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Kim Irwin ([email protected])
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Kambra McConnel ([email protected])
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RESEARCHERS AT UCLA'S JONSSON CANCER CENTER DISCOVER METHOD THAT BOOSTS IMMUNE SYSTEM WITH SIMPLE DAILY INJECTION, MAY LEAD TO NEW VACCINE TREATMENTS FOR CANCER
For the first time, researchers at UCLA's Jonsson Cancer Center have discovered a way to increase the number and function of rare and powerful immune system cells inside the human body, a process previously only possible in a laboratory.
Daily injections of two immune system hormones resulted in the growth and activation of a large number of dendritic cells, specialized blood cells that recognize foreign substances and stimulate an immune response to fight invaders. Now, UCLA researchers hope to couple this immune system booster with vaccine treatments as a new weapon in the battle against cancer.
The discovery was tested in an early phase clinical trial at UCLA's Jonsson Cancer Center. The findings are reported Saturday, April 1, in the journal Cancer Research (http://www.aacr.org) in an article authored by cancer researchers Dr. Michael Roth and Dr. Robert Figlin.
This new method for growing dendritic cells inside patients resulted from 10 years of basic and clinical research by a multidisciplinary team of UCLA physicians and scientists, Roth and Figlin said.
"I think this is a major step toward making vaccine therapies more patient friendly and less costly," said Figlin, a researcher and physician at UCLA's Jonsson Cancer Center. "We were very surprised at our findings, and very pleased."
Further testing of the immune system hormones may begin at UCLA in about three months and is expected to focus on prostate cancer, Figlin said.
Dendritic cells are thought to be the key cells in the body that take up and process abnormal proteins and molecules from such invaders as bacteria, viruses and allergens. Dendritic cells process abnormal proteins from these invaders and uses them to stimulate an immune response. Dendritic cells are what allow the body to respond to immunizations against illnesses like the measles, tetanus or the flu - protecting the body from future infection, Roth said.
For some reason, however, dendritic cells aren't successful stimulating the body to fight off cancer, even though tumor cells express abnormal proteins and molecules. Scientists believe that cancers trick the immune system, preventing the dendritic cells from responding to the invasion.
"Dendritic cells removed from cancer patients don't function," said Roth, a cancer and tumor immunology researcher at UCLA. "It's as if they've been turned off."
One theory about why that might happen is that while dendritic cells are extremely powerful, they're also very rare, accounting for just one-tenth of one percent of white blood cells. UCLA researchers theorized that if the number of dendritic cells could be increased and their function restored, cancer patients might be able to fight the deadly disease using their own immune systems, eliminating the need for conventional therapies such as chemotherapy, which are associated with debilitating side effects.
In 1996, Roth and colleague Sylvia Kiertscher were the first to report that certain blood cells called monocytes - more common in the human body than dendritic cells - could be persuaded to mature into dendritic cells when in the presence of two immune systems hormones called Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin-4 (IL-4). Compared to mature dendritic cells, which comprise only a small fraction of white blood cells, monocytes make up 5 to 10 percent of blood cells, Roth said.
"Discovering that monocytes could mature into dendritic cells was an important finding because monocytes are much more plentiful in the blood, providing a ready source for preparing dendritic cells," Roth said.
Building on that discovery, UCLA cancer researchers and scientists at other institutions set out to grow dendritic cells outside the human body. They removed large quantities of blood from patients, grew monocytes into dendritic cells in the lab, stimulated them with some form of abnormal protein from a person's tumor, and then injected the dendritic cells back into patients. The idea was that dendritic cells, once activated and loaded with abnormal tumor proteins, would stimulate the immune system to recognize cancer as an invading enemy and attack.
Initial trials using this approach resulted in some success, making researchers optimistic about the potential of dendritic cell therapy. The process, however, is labor intensive and costly, and requires that patients have large catheters inserted into their veins in order to draw blood for the harvest of monocytes.
"What we envisioned was another way to accomplish the same thing," Roth said. "Instead of taking the blood out, growing it in a lab and re-infusing it into the patient, we could give the immune-stimulating hormones directly to the patients and allow the monocytes to mature into dendritic cells in their own bodies."
Based on early results, the administration of these immune-stimulating hormones seems to be working, Roth and Figlin said. No expensive processing facilities are needed and patients can give themselves the injections at home, eliminating the need for a trip to the hospital. And the side effects are minimal, Figlin said.
In all, 21 patients with advanced cancers took part in the early testing at UCLA. Patients received GM-CSF alone or GM-CSF with escalating doses of IL-4. The study determined optimum dose levels and that the treatment was safe for the patients, Figlin said. It also proved that GM-CSF alone had no impact on dendritic cells, but that the two hormones together, especially at higher doses of IL-4, prompted monocytes to mature into dendritic cells. Several patients in the study showed tumor responses to the therapy, and one patient showed a "clinically significant and sustained tumor regression," according to the article in Cancer Research.
"There was about a 100 fold increase in the number of dendritic cells in patients who got the combination therapy," Roth said. "That means the body might have enough dendritic cells to stimulate the immune system to fight cancer."
The treatment was given intermittently, with patients giving themselves daily injections for two weeks, taking a break, and following that with two more weeks of injections.
"One of the real advantages of this approach is not only does it appear to be working, but it's potentially user-friendly and involves a relatively non-toxic therapy that can be administered at home," Roth said. "But there's a long way to go to optimize this therapy. To see positive results in a phase one trial is very exciting, but this has only been done in a limited number of patients and more study needs to be done."
Roth did most of the laboratory research that served as a foundation for the study, while Figlin cared for the patients. Figlin hopes to replicate the success from phase one in future phase two trials. He said the team will focus on prostate cancer, in part because a patient from the phase one trial with prostate cancer had a positive response to the immune boosting hormone treatment.
The experimental therapy could be applied to all cancers. Some cancers, like prostate, might respond to the boost in the immune system alone, while other cancers might require that a vaccine be used in concert with the hormones, Figlin said.
Figlin said vaccine therapy for cancer is "exploding, especially as we get new technological advances that make it easier to understand the biology of cancer."
"This harnesses the body's own immune system to fight cancer," Figlin said. "And it's another good example of how to translate science from the lab into care for our patients."
-UCLA-
For more information about UCLA's Jonsson Cancer Center, its people and resources, visit our site on the World Wide Web at http://www.cancer.mednet.ucla.edu.
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