leukemia cells more effectively in a patient following infusion.

In mice and now patients, the NK cells were trained by the chemical signals were shown to divide more often, persist longer, and produce more interferon gamma than untrained NK cells.

In order for a patient to prepare to this NK cell therapy, they are required to undergo chemotherapy so that it can suppress the immune system, and allow the donor’s activated NK cells enough time and space to multiply in the bloodstream and attack cancer cells. Once the immune system recovers, it begins to clear the donor NK cells from the patient’s body, eliminating any long-term adverse events.

Authors noted that the phase 1 trial was primarily designed to test the safety of the new immunotherapy. Initially, patients received the lowest doses of cells so that researchers could monitor them for toxic side effects.

Researchers found that the study patients experienced few side effects the NK cells to date, and that side effects that did occur were mild.

“We escalated the dose as the trial went on and we saw remissions at each dose level, even the lowest one,” Fehniger said. “Now that we have established the safety of this immune therapy, we would like to find out how consistently the patients respond when we treat a large number at the highest dose level, which is what we’re in the process of doing now.”

This new approach will most likely be combined and investigated with other immunotherapies, according to researchers. Additionally, they are looking for new ways to harness the memory-like NK cell therapy in clinical trials, including testing the cells with mini bone marrow transplants to determine if the 2 strategies can together improve response rates.

Furthermore, researchers are preparing to investigate the novel immune therapy in pediatric patients whose AML has relapsed.