Current issue
Boosting immunity via vaccine
A therapy based on dendritic cells
is tested in cancer patients
BY LYNN LOVE
When scientists began treating advanced cancer
patients with an experimental vaccine in July 2003, they hoped
their formula would boost the patients’ natural killer T
cells, fast-responding components of the immune system that are
thought to attack some viruses and tumors and quickly alert the
immune system to danger.
Not only did natural killer T cells
proliferate, but they also spurred other, slower-responding immune
system cells into action. And the effects lasted for more than
three months in each of the five patients in whom the vaccine has
been tried over the past two years, far longer than the typical
short-lived natural killer T cell response.
The surprisingly positive findings, which were
published in the May 2 issue of the Journal of Experimental Medicine, are encouraging Rockefeller University researchers to
pursue additional clinical studies using vaccines based on natural
killer T cells against both cancer and viral infections.
“This study clearly demonstrates the
feasibility to specifically boost this important immune cell in
humans and therefore opens the door for targeting the innate arm of
the immune system against pathogens and cancer,” says study
senior author Madhav Dhodapkar, who is the Irene Diamond
Associate Professor and head of the Laboratory of Tumor Immunology
and Immunotherapy.
Natural killer T cells are part of
what’s known scientifically as the innate immune response, or
that part of the immune response that should, under normal
circumstances, respond quickly. Most prior cancer vaccines have focused
on the adaptive immune system. What’s more, prior attempts to
mobilize natural killer T cells in humans have met with limited
success.
But the vaccine designed by Dhodapkar and his
colleagues also led to an enhancement in adaptive immunity, the
delayed immune response that is more fine-tuned to specific foreign
invaders like microbes or mutated cells. The result suggests a
successful link between innate and adaptive immune response
prompted by the new vaccine.
“Early events of the immune system may
determine what happens down the line,” says Dhodapkar.
“In cancer, we’ve learned that both arms of the immune
system are defective.” The absence of a coordinated immune
response may allow cancer cells to grow and spread.
The process for creating the vaccine used in
this investigation is known as ex vivo amplification. Scientists at
Rockefeller University and elsewhere have devised methods to expand
patients’ own dendritic cells, specialized cells that are at
the heart of the body’s immune system, outside of their
bodies, then expose the cells to antigen or load them with powerful
drugs and send them back inside the body to deliver emphatic
messages or finely tailored treatments.
Because the dendritic cell is central to the
immune system’s operations, it is capable of more precise
control of immune mechanisms and better delivery than traditional
treatments that send antigen or drugs randomly into the
bloodstream. KRN-7000 (manufactured by Kirin Breweries, Japan), the
drug used in this study, is known to be safe, but was not effective
at expanding natural killer T cells in prior trials when used
alone. Specialized delivery via dendritic cells arguably makes the
difference in the drug’s efficiency.
Using mature, rather than developing,
dendritic cells likely also contributed to the consistent results,
says coauthor Ralph Steinman, a senior Rockefeller University scientist who
discovered the dendritic cell in 1973. Naturally occurring mature
dendritic cells are known to do two things. One is to process and
present antigen, or material considered foreign to the body,
allowing other immune system cells to recognize foreign material
and tumor cells. The other is to deliver “accessory”
signals to immune system cells so that they develop into helpers or
killers focused on removing an antigen. Among these accessory
signals are cytokines.
“The interaction of mature dendritic
cells with natural killer T cells results in the production of many
immune-enhancing cytokines,” Steinman says. When scientists
elsewhere carried out an experiment similar to the current study,
but used immature dendritic cells, results were limited and not
consistent.
The Rockefeller researchers now are planning
another clinical study, in a larger population, to build on the
current approach both by improving the function of the natural
killer T cells and the downstream recruitment of other immune
system cells. “This study is an
important first step and provides some new clues about how the
immune system works, but we need to build on this to improve
clinical efficacy. Fortunately, we already have several new
insights from the bench along these lines that are ready to be
translated to the bedside,” says Dhodapkar. “The next
challenge is to test these approaches in our patients.”
“The principle of this vaccine is valid
for both cancer and infectious disease,” says Dhodapkar.
“These findings therefore support testing this approach in
chronic viral infections such as HIV or hepatitis C.”
May 13, 2005
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