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Boosting immunity via vaccine
A therapy based on dendritic cells is tested in cancer patients
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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