Cancer Killing Breakthrough with Leukemia May Lead to Gene Attacks on Other Cancers
Within three weeks, the tumors had been blown away - Watch Video
Aug. 10, 2011 - In a cancer treatment breakthrough 20 years in the making, researchers 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, according to the
University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine.
The medical team reports the cancer-killing cells are still active.
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."
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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."
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.
"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
"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
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.
Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented
medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from
the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.
The University of Pennsylvania Health System's patient care facilities include:
The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn
Presbyterian Medical Center; and Pennsylvania Hospital the nation's first hospital, founded in 1751. Penn Medicine also includes additional
patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In
fiscal year 2010, Penn Medicine provided $788 million to benefit our community.
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