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Gene Therapy Cures Adult Leukemia


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Updated: 4/10 10:59 am Published: 11/27/2012 8:10 pm


Aug. 10, 2011 -- Two of three patients dying of chronic lymphocytic leukemia (CLL) appear cured and a third is in partial remission after infusions of genetically engineered T cells.

The treatment success came in a pilot study that was only meant to find out whether the treatment was safe, and to determine the right dose to use in later studies. But the therapy worked vastly better than University of Pennsylvania researchers David L. Porter, MD, Carl H. June, MD, and colleagues had dared to hope.

"Our results were absolutely dramatic. It is tremendously exciting," Porter tells WebMD. "These kinds of outcomes don't come around very often. We are really hopeful that we can now translate this into treatment for much larger numbers of patients and apply this technique to other diseases and to many more patients."

Excitement is spreading as oncologists learn about the findings. "I think it is a big deal," says Jacque Galipeau, MD, professor of hematology and medical oncology at Emory University Winship Cancer Center. Galipeau was not involved in the Porter study.

"Here's this guy, the handwriting is on the wall, any hematologist will tell you he is a goner -- this guy was essentially cured," Galipeau tells WebMD. "These genetically engineered cells did what everyone in the field has tried to do for 20 years. The man probably had kilograms of disease in his body, and the cells mopped it up completely."

The treatment uses a form of white blood cells called T cells harvested from each patient. A manmade virus-like vector is used to transfer special molecules to the T cells. One of the molecules, CD19, makes the T cells attack B lymphocytes -- the cells that become cancerous in CLL.

All this has been done before. These genetically engineered cells are called chimeric antigen receptor (CAR) T cells. They kill cancer in the test tube. But in humans, they die away before they do much damage to tumors.

What's new about the current treatment is the addition of a special signaling molecule called 4-1BB. This signal does several things: it gives CAR T cells more potent anti-tumor activity, and it somehow allows the cells to persist and multiply in patients' bodies. Moreover, the signal does not call down the deadly all-out immune attack -- the feared "cytokine storm" -- that can do more harm than good.

This may be why relatively small infusions of the CAR T cells had such a profound effect. Each of the cells killed thousands of cancer cells and destroyed more than 2 pounds of tumor in each patient.

"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," June says in a news release. 'It worked much better than we thought it would."

CLL Patient Describes CAR T-Cell Treatment

The treatment was not a walk in the park for patients. One of the three patients became so ill from the treatment that steroids were needed to relieve his symptoms. The steroid rescue may be why this patient had only a partial remission.

"Those engineered T cells don't hug the cells to death. They release an array of substances, nasty things that have evolved to clear virus- infected cells from your body," Galipeau says. "But now they are using this to melt down a couple of pounds worth of tumor burden, you will get some side effects."

One of the patients, whose case is reported in the New England Journal of Medicine, described his experience in a University of Pennsylvania news release. The patient chose not to identify himself by name, although he discloses that he has a scientific background. He was diagnosed with CLL at age 50; 13 years later his treatment was failing. Facing a bone-marrow transplant, he jumped at the chance to enter Porter's clinical trial of CAR T cells.

"It took less than two minutes to infuse the cells and I felt fine afterward. However, that fine feeling changed dramatically less than two weeks later when I woke up one morning with chills and a fever," he says. "I was sure the war was on. I was sure the CLL cells were dying."

A week later the patient was still in the hospital when Porter brought him the news that the CLL cells had disappeared from his blood.

"It was working and I was winning," the patient says. "It was another week later that I got the news that my bone marrow was completely free of detectable disease. It has been almost a year since I entered the clinical trial. I'm healthy and still in remission."

Is he cured? Doctors hate to declare a cure until patients have been cancer-free for at least five years. But there are signs the CAR-T cells persist in patients' immune memory, ready to mop up any CLL cells that reappear.

And there's a big downside. The CAR T cells that fight CLL also kill off normal B lymphocytes. These are the cells that the body needs to make infection-fighting antibodies.

As long as the CAR T cells persist -- which may be for the rest of patients' lives -- patients will require regular infusions of immune globulin.

Hope for Cancer Patients, but Treatment Years Away

CLL is the second most common form of adult leukemia. In the U.S. there are about 15,000 new cases and about 4,400 deaths each year.

Cure is possible, but it requires a risky bone marrow transplant. About 20% of patients don't survive this treatment -- and even when they do, there's only a 50-50 chance of a cure.

CAR T cells appear to be a much better option. But the amazing success now reported came very early in the development of this new treatment. Only a few of the thousands of CLL patients facing death will be able to enter the still-small clinical trials testing CAR T cells.

"The distressing thing is the need will far, far, far outweigh any slots in clinical trials," Galipeau says.

But Porter says his team is energized by the early success and is pushing forward as quickly as possible. Even so, a lot of work remains to be done.

"We've treated only a very small numbers of patients," Porter says. "So part of the goal is to see these results in more people, see that the results are sustained, and that it is safe over time. We need to find the appropriate dose and to make incremental modifications. And now we have shown activity, we can try and apply it earlier in the course of the disease. We have reason to think treating patients sooner may be even safer and more effective.

Although the CAR T cells in the study were designed to fight CLL, there's good reason to hope they can be effective in other forms of cancer. The catch is that it can work only on tumor cells that carry markers flagging them for destruction. Normal cells that carry the same markers will also be destroyed.

Many cancers are known to carry such markers, and there's hope of finding more.

"We have a clinical trial at the University of Pennsylvania with an anti-mesothelin molecule [which marks mesothelioma, ovarian, and pancreatic tumors]," Porter says. "There are other trials around the country trying to target renal cell carcinoma [kidney cancer] and myeloma [skin cancer]. We are hoping to identify other tumor targets, particularly in other leukemias, to adapt this technology."

Porter, June, and colleagues report their findings in the Aug. 10 early online versions of two major journals: The New England Journal of Medicine and in Science Translational Medicine.


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