Alternative Vaccine Strategy Shows Promise in Prostate Cancer Patients

New research indicates that giving patients a continuous low dose of an immune system booster, a method known as metronomic dosing, as part of a therapeutic prostate cancer vaccine strategy is safe and produces similar immune responses and fewer side effects than the more common dosing method, which is not well tolerated by many patients. This study, led by researchers at that National Cancer Institute (NCI), part of the National Institutes of Health, was published in the Aug. 15, 2008, issue of Clinical Cancer Research.

The vaccine used in this study is designed to stimulate an immune response against prostate-specific antigen (PSA), a protein produced by the prostate that is often found at elevated levels in the blood of men who have prostate cancer and some non-cancerous prostate conditions. In the study, researchers examined the side effects and immune responses of patients treated with a three-pronged approach: the vaccine, radiation therapy, and an alternative dosing regimen of an immune system booster, interleukin-2 (IL-2). The patients all had localized prostate cancer, had not undergone surgery to remove the prostate, and were candidates for radiation therapy as their primary form of treatment.

"Developing an alternative method of administering vaccine therapy that is well tolerated by most patients and produces similar immune responses to standard methods may help further the development of vaccine therapies for prostate cancer," said James L. Gulley, M.D., Ph.D., of NCI’s Center for Cancer Research.

Therapeutic cancer vaccines are designed to treat cancer by stimulating the immune system to attack tumor cells without harming normal cells. Several proteins, including PSA, are overexpressed, or produced in excess amounts, by cancer cells and have shown potential to serve as triggers in initiating immune responses. These findings have led to the development of cancer vaccines that target these proteins. The proteins are also known as tumor-associated antigens. To heighten the body’s natural defenses, immune system boosters, such as IL-2, are often given with the vaccines. IL-2 administration, however, is frequently associated with substantial side effects, including fatigue and high blood sugar.

In a previous study involving the same prostate cancer vaccine, IL-2 was given to 19 patients daily for five days during each 28-day vaccine treatment cycle, and a large majority of the patients had to have the dose of IL-2 reduced or discontinued, primarily because of fatigue.

In this new study, the researchers sought to decrease the side effects associated with IL-2. To do this, the team treated 18 patients with the vaccine and radiation therapy, but with lower doses of IL-2 given over a longer period of time. The patients received the same total amount of IL-2 as in the previous study, but it was administered in smaller daily doses for 14 days of each 28-day treatment cycle.

With metronomic dosing, less than a quarter of the patients had side effects that required their dose of IL-2 to be reduced.

The research team also found that metronomic dosing of IL-2 produced effects on immune cell populations and immune responses that were similar to those observed previously with the standard dosing method. Five of eight evaluated patients had at least a three-fold increase in immune cells that were directed against PSA. The researchers also noted that, similar to the standard dosing method, metronomic dosing of IL-2 induced immune responses against other prostate cancer antigens in some patients.

"Based on safety and feasibility, metronomic dosing appears to be superior to standard dosing and administration," said Gulley. "More research is needed to evaluate the efficacy of this dosing method in treating prostate cancer."

For more information on Dr. Gulley’s research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5686.

For more information about cancer, please visit the NCI website at http://www.cancer.gov, or call NCI’s Cancer Information Service at 1-800-4-CANCER ( 1-800-422-6237 ).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


Reference:

Lechleider RJ, Arlen PM, Tsang K, Steinberg SM, Yokokawa J, Cereda V, Camphausen K, Schlom J, Dahut WL, and Gulley JL. Safety and immunologic response of a viral vaccine to PSA in combination with radiation therapy when metronomic-dose IL-2 is used as an adjuvant. Clinical Cancer Research. August 15, 2008.

Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang K, Yokokawa J, Hodge JW, Menard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, and Dahut W. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clinical Cancer Research. 2005;11:3353-62.

Researchers identify promising cancer drug target in prostate tumors

June 27, 2008

Jean Zhao, PhD, (right) is a senior author of the report.

Scientists at Dana-Farber Cancer Institute report they have blocked the development of prostate tumors in cancer-prone mice by knocking out a molecular unit they described as a "powerhouse" that drives runaway cell growth.

In an article that is being published as an advanced online publication by the journal Nature, the researchers said the growth-stimulating molecule called p110beta – part of a cellular signaling network disrupted in several common cancers – is a promising target for novel cancer therapies designed to shut it down. Lead authors of the report are Shidong Jia, MD, PhD, Zhenning Liu, PhD, Sen Zhang PhD, and Pixu Liu, MD, PhD.

The p110beta molecule and a counterpart, p110alpha, are "isoforms" – slightly different forms – of an enzyme called PI(3)K that is an intense focus of cancer research and drug development. PI(3)K is the linchpin of a cell-signal pathway that responds to growth factor signals from outside the cell.

When activated by growth factor receptors, PI(3)K turns on a cascade of genes and proteins that drives cells to divide and grow. The molecular accelerator is normally kept under control by a tumor-suppressor protein, PTEN, which acts like a brake to curb excess cell growth that could lead to cancer.

Slices of mouse prostate tissue show tumor (top left, irregular cells) in mice with a broken PTEN tumor suppressor protein but normal p110beta protein. pAKT cancer pathway is activated (lower left, brown area.) When p110beta was knocked out, pAKT pathway was silent (lower right) and prostate tissue was cancer-free (top right). Courtesy of Shidong Jia, Dana-Farber Cancer Institute.


Mutations that inactivate PTEN – in effect releasing the brake on growth signals – are found in a significant proportion of prostate, breast and brain tumors. The senior authors of the new report, Jean Zhao, PhD, and Thomas Roberts, PhD, previously showed that blocking p110alpha protein inhibits cancerous growth induced by various cancer-causing proteins, such as Her2 and EGFR. With that knowledge in hand, the researchers, in collaboration with pharmaceutical companies, are developing p110alpha blockers.

P110beta, by contrast, was thought to be a relatively insignificant player in tumors. However, "the surprise in this paper is that p110beta has been found to be a bigger player than p110alpha in tumors that result from PTEN loss," noted Zhao. "Now the drug companies, which have been focusing on p110alpha, will have to think about making p110beta inhibitors as well."

Both forms of the p110 molecule have dual tasks: they are involved in responding to insulin signals – a metabolic function – as well as relaying growth signals from outside the cell. But the importance of 110beta had been vastly underestimated, the researchers said, for reasons they don’t entirely understand.

"We knew that when cells are stimulated with growth factor signals, the activity of p110alpha, but not p110beta, rises rapidly and sharply in triggering excess cell growth," Zhao said. "We speculate that 110beta may be providing a low-level but steady growth stimulus and when PTEN is lost, it becomes an important source of cell proliferation signals."

The new findings stem from experiments in which the scientists disabled the p110beta protein in mice as a way of exploring its normal functions. In one of the experiments, the researchers "knocked out" p110beta in mice that also lacked the PTEN tumor suppressor protein and were therefore highly prone to prostate cancer. Mice that lacked PTEN but had functioning p110beta proteins all developed early prostate cancers by 12 weeks of age. In contrast, the "knockout" mice with no p110beta function remained free of prostate cancer even though the PTEN "brake" had been disabled.

The scientists concluded, as a result, that p110beta becomes a "powerhouse" to drive cancerous cell growth when PTEN function is missing.

In light of the new findings, there is likely to be great interest in finding drugs or other tools to block the p110beta protein in cancers where mutations in PTEN have unleashed the overactive growth signals, said Zhao, who is also an assistant professor of surgery at Harvard Medical School.

The task is made somewhat easier, said Roberts, by the fact that "we know what the inhibitor should look like because of our work on p110alpha inhibitors."

Roberts, who is also a professor of pathology at Harvard Medical School, said that drugs designed to block the p110alpha form are on their way to clinical testing, but he could not predict when p110beta inhibitors might become available for clinical testing.

The research was supported by grants from the National Institutes of Health and the Department of Defense for Cancer Research.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.