Why Don't Cancer Vaccines Work Better?

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Building better therapeutic vaccines for chronic infections

Study finds that poor T cell responsiveness limits current approaches

PHILADELPHIA - In recent years, researchers have become increasingly

interested in developing therapeutic vaccines.

Most Americans are familiar with prophylactic, or preventive

vaccines, which protect an individual from infections; examples

include the common pediatric vaccines as well as the flu shot. But

therapeutic vaccines are designed instead to be administered to

patients who have already acquired chronic infections, such as HIV or

hepatitis. These therapeutic vaccines aim to enhance the immune

system's ability to combat an infectious agent, such as a virus.

Researchers are also developing therapeutic vaccines to treat a

variety of cancers.

But many experimental therapeutic vaccines have thus far fallen short

of expectations. Now, scientists at The Wistar Institute and Emory

University offer details about what may prevent the immune system

from responding effectively to a therapeutic vaccine during a state

of chronic infection. Their findings suggest how scientists might

alter therapeutic vaccination approaches to make the immune system

respond better. Their work is published today in the Journal of

Virology.

" In this study, we wanted to look at why therapeutic vaccines are

generally less effective than prophylactic vaccines, " says E.

Wherry, Ph.D., assistant professor in Wistar's Immunology Program and

lead author of the study. Wherry conducted the research as a

postdoctoral fellow in the Emory University laboratory of Rafi Ahmed,

Ph.D., before joining Wistar earlier this year. " What we found was

that the T cells in the chronically infected mice responded poorly to

the vaccine. "

Specifically, Wherry says, the T cells failed to proliferate, or

expand in number. This failure to proliferate seemed to correlate

with a high viral load, which suggests several directions researchers

might pursue in improving response to therapeutic vaccines.

" The ongoing stimulus to the immune system that occurs in chronic

infection seems to prevent the immune cells from responding optimally

to a therapeutic vaccine, " Wherry says. " If we could lower viral load

before therapeutic vaccination, we might be able to improve

efficacy. "

The next step for the research, Wherry says, will be to combine

therapeutic vaccines with other modalities that either lower viral

load or enhance T cell function, particularly the proliferative

capacity of T cells. Possible examples include anti-virals that could

be given prior to therapeutic vaccination, or a cytokine that might

boost the proliferation or survival of responding cells.

Wherry's group at Wistar is continuing to work on understanding at a

fundamental level why the T cell proliferation is poor when a

therapeutic vaccine is administered during a state of chronic

infection. He is also planning to compare the immune response using

different therapeutic vaccine platforms. While Wherry's primary

interest is in chronic infection, he notes that research in this area

should inform the design of better therapeutic cancer vaccines as

well because many of the deficiencies in immune response are similar

whether the antigen confronting the immune system is a virus or a

tumor.