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Study Shows That Small Protein Can Broaden Immune Response in Humans

Treating cancer patients with interleukin-7 (IL-7), a small protein that can stimulate the immune system, leads to an increase in lymphocytes, key to the production of effective immune responses, in the body, according to a new study by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). The demonstration that IL-7 is able to broaden the possible immune responses in humans could have a wide range of clinical implications. This study was published online June 23, 2008, in The Journal of Experimental Medicine.

"Our results are only a first step in a long process," said the study's lead author, Claude Sportès, M.D., of NCI's Center for Cancer Research. "Potential clinical applications need to be tested systematically in order to define the field of clinical application for the drug."

Chemotherapy and HIV infection often deplete the body of lymphocytes, thereby, reducing immune function. With aging, individuals older than 45 to 50 years are generally incapable of regenerating significant amounts of naïve T lymphocytes, because of the progressive loss of function of the thymus, the organ where T lymphocytes differentiate in order to perform very specific functions. In contrast, in younger adults, restoration of naïve T cell populations takes 12 to 24 months. Naïve T cells are essential for the immune system to be able to adapt to new pathogens encountered in life and to support the body's ability to fight cancer.

IL-7 is a naturally produced cytokine that is essential for T cell development during fetal life. Cytokines are small proteins produced by cells of the immune system that help regulate immune responses. IL-7 remains critical after birth for maintaining some types of T cells in the body. Previous research in animal models has shown that IL-7 can help restore T cell populations.

To assess the effects of IL-7 treatment in humans, the researchers administered a laboratory-generated form of IL-7 (rhIL-7) to 16 cancer patients with solid tumors, who had not responded to standard treatment, under their skin every other day for 14 days. The patients, whose ages ranged from 20 to 71 years, each received a total of eight doses of rhIL-7. The researchers found an increase in the total number of lymphocytes in the patient's bloodstreams. The number of CD4+ T cells increased by about 300 percent and the number of CD8+ T cells increased over 400 percent. One function of CD4+ T cells is to act as "helper" cells and recruit the activity of other immune cells, whereas CD8+ T cells act directly as cytotoxic T cells that kill infected cells and tumor cells. The greatest effect of rhIL-7 was on naïve CD4+ and CD8+ T cells. Remarkably, this cytokine promoted the expansion of naïve T cells in older individuals, returning their T cell profile in the blood to what is seen in younger people and children. Treatment with rhIL-7 also had a notable effect on the number of memory CD4+ T cells, which play a key role in the body's defense against tumors and chronic, persistent viral infections.

The changes induced by rhIL-7 reflected increases in the total numbers of lymphocytes in the body. These higher lymphocyte numbers remained elevated for up to six weeks after treatment ended. The researchers found that rhIL-7 caused increases in lymphocyte proliferation as well as an influx of lymphocytes into the bloodstream from lymphoid tissues, such as the lymph nodes and the spleen. They did not observe a direct effect on the thymus during this two-week study; however, other studies have shown that, in adults, participation by the thymus in immune cell restoration may take several months after T cell depletion.

"These findings may lead to a large number of clinical applications for IL-7," said Sportès. "For example, there might be therapeutic applications in immune-compromised individuals, such as in cancer or HIV-infected patients, to boost lymphocyte counts and immune responses. It might also be used to enhance immune responses to conventional vaccines, particularly in older individuals, as well as responses to cancer vaccines or other forms of cancer immunotherapy."

"NCI has long been at the forefront of the clinical development of IL-7, and we plan to continue exploring the biologic properties of IL-7 in humans and to define its clinical applications," added Sportès.

The study was conducted by researchers in the Experimental Transplantation and Immunology Branch of NCI's Center for Cancer Research, in close collaboration with the Pediatric Oncology Branch; the NIH Clinical Center; Cytheris, Inc., Rockville, Md.; and The Cancer Center at Hackensack University Medical Center, Hackensack, N.J.

For more information on Sportès' research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5907.

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:
Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, Fry TJ, Engels J, Buffet R, Morre M, Amato RJ, Venzon DJ, Korngold R, Pecora A, Gress RE, and Mackall CL. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of na´ve T cell subsets. The Journal of Experimental Medicine. Online June 23, 2008.

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