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Recruiting an Old Drug for a New Purpose in Battle Against Pediatric AML

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000558217.47163.be
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Allison J. Kaeding, MD, is waist-deep in translational research projects that are taking advantage of work already done in solid tumor research and “pivoting it, hopefully in a quick way” for application in pediatric acute myeloid leukemia (AML).

An acting instructor at the University of Washington, Department of Pediatrics, Division of Pediatric Hematology/Oncology, and research associate with Fred Hutchinson Cancer Research Center, Kaeding has been instrumental in research that may eventually repurpose an antibody conjugate called anetumab ravtansine (AR), effective in targeting mesothelin found in adult pancreatic, ovarian, and triple-negative breast cancers. She is trying to discover if AR can also successfully target mesothelin which has now been found to overexpress in pediatric AML.

“Pediatric AML is a deadly cancer,” said Kaeding. “When treating [this], we are nowhere near the success that has been achieved in pediatric acute lymphoblastic leukemia (ALL). This represents a critical research need.” It is one she and her colleagues have tackled and are advancing quite impressively.

A native of Fargo, N.D., Kaeding was the first of her nuclear family to attend a 4-year college. She recalls an early fascination with science and medicine. “In looking back, I suppose you could say I did nerdy things as a kid,” she revealed with humor. While classmates were tacking up posters of their favorite band on their bedroom walls, Kaeding was intrigued with something else.

“The NIH had recently sequenced the human genome, and they publicly offered a poster of the genome, which highlighted various genes, and was packaged with a little information booklet. I sent away for that and I was thrilled to have it. I probably kept that a secret from the other kids in my school,” she chuckled.

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Experiencing Research

During undergraduate studies at the University of Michigan, Kaeding worked in an environmental microbiology lab and found a love of research. When an interest in medicine matured, she went to medical school at Johns Hopkins, Baltimore.

It was there that she met Patrick Brown, MD, a researcher who was giving a presentation about his work in ALL that occurs in infants. “It is a unique disease characterized by translocation of one particular gene. I was intrigued to learn that this very aggressive cancer can arise from a single genetic abnormality. I sat there thinking, ‘This is so incredibly interesting; clearly it is the most interesting thing there is.’

“I applied to a program called the Dean's Research Award and was given a grant to take a year off from medical school to do research. I worked with Pat Brown and had my first lab experience working with human cells, doing correlative biology studies for the phase III trial of a kinase inhibitor in infant ALL patients.”

It was a hefty experience that would further establish Kaeding's insatiable love of research. “It was a very important trial, and I ended up giving platform presentations at ASPHO and ASH meetings that year. What an experience,” she marveled. “In the end, the drug was found to be non-effective. But negative results are also important results.”

After that research year, Kaeding completed medical school and stayed at Johns Hopkins for a pediatric residency, which rotated through the hematology-oncology and bone marrow services.

Afterward she opted to cross the country for a fellowship, noting, “I thought for a long time that Seattle is a place I could see myself living one day. So I took a chance and moved here for my fellowship, a combined program between University of Washington, Seattle Children's Hospital, and Fred Hutchinson Cancer Research Center.”

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Responding to an Urgent Need

During her fellowship, Kaeding was mentored by Soheil Meshinchi, MD, a nationally known AML researcher. It was an association that has had continuing importance. Meshinchi, having recognized that pediatric AML posed important and urgent research needs, worked with the Children's Oncology Group (COG) and established a large biology study to collect patient samples from pediatric AML patients from hundreds of the COG member sites in North America.

“We now have over 2,000 patient samples,” informed Kaeding. Working with the NIH, the researchers have taken advantage of next-generation sequencing to look for new ways to treat pediatric AML.

“The mainstays of therapy have been cytotoxic chemotherapy requiring high doses to kill AML and achieve relapse-free survival. But the dose and intensity has been escalated so much that we are reaching a ceiling in terms of side effects that include neutropenia and infections that can require hospitalization because of the long time it takes for marrow to recover after chemo. Additionally, anthracyclines cause long-term cardiotoxicity, heart failure, etc. There is an immense need for developing a targeted therapy to deliver chemo directly to cancer cells while sparing healthy tissue.”

That's where mesothelin comes into play. “There has been a number of exciting target pathways identified through the sequencing, one of which is targeting mesothelin, a protein that conveniently sits on the surface of the leukemia cell,” Kaeding told Oncology Times. “We found that mesothelin is overexpressed in about a third of pediatric AML.”

Mesothelin is infamous because it is overexpressed in a number of adult solid tumors—including pancreatic, ovarian, and triple-negative breast cancers. For that reason, Kaeding said mesothelin has been a subject of study for decades.

“There have been immunotherapies developed to take advantage of the fact that mesothelin characterizes all of those nasty solid tumors and the fact that mesothelin sits on the cell surface,” she noted. “Prior to our lab's work, there had been one or two small papers that pointed out mesothelin was present in some AML. It was never really followed up on in literature. So the demonstration in our gigantic AML study really lends a lot of credibility to that finding because of the number of patients we have and the many different ways we have been able to demonstrate and verify that mesothelin is there.”

Time is the name of the game in the next steps, said Kaeding. “We don't want to spend time reinventing the wheel. One of the ways researchers have attempted to target mesothelin is through immunotherapy, particularly with antibody-drug conjugates that allow specific binding to particular proteins conjugated with chemical linkers to chemotherapy drugs.”

The overall concept suggests that just such an infusion into the patient will result in chemotherapy being directed only to the cells that have mesothelin on their surface. Kaeding said the antibodies are very large so they don't diffuse across the cell membrane; rather, they have to be actively taken up by vesicle formation from the surface of the cell.

“The hope is that this represents a highly targeted type of therapy which will spare normal, healthy cells. We [worked to test an antibody drug conjugate] called anetumab ravtansine and have tested it in vitro in mesothelin-overexpressing leukemia cell lines and have shown that, in a number of the lines, AR does cause killing of the cells. We saw good, specific killing. It looks very promising,” explained the physician scientist.

“From there we tested with xenografted mouse models. We gave the mice human leukemia that overexpresses mesothelin, treated them with AR, and showed that giving them only this agent—nothing else, no combination chemotherapy—more than doubled their survival, as opposed to no treatment and [treatment with] traditional chemotherapy.”

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Critical Time Savings

Calling it an “incredibly exciting” finding, Kaeding said because AR is not a new compound it has already been tested in humans and has gone through phase I and II studies in adults for solid tumors.

“Since we do not have to get it approved for first-in-human testing, we are much farther down the road. This could save us years. As someone who goes into the clinic and sees patients who have an urgent need, I want to take the most expeditious strategy to get a novel therapy into the clinic.”

A phase I trial is currently being designed by Katherine Tarlock, MD, of Seattle Children's Hospital, one of the first researchers in the lab to work on mesothelin in AML, and from whom Kaeding inherited the project. It is hoped the trial will open later this year or early next year.

“It is fantastic to see a project move from pipetting in dishes to a clinical trial in just a couple years,” said Kaeding. “And for patients who have exhausted what medicine has to offer, having another thing to try is beyond important.”

Once the trial opens, Kaeding will do some of the correlative studies. “I am starting to think right now about how this could possibly fail so that if that happens we could quickly identify the means of failure and move to address it,” said a cautious Kaeding. “To do that we need to look at other immunotherapy trials and see how those failed and how relapses happened, despite those therapies.

“Looking at CD19-directed immunotherapy, which is the most well-tested model in leukemia, we can see that relapses occur when leukemia cells adapt and no longer express the target CD19. It is almost like a survival-of-the-fittest phenomenon among the leukemia cells,” she continued.

“Cancer has an ability to mutate and change because its genetic regulation is already disrupted and normal regulatory function has already failed. It can accrue other changes to the cell biology more easily because it has already surpassed that natural check. When a small subpopulation of leukemia cells changes and escapes from the immunotherapy, it presents a new threat.”

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Still Work to Be Done

Kaeding, happily married and mother to a 1-year-old daughter, lives a busy and purpose-driven life. In rare leisure moments, she enjoys running to an overlook with a view of the Puget Sound.

“I find it restorative. Running is my favorite way to de-stress and sometimes, honestly, it is when I do some of my best scientific thinking. Medical science can seem like a pretty black and white, straightforward process, but it actually requires a lot of creativity. When I am running, my brain is clear and some really good ideas flow in,” Kaeding declared.

She believes this is a powerful time to be in AML research, offering opportunities to use a wealth of knowledge about the genetic landscape of pediatric AML and the recognition “of genetic abnormalities found on a recurring basis within pediatric AML. There are number of new targets and strategies just waiting to be developed. And that gives us a very hopeful outlook,” Kaeding said.

“We've realized the power of looking at genetic abnormalities in the cell—not just at the DNA level, but also at the transcript level, the metabolism level, the epigenetic level. We are only just now figuring out what to do with all of that data and how to turn it into practical solutions. It is an exciting time. It is promising time. And it is an urgent time. There is a lot of work to do.”

Valerie Neff Newitt is a contributing writer.

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