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Serial Killer T-Cells Destroy Leukemia Tumors

August 11, 2011

In a cancer treatment breakthrough, scientists for the first time have used gene therapy to successfully destroy tumors in patients with advanced chronic lymphocytic leukemia (CLL).

Researchers from the University of Pennsylvania’s Abramson Cancer Center and Perelman School of Medicine have shown sustained remissions of up to a year among a small group of advanced CLL patients treated with genetically engineered versions of their own T cells.

The procedure, which involves removing patients’ cells and modifying them, then infusing the new cells back into the patient’s body following chemotherapy, provides researchers with a new outlook in ways to treat other forms of cancers including those of the lung and ovaries.

The study findings, which were published today in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of the use of gene transfer therapy to create killer T cells aimed at cancerous tumors.

The treatment trial included three patients suffering from CLL, a disease that affects up to 4,000 people annually in the UK. Two of the participants in the Phase I trial have been in remission for up to one year. The third had a strong anti-tumor response, and his cancer remains in check. The researchers plan to treat four more CLL patients before moving into a larger Phase II trial.

Senior study author Professor Carl June said the treatment was so powerful that tumors were destroyed in under a month with few side effects.

“Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected,” said June, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center. “It worked much better than we thought it would.”

The patients in the trial had few other treatment options. The only potential curative therapy would have involved a bone marrow transplant, a procedure which requires a lengthy hospitalization and carries a minimum 20 percent mortality risk — and even then only offers a 50 percent chance of a cure.

“Most of what I do is treat patients with no other options, with a very, very risky therapy with the intent to cure them,” said study co-author David Porter, MD, professor of Medicine and director of Blood and Marrow Transplantation. “This approach has the potential to do the same thing, but in a safer manner.”

June thinks there were several “secret ingredients” that made the difference between the uninspiring results of past trials and the remarkable responses seen in the new trial.

After removing the patients’ cells, the team reprogrammed them to attack tumor cells by genetically modifying them using a lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19.

Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL tumor cells and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits side effects typically experienced during standard therapies.

The team engineered a signaling molecule into the part of the CAR that resides inside the cell. When it binds to CD19, initiating the cancer-cell death, it also tells the cell to produce cytokines that trigger other T cells to multiply — building a bigger and bigger army until all the target cells in the tumor are destroyed.

The researchers say their success in the new trial is “unprecedented.”

“We saw at least a 1000-fold increase in the number of modified T cells,” they wrote, adding that it occurred in each of the patients in the trial. “Drugs don’t do that,” they added.

“This is very encouraging and it’s definitely a step in the right direction, although a lot more work is needed to see if it can benefit more patients as this is a small sample,” Dr David Grant of the charity Leukemia and Lymphoma Research told the Daily Mail.

“But gene transfer therapy to strengthen immune cells is a much more attractive option than toxic anti-cancer drugs and it is an approach we are also working on in Britain, so this is promising in bringing us closer to helping more patients,” he added.

Two British trials of this gene therapy are opening next year in London, one for acute myeloid leukemia and the other for acute lymphoblastic leukemia.

Dr. Walter Urba of the Providence Cancer Center in Portland Oregon cautioned that continued presence of activated T cells and memory cells might be more of a problem in other types of cancer where toxic effects on normal tissue could be severe.

“One of the big questions is … will those persistent T-cells continue to work and prevent that tumor from coming back,” Urba, who was not involved in the study, told Reuters.

The research team pioneered the use of the HIV-derived vector in a clinical trial in 2003 in which they treated HIV patients with an anti-sense version of the virus. That trial demonstrated the safety of the lentiviral vector used in the present work.

The team plans to further test the same CD19 CAR in patients with other types of CD19-positive tumors, including non-Hodgkin’s lymphoma and acute lymphocytic leukemia. They also plan to study the approach in pediatric leukemia patients who have failed standard therapy. Additionally, the team has engineered a CAR vector that binds to mesothelin, a protein expressed on the surface of mesothelioma cancer cells, as well as on ovarian and pancreatic cancer cells.

The gene therapy trial, which was expensive, was funded entirely from the academic community. 

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