Tailoring immune cells to target leukemia

Promising early trial results show engineered immune cells may help buffer against cancer relapse after bone marrow transplantation
Dr. Phil Greenberg
Dr. Phil Greenberg, head of he Immunology Program at Fred Hutch, speaks about the challenges and recent progress in the field of immunotherapy at a Solid Tumor Translational Research retreat last June in Seattle. Photo by Robert Hood / Fred Hutch News Service

Mark Tose feels like a lottery winner. The Boeing senior manager was diagnosed with an aggressive form of acute myeloid leukemia in 2013 and received a lifesaving blood stem cell transplant — but his doctors feared that this might only buy him time before his AML recurred. Six months later, Tose was infused with an experimental immunotherapy: specialized immune cells engineered to detect and eliminate any cancer cells lingering in his body.

“My understanding is that [the engineered immune cells] look for cancer in the nooks and crannies that scientists can’t even detect. They clean and scrub your system in a more thorough way [than chemotherapy],” said Tose, 61, who joined the trial hoping he could help scientists gain insights that would help other patients. He has remained cancer-free for almost two-and-a-half years since his transplant.

The early-stage trial Tose participated in using modified immune cells designed to recognize and destroy his cancer was developed by Dr. Phil Greenberg and his team at Fred Hutchinson Cancer Research Center. Ten patients with AML or myelodysplastic syndrome received this immunotherapy after a blood stem cell transplant. Patients who undergo transplantation for chronic myelogenous leukemia may also fit the trial's eligibility criteria.

Greenberg’s team has developed methods to genetically modify T cells, a type of immune cell, to specifically seek out cancer cells like Tose’s while they ignore healthy cells. On Wednesday, Greenberg presented results of the arm of the early-stage trial in which Tose is participating at the American Association for Cancer Research annual conference in New Orleans. The findings appear to show promise in preventing disease relapse after blood stem cell transplantation.

Tose was one of 10 patients who underwent the treatment in a bid to prevent relapse of their disease. None of the patients have relapsed so far, though scientists would have expected about a third of such patients to relapse within this time frame. As a group, the patients have remained in remission a median of nearly 20 months since their transplants and about 18 months since their T-cell infusions. One patient has remained in remission for three years following transplant.

While the results are encouraging, the trial is not randomized, which means that researchers cannot say with certainty that the engineered T cells prevent relapse. The next step is to test the therapy in a larger prospective trial that will give the team a stronger sense of how well the T cells hold the line against cancer cells, said Dr. Daniel Egan, a medical oncologist and hematologist at Fred Hutch who collaborates with Greenberg and runs the trial.

Tailored treatment

Immunotherapy has been making headlines recently, including varieties that trade on T cells’ cancer-killing abilities. Some strategies provide T cells with a synthetic molecule to guide them to cancer cells. Greenberg, Egan and Fred Hutch colleagues Drs. Tom Schmitt and Aude Chapuis took an approach that utilizes T cells’ own strategy to recognize and eliminate dangerous cells. T cells use a molecule called a T-cell receptor, or TCR, to recognize specific molecules that mark cells for destruction. TCRs come in a dizzying variety, so that each T cell can zero in on a specific type of cancer cell or a cell infected with a particular virus.

T cells act a bit like quality-control officers of the body, assessing a state-of-the-cell report that cells provide on their inner workings. Cells do this by chewing up all the proteins inside and sending them to their surface, cradled in a type of molecule called a human leukocyte antigen, or HLA. T cells use their TCRs to try to grasp HLA molecules — but this handshake only tightens if the HLA is paired with just the right protein snippet. If so, T cells recognize an altered cell and are triggered to attack.

Protein snippets that cause a tight TCR–HLA grip are those that signal that something has gone awry in the cell. In the case of cancer, this can be an entirely new protein snippet caused by genetic mutations, or incredibly high expression of a normal molecule in the wrong place.

Greenberg and his team had discovered that a molecule called WT1 is often produced in huge amounts by leukemia cells, but only negligibly by healthy cells. This spurred a hunt for a T cell, hiding in a specific individual, which could recognize a snippet of WT1 cradled by one of the most common HLA varieties, HLA-A*201. The team surveyed the blood of many healthy donors to find this anti-WT1 T cell. Once they’d discovered it, the researchers could use the genes that encode its TCR to confer on other T cells a similar WT1-hunting ability.

The group built this TCR into a new therapy for patients like Tose, who has the HLA-A*201 tissue type and whose diseased cells express WT1 at very high levels. Patients’ own T cells are concentrated from a blood sample, then engineered using the super anti-WT1 TCR genes. Once the T cells sport their new cancer-homing TCRs, they’re infused back into patients to begin ferreting out any cancer cells that escaped chemotherapy and transplantation.

Patient Mark Tose
Leukemia patient Mark Tose, 61, has remained cancer-free for almost two-and-a-half years since his blood stem cell transplant; his sustained remission may be due to his participation in a Fred Hutch clinical trial using modified immune cells designed to recognize and destroy any residual cancer. Fred Hutch file

A long-lived therapy

When Tose joined the clinical trial nearly two years ago, Greenberg and his team had high hopes for their engineered T cells, but they didn’t know exactly how effective they would be in people. Tose was initially told he might get two infusions spaced two weeks to a month apart.

But Tose never got the second infusion. His newly engineered T cells didn’t wane. Instead of dying off as the researchers had anticipated, they lived on and appear to be continuing to fight against his cancer. He so far hasn’t needed a booster dose.

“We’re excited that we’re detecting anti-WT1 cells months or in some cases more than a year after we infuse them into patients,” said Egan, who noted that continued presence of these engineered cells would be “an important component of a system that can respond to — and possibly someday cure — leukemia.”

Less toxicity a ‘breath of fresh air’

“Chemotherapy is godawful, barbaric torture,” said Tose, who underwent six rounds of a toxic drug regimen that wiped away his immune system, temporarily gave him a painful, boil-like skin condition and caused his airway to swell so much he needed to be intubated to breathe.

“It’s poison. They try to take you to the brink over and over to eliminate your cancer,” said Tose. When he received the infusion of modified immune cells, “I was supposed to get some flu-like symptoms, but I didn’t notice anything.”

Tose’s T-cell infusion was simple enough — he stayed overnight for observation and went home the next day. He never experienced the flu-like symptoms his doctors warned him about. Compared to the months he spent in the hospital enduring rounds of chemotherapy, “it was a breath of fresh air,” he said.

“The cells were remarkably well-tolerated,” Egan said. Some patients did exhibit flu-like symptoms, such as fever or chills, which were easily managed without need for hospitalization, he said.

“We also did not see what we call ‘on-target toxicity,’ or toxicity from anti-WT1 T cells in tissues that have a physiological level of WT1,” Egan said. Nor did they see higher levels of graft-vs.-host disease than they would have expected from donated blood stem cells.

Looking to the future

One of the potential strengths of this type of engineered T cell lies in the possible range of targets that T cells can recognize, said Egan. Because cells chew up all their proteins to hang on HLA molecules for observation, a T-cell’s target could be nearly any protein that distinguishes a tumor cell from a healthy one. Strategies that use synthetic molecules to modify T cells are only able to target molecules in their full forms, attached to the surfaces of cancer cells.

However, the variety of HLA types among people means that new TCRs must be discovered in order to provide this treatment to patients who don’t have the HLA-A*201 tissue type. Greenberg and his laboratory team are hard at work building up this library of TCRs. They estimate about nine will enable them to provide engineered T cells to nearly every patient whose tumor expresses WT1.

In addition, they’d like to see how these engineered T cells fare in place of a transplant. Usually, patients with high-risk AML and MDS are given chemotherapy to drive their cancers into remission, then undergo a transplant to eradicate the last tumor cells, Egan said. The researchers hope that engineered T cells could replace this grueling regimen for some patients, including those who cannot find a stem cell donor. The plan for this trial is currently under review.

Greenberg and colleagues are also extending their results to other cancer types, including solid tumors. Fred Hutch collaborator Dr. Sylvia Lee is leading an early-phase trial testing the anti-WT1-engineered T cells against mesothelioma, which recently enrolled three patients. Trials for ovarian cancer and pancreatic cancer are also in the works. In these trials, patients will be treated with engineered T cells that target WT1 or T cells engineered with a different TCR that directs them toward tumor cells that express another molecule called mesothelin.

Going on two years after treatment, Tose rarely thinks about his revamped T cells. His clinic visits focus on keeping the graft-vs.-host disease from his transplant in check, and making sure other transplant-related complications don’t rear their heads.

“If you told me this could reduce or eliminate the need for chemotherapy, I’d start crying right now,” he said.

Dr. Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.

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