TWO ARTICLES ON A RECENT CANCER TREATMENT BREAKTHROUGH
Genetically engineered cell offers possible cancer-killing breakthrough
Published: Thursday, Aug. 11, 2011 3:29 p.m. MDT
By Lois M. Collins, Deseret News
Research that changes a type of white blood cell so it's a weapon against cancer cells is being hailed by experts as a potential breakthrough in cancer research.
Scientists at the University of Pennsylvania turned T cells into cancer cell killers in a common type of leukemia using genetic engineering. Experts say it may be possible to engineer T cells to kill other types of cancer, including blood, breast and colon, as well.
The research, part of a very small clinical trial involving just three patients who had advanced cases of the chronic lymphocytic leukemia, is published online this week in the New England Journal of Medicine and also in Science Translational Medicine.
Two of the patients have been cancer-free for more than a year, while the other experienced improvements. The plan now, given such promising results, is to expand the trial and treat other patients, then follow them to see long-term effects, the researchers said. They also hope to test it in other, perhaps more aggressive cancers.
"This is a huge accomplishment — huge," Dr. Lee M. Nadler, dean for clinical and translational research at Harvard Medical School, told the Los Angeles Times. Nadler is credited with finding the molecule on cancer cells that the genetically engineered T cells attack.
The researchers said they added instructions to a virus for creating a molecule that binds to leukemia cells and tells the T cells to destroy them. In the clinical trial, they drew blood from the three patients who had chronic lymphocytic leukemia, infected the T cells with the virus and reinjected the blood back into the patients. The engineered T cells multiplied rapidly and killed the cancer cells, then remained for months. "They even produced dormant 'memory' T cells that might spring back to life if the cancer was to return," wrote the Times' Eryn Brown.
A CBS/Associated Press story said the therapy "resulted in armies of serial killer cells that targeted and destroyed cancer cells, even new cancer cells as they emerged. T cells typically attack viruses that way," but it noted study author
Dr. Carl June, professor of pathology and laboratory medicine at the University of Pennsylvania, said it's the first time it has been turned against cancer.
The study describes what happened after the engineered T cells were reinjected in the patient. After 13 days, "the patient began having chills and low-grade fevers associated with grade 2 fatigue. Over the next five days, the chills intensified and his temperature escalated to 102.5 degrees," they wrote, noting he suffered a variety of miserable digestive symptoms, including nausea and diarrhea. But within slightly more than three weeks of having the modified cells reintroduced, "there was no evidence of (the leukemia) in the bone marrow." Ten months out, when the study was written, that patient remained cancer free.
The researcher believe that each engineered T cell killed 1,000 cancer cells or more. They noted that the engineered cells remained for six months at high levels in the blood and bone marrow and while there they continued to express the chimeric antigen receptor.
Bone marrow transplants have been the best hope for patients suffering from chronic lymphocytic leukemia and have been the only hope for an actual cure. But the side effects have been potentially serious, even fatal, including infections and liver and lung damage. About 20 percent of those who receive such a transplant may die of complications of those side effects, rather than the leukemia that was being treated.
Dr. David Porter, director of the blood and marrow transplant program at the Hospital of the University of Pennsylvania and a study co-author, told the Los Angeles Times that earlier efforts to modify T cells have been disappointing. It was different this time because the researchers added more instructions to the virus telling the cells to "multiply, survive and attack more aggressively."
The National Cancer Institute describes leukemia as "cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the bloodstream." It says 44,000 new cases are diagnosed each year and about 22,000 people die from the disease. The institute also offers an online guide to the disease and its treatments.
The Mayo Clinic says that the form of leukemia called chronic lymphocytic leukemia affects a group of white blood cells called lymphocytes, which help the body fight infection.
One of the patients, who asked not to be identified, issued a statement through the university. He said chemotherapy worked for years, but it stopped. Now, he wrote, "I'm healthy and still in remission. I know this may not be a permanent condition, but I decided to declare victory and assume that I had won."
Genetically Modified "Serial Killer" T Cells Obliterate Tumors in Patients with Chronic Lymphocytic Leukemia, Penn Researchers Report
(PHILADELPHIA) -- In a cancer treatment breakthrough 20 years in the making, 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 chronic lymphocytic leukemia (CLL) patients treated with genetically engineered versions of their own T cells. The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma. The findings, published simultaneously 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 "serial killer" T cells aimed at cancerous tumors.
"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," said senior author Carl June, MD, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, who led the work. "It worked much better than we thought it would."
The results of the pilot trial of three patients are a stark contrast to existing therapies for CLL. The patients involved in the new study 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 at least a 20 percent mortality risk -- and even then offers only about a 50 percent chance of a cure, at best.
"Most of what I do is treat patients with no other options, with a very, very risky therapy with the intent to cure them," says co-principal investigator 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."
Secret Ingredients
June thinks there were several "secret ingredients" that made the difference between the lackluster results that have been seen in previous trials with modified T cells and the remarkable responses seen in the current trial. The details of the new cancer immunotherapy are detailed in Science Translational Medicine.
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.
Serial Killers
"We saw at least a 1000-fold increase in the number of modified T cells in each of the patients. Drugs don't do that," June says. "In addition to an extensive capacity for self-replication, the infused T cells are serial killers. On average, each infused T cell led to the killing of thousands of tumor cells – and overall, destroyed at least two pounds of tumor in each patient."
The importance of the T cell self-replication is illustrated in the New England Journal of Medicine paper, which describes the response of one patient, a 64-year old man. Prior to his T cell treatment, his blood and marrow were replete with tumor cells. For the first two weeks after treatment, nothing seemed to change. Then on day 14, the patient began experiencing chills, nausea, and increasing fever, among other symptoms. Tests during that time showed an enormous increase in the number of T cells in his blood that led to a tumor lysis syndrome, which occurs when a large number of cancer cells die all at once.
By day 28, the patient had recovered from the tumor lysis syndrome –– and his blood and marrow showed no evidence of leukemia.
"This massive killing of tumor is a direct proof of principle of the concept," Porter says.
The Penn team pioneered the use of the HIV-derived vector in a clinical trial in 2003 in which they treated HIV patients with an antisense version of the virus. That trial demonstrated the safety of the lentiviral vector used in the present work.
The cell culture methods used in this trial reawaken T cells that have been suppressed by the leukemia and stimulate the generation of so-called "memory" T cells, which the team hopes will provide ongoing protection against recurrence. Although long-term viability of the treatment is unknown, the doctors have found evidence that months after infusion, the new cells had multiplied and were capable of continuing their seek-and-destroy mission against cancerous cells throughout the patients' bodies.
Moving forward, the team plans to test the same CD19 CAR construct 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.
In addition to June and Porter, co-authors on the NEJM paper include Bruce Levine, Michael Kalos, and Adam Bagg, all from Penn Medicine. Michael Kalos and Bruce Levine are co-first authors on the Science Translational Medicine paper. Other co-authors include June, Porter, Sharyn Katz and Adam Bagg from Penn and Stephan Grupp the Children's Hospital of Philadelphia.
The work was supported by the Alliance for Cancer Gene Therapy, a foundation started by Penn graduates Barbara and Edward Netter, to promote gene therapy research to treat cancer, and the Leukemia & Lymphoma Society.
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