A team from the Perelman School of Medicine and the
Abramson Family Cancer Research Institute at the University of Pennsylvania
found that the FDA-approved drug daclizumab improved the survival of breast
cancer patients taking a cancer vaccine by 30 percent, compared to those
patients not taking daclizumab.
This proof-of-concept
study is published this week in Science Translational Medicine. Senior authors
of the study are Robert H. Vonderheide, MD, DPhil, associate professor of
Medicine, and James Riley, PhD, associate professor of Microbiology.
The team proposed that
daclizumab, already used for kidney
transplantation, would be effective in depleting regulatory T cells (Tregs)
and restoring the immune system's ability to fight tumors. Tregs are an
important population of white blood cells that
help turn off the immune system when the system's job is done. Cancer immunotherapy has
been used for the last decade, but researchers have been trying to tweak the
system to get immune cells to react more robustly to destroy tumors. In time,
though, the body slams on the breaks, rendering vaccines less effective.
Tumor cells exploit
Tregs, drawing them to the tumor area. Tregs are essentially hijacked by the
tumor, surrounding even the smallest tumors in a protective shell, preventing
other tumor-fighting white blood cells from getting to tumor cells at the core.
Tregs rely on a
particular protein, called IL-2, for most of their functions. Daclizumab is an
antibody that binds to the CD25 receptor on the surface of Tregs to which IL-2
binds. Tregs are deprived of IL-2 in the presence of daclizumab since it binds
to the CD25 receptor instead of IL-2.
But rather than causing
Tregs to die, using normal lymphocytes from a biobank at Penn run by
Riley, the team found the lack of IL-2 forces Tregs to convert into normal T
cells that no longer surround the tumor.
Once this happens, the
tumor-fighting immune
cells might be able to make their way into the tumor.
To bring this idea to
patients, the team then designed a clinical trial, which was directed by
co-author Kevin Fox, MD, professor of Medicine, and administered daclizumab to
10 patients with metastatic breast cancer prior to giving them an experimental
breast cancer vaccine developed and manufactured at Penn.
"Daclizumab worked
incredibly well," says Vonderheide.
There were no detectible
side effects, and the T-cell conversion in the patients on daclizumab lasted
two months. Their tumors didn't shrink, but in six out of the 10 patients the
tumors did stop growing. And, the daclizumab patients had an increased survival
of about seven months compared to patients on the cancer vaccine alone.
To date, says
Vonderheide, all previous attempts to eliminate Tregs have been toxic and
short-lived, but the effects of daclizumab were observed to be rapid,
prolonged, and consistent.
"Although we tested
our approach in patients with breast cancer, we know that Tregs can block the
immune response against most human cancers," says Vonderheide. "Drugs
like daclizumab might be useful for most cancer patients, especially those
receiving other types of immune therapy.
Although Tregs do help
prevent autoimmunity, we did not observe an autoimmune response because we did
not convert all Tregs in the body, only those cells that seem to protect the
tumor. Going after only some, but not all Tregs, we believe, was an important
and unique aspect of our study. Although there is a great deal of work to do to
confirm our findings, we believe this will have major implications for cancer vaccine regimens
in other types of cancer."
Although daclizumab is
not currently available from its manufacturer, a second trial with a related
FDA-approved drug is slated to open for enrollment at Penn this summer for
patients with metastatic breast cancer.
More information: This work was supported by the National Cancer Institute of the
National Institutes of Health under grant CA111377; the Juvenile Diabetes
Research Foundation (JDRF); the Collaborative Centers for Cell Therapy and the
JDRF Center on Cord Blood Therapies for Type 1 Diabetes; the Breast Cancer
Research Foundation; and the Abramson Family Cancer Research Institute.
Vonderheide and co-author Susan Domchek declare a potential financial conflict
of interest related to inventorship on a patent regarding hTERT as a
tumor-associated antigen for cancer immunotherapy (Cancer immunotherapy and
diagnosis using universal tumor associated antigens, including hTERT, U.S.
Patent 7851591).
Journal reference: Science
Translational Medicine
Provided by University
of Pennsylvania School of Medicine
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