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 August 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."
- 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 Prostate-Specific Antigen in Combination with Radiation Therapy when Metronomic-Dose Interleukin 2 Is Used as an Adjuvant. Clinical Cancer Research, 2008; 14 (16): 5284 DOI: 10.1158/1078-0432.CCR-07-5162
- 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 (9): 3353 DOI: 10.1158/1078-0432.CCR-04-2062
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