NEWS

Scientific Interest in Newcastle Disease Virus Is Reviving

Nancy J. Nelson

The story of Newcastle disease virus therapy has taken many twists and turns — spanning two continents and many decades.

Early success with the viral vaccine in humans was first reported in the United States in the early 1980s, but it is not until recently that interest in the virus has resurfaced both in the alternative medicine community and among researchers in academia and private industry. The National Cancer Institute has just signed a Cooperative Research and Development Agreement with Pro-Virus, Inc., in Gaithersburg, Md., to carry out early trials, and phase III trials are beginning in Europe.

Several scientists now agree that Newcastle disease therapy has all the hallmarks of "promise." The virus preferentially kills tumor cell lines, is remarkably effective in killing tumors in animals, and appears to be both safe and to varying degrees, effective in phase II studies both here and in Europe. Moreover, the therapy is deemed relatively safe and no serious side effects have been seen in any of the trials so far.

NCI also is in the process of making information available about the vaccine on its Web site in response to consumer calls to the Cancer Information Service, a nationwide telephone service for the public.

"MTH-68 (a viral strain of the Newcastle virus used in Hungary) has been promoted for the treatment of cancer in some of the alternative medicine literature for many years," said Jeffrey D. White, M.D., director of NCI's Office of Cancer Complementary and Alternative Medicine.

Newcastle disease virus was first isolated in 1927 in Newcastle, England, in domestic chickens where it causes severe disease, affecting the alimentary and respiratory tract as well as the central nervous system. However, for more than 50 years an attenuated NDV vaccine has been used successfully in chickens to prevent disease. The virus's natural hosts are birds, but other than mild fever for a day, there have been few adverse effects in humans.

The NDV vaccines are used to treat cancer rather than prevent it (as in chickens) and contain either the virus alone or viral-infected tumor cells taken from the patient's own tumor or tumor cell lines grown in the laboratory. For the majority of human trials to date, viral-infected tumor cells from a patient's own tumor have been used, but how the vaccine works is not yet clear.

However, three cellular mechanisms have been proposed. First, lytic strains of the virus may simply kill the tumors directly. Secondly, for non-lytic strains, the viral proteins inserted into the tumor cell membrane after infection may enhance an immune response. And finally, the virus itself may stimulate the host to produce cytokines such as interferons or tumor necrosis factor, which in turn lead to the activation of natural killer cells, macrophages, and sensitized T cells. Because NDV activates both interferon and tumor necrosis factor in its host, the third mechanism is considered a likely possibility.

Newcastle Pioneer

The pioneer in NDV therapy was William A. Cassel, Ph.D., who retired more than 10 years ago from Emory University's Department of Microbiology and Immunology in Atlanta, Ga. In phase II trials with malignant melanoma patients in the 1970s, Cassel saw a 12% progression to disseminated disease in the treated group after 3 years, compared to 95% in a group of historical controls. He has continued treating the original 32 patients and an additional 51 melanoma patients to this day. Most patients received NDV-infected human melanoma cell lines; four patients received vaccine containing their own viral-infected tumors.



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Dr. William A. Cassel

 
In a 15-year follow-up study, whose results appeared in Molecular Medicine this year, it was reported that the first group had a 59% survival rate and the second 53%, compared to 38% in historical controls. Initially, patients had no detectable disease beyond regional lymph nodes, which were removed prior to vaccine therapy.

Douglas R. Murray, M.D., Department of Surgery at Emory and co-author on Cassel's papers, continues to treat the 38 patients who are still living with vaccinations every 6 months or less. Murray said that Cassel froze large stocks of the vaccine, so continuing long-term treatment is possible.

Meanwhile, Cassel's work caught the eye and imagination of several other groups.

One group in Chicago used his strain to conduct a series of experiments with tumor cell lines and animals. Robert M. Lorence, M.D., Ph.D., at Rush-Presbyterian-St. Luke's Medical Center, Chicago, showed in l994 that a single injection of Cassel's live NDV caused complete regression of human neuroblastoma tumors in 17 out of 18 athymic mice and in the one tumor that showed a partial response, there was complete regression after a second NDV treatment. No significant acute or chronic side effects of live NDV were noted.

Similar effects were observed in mice injected with a human sarcoma tumor line and subsequently treated with live virus. Complete tumor regression occurred in 8 out of 10 athymic mice. A year later, no tumors had recurred in any of them.

Spurred on by the animal results, Lorence went on to Pro-Virus Inc., to develop the virus and eventually approached the NCI.

"They presented a large amount of impressive preclinical data." said James A. Zwiebel, M.D., senior investigator at NCI's Investigational Drug Branch. "Lorence has taken that same kind of quality from his previous papers to the [Gaithersburg] company." The vaccine strain, PV701, a cousin of Cassel's original strain, was approved by NCI over a year ago and Zwiebel said that NCI will carry out several early human trials in collaboration with the company very soon.

Also impressed by Cassel's results, Joseph Sinkovics, M.D., and Joseph Horvath, M.D., at the Cancer Institute at St. Joseph's Hospital in Tampa, began trying to reproduce his protocol with melanoma patients a few years ago. Horvath said that about 40 patients have been given the vaccine, but it is too early to evaluate results.

Cheryl Armstrong, M.D., associate professor of dermatology at Emory, became intrigued with Cassel's study after she came to the university 5 years ago.

"The results were so dramatic that I wondered if there was something else we could do," she said. "I discovered that the patients and surgical oncologists here would love an opportunity to have new trials going."

Even though the melanoma cell lines Cassel used are gone, she recently isolated live virus from patient vaccines he left behind, deciding to use a mouse melanoma model to get more preclinical data. So far, the results in mice have been encouraging.

"Our preliminary data show that the vaccine can inhibit established metastatic and cutaneous tumors and prevent tumors from developing," Armstrong said. "So, if we feel convinced that this is a viable alternative, we'd like to get started with human studies again."

European Trials

While researchers in the United States try to duplicate Cassel's work in mice or early human trials, in Europe several phase II trials have been completed and a phase III study is now under way. One scientist, Volker Schirrmacher, Ph.D., at the Cancer Research Center, Tumor Immunology Program, in Heidelberg, said that Cassel warned him about the difficulties of doing viral oncolysate research — because "clinicians are more interested in chemotherapy, scientists are skeptical about viral therapy, and health insurance companies refuse to pay for the trials."



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Dr. Volker Schirrmacher

 
Many of these predictions turned out to be right. "I had as many frustrating experiences as he did," Schirrmacher said, although in spite of these roadblocks he completed a raft of experiments with a non-lytic strain of NDV virus called Ulster in tumor cell lines, animals, and people. He published his findings with T. Ahlert, M.D. and other clinical colleagues from several phase II trials in which renal, breast, kidney, and colon cancer patients were treated with their own NDV-infected tumor cells.

The results have been encouraging. Fifty-seven percent (23 out of 40) of advanced renal cell carcinoma patients responded to vaccine treatment combined with low doses of IL-2 and interferon alpha.

In another phase II trial, Schirrmacher and his colleagues found that the 5-year survival rate of 28 colon cancer patients (Duke's C) treated with vaccines was 86%, compared to 42% for historical controls. Finally, using the viral vaccine as a adjunct to conventional treatment such as surgery, chemotherapy, radiotherapy, or hormone therapy, Schirrmacher reported in 1997 that after 5 years, 79% of 32 breast cancer patients treated with the highest number of viable tumor cells were alive, versus 50% of 31 breast cancer patients treated with the poorer quality vaccine.

Schirrmacher said that a randomized, placebo-controlled phase III study in breast cancer patients of medium risk has already started in Europe with more than 20 clinics participating. (Further information about the trials is available on the internet: http://www.brustkrebs-impfstoff.de.)

Hungarian Link

Another more elusive player in the NDV story is Hungarian physician Laszlo K. Csatary, M.D., now of the United Cancer Research Institute, Alexandria, Va. Csatary was initially motivated to treat patients with live virus when he saw the regression of metastatic stomach cancer in a Hungarian chicken farmer simultaneous with a NDV outbreak.

He reported in 1993 the results of a phase II trial in Hungary in which 33 patients with advanced cancers were treated with inhalations of the strain of live NDV virus known as MTH-68/N. Fifty-five percent (18 out of 33) of patients, primarily those with colorectal cancer, responded to treatment compared to 8% (2 out of 26) of patients who did not receive treatment. After 2 years, there were 7 survivors in the treated group compared to none in the control group.

Csatary claims in a 1999 paper to have treated over 300 patients at a private Budapest clinic, and is hoping to carry out trials in the United States. When the data was presented to NCI earlier this year, further documentation was requested.

"The data didn't allow us to make a clear evaluation of whether the virus was responsible for the therapeutic benefits seen in some of the patients," said Zwiebel. Many of the patients were receiving additional therapies.

"We're very interested in hearing more from the Csatarys," continued Zwiebel. "No decision has been made yet whether we will work with MTH-68."

The Hungarian scientific community also has had difficulty evaluating the clinical effects of MTH-68. The Presidium of the Hungarian Scientific Medical Council said in 1998 that the Csatary Center for Virus Therapy in Hungary had treated over 4000 people, in spite of having permission to treat only 300. The Presidium also stated that the Center had violated their agreement by not providing documentation of therapeutic benefit, and warned that further human experiments were "subject to criminal sanctions."

But the Csatarys continue to believe in the benefits of the viral therapy. And at least two web sites are championing the benefits of MTH-68, one of which directs patients to the Csatary Center in Hungary for 2 to 3 weeks; costs range from $5000 to $6000.

There are still some unknowns with NDV therapy besides its cellular mechanism. It is not clear whether one strain of virus is more effective than another, or whether the patient's own cells are more effective than tumor cell lines. Also worrisome is that there are no antiviral agents as yet to treat NDV infections, if symptoms arise, and no studies have been done in an organized fashion to evaluate how NDV therapy will interact with chemotherapy, radiation, or cytokines versus using it as a direct, anti-cancer therapy itself.

Whatever the answers turn out to be, it seems clear that both the effectiveness of the vaccine in early human trials in the United States and in large randomized trials in Europe will be known relatively soon.


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