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11.08.2011 news No Comments

Genetically Modified ‘Serial Killer’ T-Cells Obliterate Tumors in Leukemia Patients

20110811-084849.jpgScienceDaily (Aug. 10, 2011) — 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 in the New England Journal of Medicine and Science Translational Medicine on August 10, 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.

17.12.2010 news 1 Comment

FDA revokes Avastin approval for breast cancer.

Genentech imageWASHINGTON (AFP) The US Food and Drug Administration said Thursday that Avastin is not an effective treatment for breast cancer and said it would take steps to revoke market approval and change the drug’s label.

Acting on the advice of an expert panel earlier this year, the FDA said the drug, also known as bevacizumab, carries risks such as severehigh blood pressure and hemorrhage and does not prolong overall survival in women suffering from breast cancer.

Meanwhile, European experts urged restricting the drug’s use to be combined with just one type of chemotherapy, instead of with several as is the current practice.

The FDA “is recommending removing the breast cancer indication from the label for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use,” it said in a statement.

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04.08.2010 blog, news No Comments

FDA Medical Device Regs Updated

Medtronic, Stryker, J&J Face New U.S. Rules for Medical Device Approvals
By David Olmos and Sophia Yan – Aug 3, 2010 9:01 PM PT

Medical device makers Medtronic Inc., Johnson & Johnson and Stryker Corp. face new safety rules under a revamped program laid out by U.S. regulators that may help speed approval of products from condoms to CT scanners.

The Food and Drug Administration released the proposed new requirements for the so-called 510(k) program that covers products similar to previously approved devices, or about 90 percent of products cleared for sale.

Medical device companies say the 510(k) process is rife with delays and inconsistent requirements, while consumer advocates say patients are at risk because of inadequate safety rules. The new proposals address both issues, giving device makers a more predictable process while insisting they provide more safety data, said Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health. read more

05.06.2010 news No Comments

Parma hospital part of settlement in heart device kickback scheme

By Peter Krouse, The Plain Dealer June 04, 2010, 11:39AM

PARMA, Ohio — Parma Community General Hospital must pay part of a $3.9 million settlement that resolves civil allegations that St. Jude Medical Inc. paid illegal kickbacks to two hospitals to secure heart-device business, the U.S. Justice Department announced Friday.

The kickbacks represented improper rebates paid to Parma Community General and Norton Healthcare of Louisville, Ky., according to the Justice Department.

St. Jude, based in St. Paul, Minn., will pay $3.725 million under the settlement, Parma Community General will pay $40,000 and Norton Healthcare will pay $133,000

The investigation was initiated by a whistleblower named Jerry Hudson who worked for St. Jude. He received $640,050 as part of the settlement, the Justice Department stated. read more

19.01.2010 news 1 Comment

New Technology for Fibroid Ablation.

News from the Wall Street Journal on a novel new minimally invasive device  that treats fibroids in women.

Of all the pains and indignities the female body suffers, some of the most common are uterine fibroids—benign tissue growths in the womb. It’s estimated that as many as 70% of women develop them at some point. Most are asymptomatic and women never know they’re there. But in about one-third of cases—even more among African-American women—the fibroids become large enough to cause pain in the back, abdomen and pelvis, bloating and very heavy menstrual bleeding. Some grow to be as large as a grapefruit and can interfere with other organs.

The standard treatment is a hysterectomy, which permanently removes the uterus along with the fibroids. More than 200,000 hysterectomies are performed in the U.S. each year for fibroids; it’s the second most common surgical procedure for women, after Cesarean sections. read more