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
"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
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.
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 naïve
T cell subsets. The Journal of Experimental Medicine. Online
June 23, 2008.