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Recruiting a Dangerous Foe to Fight Cancer and HIV

Biotechs have high hopes that a bacterium that causes food poisoning can boost the body's immune system as well as be enlisted to build vaccines against deadly diseases



Courtesy of the Department of Health and Human Services Centers for Disease Control and Prevention; Elizabeth White

If you are pregnant or know anyone who is pregnant, you have almost certainly heard of Listeria, a dangerous bacterium that contaminates vegetables, dairy and meat. It is something you want to avoid: Listeria infections kill about 500 people a year in the U.S., and 2,000 more become seriously ill with food poisoning. Pregnant women are about 20 times more likely to become infected.

So it might surprise you that scientists want to inject patients who have HIV and cancer with the bacterium, whose scientific name is Listeria monocytogenes.

That is because Listeria creates a strong immune response in the body. Medical researchers are trying to harness this behavior by creating their own modified version of Listeria that is less dangerous as a bug, strengthens the immune system in general, and has the ability to get inside tumors. Once inside the tumor, the idea is for this bioengineered Listeria to give the immune system the green light to terminate the tumor with extreme prejudice.

"When you're dealing with cancer, you want autoimmune responses, and Listeria invokes these responses," says John Rothman, the vice president of clinical development at Advaxis, Inc., a biotech in North Brunswick, N.J., that is working on a Listeria-based vaccine, Lovaxin C. "Listeria is a pretty nifty bug for this purpose," adds Rothman. "We're co-opting a lot of evolution here because Listeria modifies the immune system in a lot of ways."

Advaxis tested the safety of Lovaxin C between 2005 and 2007 in 15 women with progressive, recurrent or advanced cervical cancer who previously had been treated unsuccessfully with chemotherapy, radiotherapy or surgery. The women reacted with symptoms including headache, fever and chills, which Rothman attributes to the body's immune response designed to fight the Listeria infection. The company concluded that the patients generally tolerated Lovaxin C well, depending on the strength of the dose given. Too much of the drug did cause high fevers and significant drops in blood pressure. "Both the response rate and survival data are encouraging," Rothman says.

The company announced Tuesday that it expects to initiate phase II Lovaxin C testing in the U.S. this summer for the treatment of cervical intraepithelial neoplasia, an overgrowth of cells in the cervix caused by the human papillomavirus—a sexually transmitted virus that can lead to invasive cervical cancer if not diagnosed properly and left untreated. Advaxis also wants to test the drug's effectiveness combating head and neck cancers.

Advaxis's researchers are not the only ones looking to make Listeria into an effective vaccine. Using the bug to create and deliver vaccines dates back to the early 1990s, when University of Pennsylvania School of Medicine microbiologist Yvonne Paterson and University of California, Berkeley, microbiologist Daniel Portnoy showed that L. monocytogenes replicates in a host cell's cytoplasm (its gelatinous fluid filling) and can move from one cell to another. In fact, Advaxis draws on more than a decade's worth of research by Paterson, a breast cancer survivor who has committed herself to developing medicine that can find and destroy cancer cells and better prevent and treat infectious diseases such as HIV.

One of the concerns about Listeria is that, even if it reproduces slowly in a patient, this could be dangerous to patients suffering from already compromised immune systems, says Darren Higgins, an associate professor of microbiology at Harvard Medical School who has performed his own experiments on Listeria to find a strain that stimulates the immune system but does not reproduce inside the body. That's a key concern in patients with HIV—the virus's middle name, "immunodeficiency," says it all—and those who have had chemotherapy, which also ravages the immune system.

Taking this a step further, Anza Therapeutics, which late last year spun out of Concord, Calif., biopharmaceutical company Cerus Corporation, is testing an approach to making vaccines that employ Listeria which is dead, and thereby unable to reproduce, although still able to stimulate the immune system. "The big worry about Listeria is that it can cause listeriosis in people with weakened immune systems," says Tom Dubensky, Anza's co-founder and chief scientific officer. "Many live attenuated vaccines have the ability to revert to being dangerous again." Anza, with funding from the U.S. National Institutes of Health and the Bill & Melinda Gates Foundation, is hoping this approach, still in animal testing, can be used to develop a vaccine for hepatitis C virus (HCV) and HIV. Anza is also testing a second approach—presently in human clinical trials—to vaccine development that uses a form of live, but weakened Listeria that is modified so it cannot revert to its dangerous behavior. The company is conducting U.S. Food and Drug Administration–approved early-stage clinical studies of this approach at various sites in the U.S. on patients with advanced cancers.

Higgins and H. G. Archie Bouwer, an immunology research scientist at the Earle A. Chiles Research Institute and Portland VA Medical Center, reported in a March 2006 Proceedings of the National Academy of Sciences USA article using a weakened strain of Listeria to vaccinate monkeys against larger doses of the bacterium. It worked: "Our Listeria studies demonstrate the potential to generate vaccine strains of bacteria that are effective, yet safe for both healthy and immunocompromised individuals," they wrote, referring to people with HIV or who have been through the ravages of chemotherapy.

Higgins says that Listeria could be used to make improved vaccines for diseases other than cancer and HIV as long as researchers can figure out which targets to tell the immune system to fight. "Listeria monocytogenes is potentially a great delivery vehicle," he says, "but you need to know what to deliver."

The use of Listeria as a vaccine is promising, but it is too early to tell just how effective it might be, agrees Stanley Plotkin, emeritus professor of pediatrics at the University of Pennsylvania and an executive advisor to pharmaceuticals company Sanofi Pasteur. "We'll have to see if the promising results in animals will be borne out in human trials," he says. One of the bacterium's attractive features, for example, is that it might help the immune system fight viruses within cells—a notoriously tricky problem for vaccines—because Listeria lives within cells, instead of floating around the bloodstream.

So far, however, the effectiveness of Listeria and other potential building blocks for vaccines against cancer or HIV remains unproved. It will be five years before researchers are able to identify the best vectors, and another decade before there is a licensed vaccine, he adds, "if we're lucky."

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