Immunotherapy shows promise in preventing leukemia relapse

Hutch News

Immunotherapy shows promise in preventing leukemia relapse

Group of 12 high-risk patients who received engineered T cells after bone marrow transplant still in remission after more than two years

Dec. 5, 2016
Dr. Aude Chapuis and her Fred Hutch colleagues are working to use the human immune system to target and cure cancer.
Photo by Robert Hood / Fred Hutch News Service

For patients with high-risk acute myeloid leukemia, relapse after bone marrow transplant signals a low chance of survival. But results from a small trial of genetically engineered immune cells show promise for keeping these patients out of danger: Of the 12 AML patients who received this experimental T-cell therapy after a transplant put their disease in remission, all are still in remission after a median follow-up of more than two years.

Giving these cells after transplant when disease is in remission “might actually be helping patients who have a high risk of relapsing to not relapse down the line,” said Dr. Aude Chapuis of Fred Hutchinson Cancer Research Center, one of the study’s leaders. Chapuis presented these results Monday at the 2016 annual meeting of the American Society of Hematology in San Diego, California.

The findings in this group of trial participants contrast with the outcomes the researchers observed in a cohort of similar patients who received transplants around the same time but did not receive engineered T cells. In all of these transplant-only patients, the transplants produced remissions, but more than a quarter of them relapsed within just 10 months.

As an early trial with a small number of patients and no randomized control group, this trial is a beginning, not a final answer. Nevertheless, the difference in outcomes between the two groups suggests that the patients in the engineered T-cell group “are getting a protective effect from the cells that they are receiving,” Chapuis said.

‘I really think we can do better’

In the experimental T-cell therapy tested in this trial, certain T cells from each patient’s transplant donor were genetically engineered to produce receptors that allowed the T cells to recognize, very specifically, a target molecule called WT1.

WT1 appears in cells during early development in the womb. Then, it mostly disappears ― unless a cancer develops. The molecule, named for its initial discovery in a type of kidney cancer called Wilms tumor, has since been linked to many different kinds of cancer, including leukemia. WT1 is 10 to 1,000 times more common in leukemia cells than their noncancerous cousins, making it a natural target for therapies designed to destroy cancer cells while leaving most healthy cells alone.

This is the team’s first trial of this strategy, which was initially developed in the lab of Dr. Phil Greenberg, one of the study’s leaders and the head of Fred Hutch’s Program in Immunology. Because it was the first study of this particular approach, the researchers focused on a high-risk group — AML patients undergoing bone marrow transplant who had certain genetic or disease characteristics that decrease the chance of long-term transplant success — “a hard population of patients,” Chapuis said, many of whom “were horribly sick.”

“If you’ve got high-risk disease, you’ve got a really bad prognosis, even if you do transplant,” Chapuis said.

Each patient’s therapy was created just for them in a specialized Fred Hutch facility. Certain T cells from each patient’s matched donor were given the genetic instructions to make a receptor that specifically reacts to WT1. Then came a blood stem cell transplant: Patients’ leukemic bone marrow and blood cells were destroyed and replaced with healthy cells from their donors. A month later, when the team examined these 12 patients’ marrow, they found no trace of the cancers. Rapidly thereafter, once the transplanted cells fully engrafted, each patient then received up to 10 billion of the genetically engineered donor cells, infused into their arm through an IV.

It’s been 27 months, on average, since these patients’ transplants. Not only have none of them relapsed, most still have the cancer-targeting T cells circulating in their bodies, Chapuis said. She and her colleagues hope that these immune cells will continue to survive and wipe out any new cancer cells that develop in the future.

“They basically have drones that could potentially get rid of whatever disease pops up in the future. That’s the hope,” Chapuis said.

Chapuis’s role in this trial is on the laboratory side of the research, ensuring the quality of the genetically engineered cell products and monitoring the activity of the cells after infusion. She co-leads this research with Greenberg and Dr. Dan Egan of Fred Hutch, the trial’s principal investigator and the care provider for trial participants. The study was supported by funding from the National Institutes of Health and Fred Hutch spinoff Juno Therapeutics, of which Greenberg is a scientific co-founder.

Outside of this trial, Chapuis treats cancer patients at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. Watching her patients undergo bone marrow transplant ― itself the first clear and reproducible example of cancer immunotherapy, developed at Fred Hutch ― has made her want to work toward something better. For her, that something is T-cell therapy.

“That’s my source of inspiration. I’m always horrified by the intense treatment that we inflict on bone marrow transplant patients and the hardship that we make them go through. And I really think we can do better,” Chapuis said. “That’s why I’m doing this.”

Dr. Aude Chapuis

Dr. Aude Chapuis

Photo by Bo Jungmayer / Fred Hutch News Service

Different receptors, different strategies

The T-cells in this trial were genetically engineered to produce a naturally occurring T-cell receptor, isolated from an anonymous blood donor, that the researchers found to have a particularly strong affinity for WT1.

Some other ongoing T-cell therapy trials around the world, including at Fred Hutch, use a different kind of synthetic receptor called a chimeric antigen receptor, or CAR.

Both kinds of receptors have their advantages, and they can recognize different types of molecular targets.

Strategies that use natural T-cell receptors have one big limitation. Unlike CARs, T-cell receptors are tissue type-specific. And there is an incredible diversity of tissue types in the human race, determined by cell molecules called HLAs that help T-cell receptors to recognize their targets. The WT1-targeting T-cell receptor used in this trial can only work with the most common variant of its HLA partner, which is found in 40 percent of white patients and a smattering of people from other races.

“We basically went for the HLA … that has the more broad applicability, so it can catch the 40 percent. Ultimately the goal is to broaden this to more HLA types,” said Chapuis, noting that this is an area of ongoing research among her Fred Hutch collaborators.

‘Bench to bedside and bedside back to bench’

The 12 patients on this trial whose cancers are still in long-term remission after receiving the T-cell therapy comprised just one of two groups of patients on the trial who received the engineered T cells. A second group of 12 patients received infusions of the cells after transplant ― except in these patients, the transplants had not succeeded in putting their cancers in remission.

The outcomes in the second group were different, and the researchers are working to figure out why. Although the researchers’ tests showed that the engineered cells were killing off some of the patients’ cancer cells, so far, the T-cell therapy does not seem to be helping patients survive longer.

There are several reasons why this might be, Chapuis said. One is the fact that the patients had residual cancer cells in their marrow, despite the intensive therapy they had undergone ― this meant that their disease was much more aggressive by nature than the cancers of those patients whose transplants had put them into remission. The genetically engineered T cells also did not survive as long in these patients and, in some cases, it appeared that the patients’ cancers had changed, losing the WT1 targets that marked them for destruction by the T cells.

Chapuis said “intense research” is underway at Fred Hutch to figure out how to solve these problems. Next year, the team hopes to enroll a few more participants to test an adjusted strategy for transplant patients in this particularly challenging situation.

“It’s bench to bedside, and bedside back to bench,” she said.

Susan Keown, a staff writer at Fred Hutchinson Cancer Research Center, has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org or on Twitter (@sejkeown).

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