The statistics are grim: For patients with high-risk acute myeloid leukemia, more than 60% will relapse within two years of a bone marrow transplant. The return of their cancer is the leading cause of death for these patients.
But results from a small trial of genetically modified immune cells hint at a way of protecting these patients. Scientists at Fred Hutchinson Cancer Research Center used engineered T cells to prevent relapse in 12 AML patients after a bone marrow transplant put their disease in remission. They all remain cancer-free after a median follow-up of more than three years.
Those findings contrast with outcomes in a cohort of similar patients who received transplants around the same time but did not receive engineered T cells. In this comparison group of 88 patients, 46% relapsed.
The trial was small and non-randomized, noted Dr. Aude Chapuis, one of the study’s leaders, and it was limited to very sick patients. But the researchers are encouraged by the results.
“These patients don’t have any options when it comes to preventing relapse, but here we feel we have a signal,” Chapuis said. “We’re very excited to pursue it further.”
The trial described in the Nature Medicine paper grew out of Fred Hutch’s trailblazing research into a particular type of adoptive T-cell therapy. Dr. Phil Greenberg, one of the study’s leaders and the head of Fred Hutch’s Program in Immunology, initially developed the approach. It involves refining the receptors on a T cell to target cancer-specific molecules.
For this trial, the T cells were engineered to home in on a protein called WT1, which is far more common on leukemia cells than on healthy ones. The team first published results of its WT1 research in 2013. Back then, the scientists observed that the engineered T cells could directly target and kill some leukemia cells.
But they also observed significant variation in how sensitive the modified T-cell receptors were to WT1. That sparked a hunt for a T-cell receptor with an exceptionally strong affinity for the protein. The researchers screened cells from many healthy donors before finding one receptor that was especially "sticky" for WT1. Using the sticky receptor as a blueprint, the team could insert genetic instructions for it into other T cells, enabling them to make this anti-WT1 receptor.
Billions of these engineered T cells were given to each of the 12 AML patients on the trial. More than three years later, the researchers could still detect T cells in these patients that expressed the genetically modified receptor — suggesting this type of treatment could provide long-lasting protection against the return of cancer, Chapuis said.
The study also offers a proof-of-principle that scientists could expand the number of targets for engineered T-cell therapies, Chapuis said. The approach of creating an optimal T-cell receptor could extend cell therapy to many more types of cancers. “Successfully going after WT1 opens the door to more targets for immunotherapy,” Chapuis said.
The researchers said that the particular T-cell receptor technology used in this trial won’t be developed further for patient use. But as they’ve been doing for years, Chapuis, Greenberg and Fred Hutch colleagues will continue to refine and improve their approach based on what they’ve learned in the hopes of bringing immunotherapy to more patients. They’re already working in the lab on the next iterations, which aim to make these treatments more effective and longer-lasting.
“We’ve learned a lot through this trial,” Chapuis said. “Our 2.0 will be better as we go from bench to bedside and back again.”
This research was supported by grants from the National Institutes of Health as well as funding from the Damon Runyon Cancer Research Foundation, the Guillot Family (in honor of Zach), Fred Hutch’s Immunotherapy Integrated Research Center, and Juno Therapeutics, a Celgene company.
Competing Interests: Drs. Aude Chapuis and Phil Greenberg have received research funding from Juno Therapeutics. Greenberg consults for and previously had an ownership interest in Juno.
Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.
Jake Siegel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, he covered health topics at UW Medicine and technology at Microsoft. He has an M.A. from the Missouri School of Journalism.
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