1. What is Newcastle disease virus?

   Newcastle disease virus (NDV) is a virus that causes a deadly infection in many kinds of birds. In humans, NDV causes mild flu-like symptoms or conjunctivitis (an infection of the eye that is also called pink eye) and/or laryngitis (an irritation and swelling of the voice box and the area around it).

   Like other viruses, NDV infects cells (called host cells) and then uses those cells to replicate (make copies of) itself. Researchers are interested in NDV because it replicates itself more quickly in human cancer cells than in most normal human cells and it can kill the host cells. For these reasons, the virus is being studied as a treatment for cancer.

2. What is the history of the discovery and use of Newcastle disease virus as a complementary or alternative treatment for cancer?

   The first report that NDV may be useful as a cancer treatment was published in 1964. For 20 years before this report, NDV was used in a vaccine to prevent Newcastle disease in birds. During that time, it was learned that NDV caused only minor illness in humans. The mild side effects caused by NDV in humans and its ability to replicate up to 10,000 times faster in human cancer cells than in most normal human cells, led researchers to look more closely at NDV as a possible cancer treatment.

3. What is the theory behind the claim that Newcastle disease virus is useful in treating cancer?

   There are many strains of NDV, and they may be either lytic or nonlytic for human cells. Lytic strains kill the infected cell by damaging its outer membrane (layer of tissue). Nonlytic strains kill by blocking the basic processes a cell needs to live. Lytic strains of NDV have been studied in humans because they can kill cancer cells directly, but both lytic and nonlytic strains have been used to make vaccines to help the immune system fight cancer.

4. How is Newcastle disease virus administered?

   The way NDV is given depends on how the virus is used to target cancer cells. It may be used to directly infect the patient with NDV or to make cancer vaccines. Cancer vaccines made with NDV may improve the body’s natural immune response to cancer, causing it to attack and kill more cancer cells than it would if the NDV were not present. Researchers are studying 3 ways of using NDV as a possible cancer treatment:

   • Infection of the cancer patient with NDV

     NDV can be injected directly into the tumor, a muscle, or a vein (intravenous injection), or into the colon. The virus can also be inhaled. As explained in Question 1, NDV infects cells and then replicates itself, creating more copies of the virus that can then infect cells throughout the body. This process targets and kills cancer cells by damaging the cells' outer membranes.

   
   
   
   • Oncolysate vaccine.

     Oncolysate vaccines are made using pieces of cancer cell membranes infected with NDV. Oncolysate-based vaccines are injected under or into the skin.

   
   
   
   • Whole-cell vaccine

     Whole-cell vaccines are made using whole tumor cells infected with NDV. The tumor cells used in the vaccine are changed in the laboratory so that they cannot multiply or infect the patient. Whole-cell vaccines with NDV are given only by injection under the skin.

   
   
   
5. Have any preclinical (laboratory or animal) studies been conducted using Newcastle disease virus?

   A number of preclinical studies have been done with NDV. Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be useful in humans. These preclinical studies are done before any testing in humans is begun. The following has been learned from preclinical studies:

   • NDV replicates more quickly in human cancer cells than in any other type of cell.
   • Some types of NDV are able to directly kill certain types of cancer cells.
   • NDV and NDV-infected cancer cells can cause the immune system to respond in different ways.

   A few of these studies used human cells, but most used animal cells. Based on these and other laboratory findings, clinical trials (research studies with people) using NDV were begun.

6. Have any clinical trials (research studies with people) of NDV been conducted?

   Clinical trials of NDV have been done but have not proven that NDV is effective as a cancer treatment. Some of the trials reported positive results and some did not. Most of the studies enrolled only small numbers of patients who also received standard treatments. None of the trials published in English were randomized and few were controlled. Randomized clinical trials give the highest level of evidence. In randomized trials, volunteers are assigned randomly (by chance) to one of 2 or more groups that compare different factors related to the treatment. In a controlled clinical trial, one group (called the control group) does not receive the new treatment being studied. The control group is then compared to the groups that receive the new treatment, to see if the new treatment works. Randomized controlled trials, enrolling larger numbers of people, are needed to confirm the results of studies done so far on the use of NDV to treat cancer.

   Clinical trials studying the use of NDV as a cancer treatment have been done in the United States, Germany, and Hungary. Below are brief descriptions of these studies.

   Studies Using Oncolysate Vaccines

   Four clinical trials in the United States studied the use of NDV oncolysates in patients with metastatic melanoma. Three of these studies, a phase I clinical trial and 2 phase II clinical trials, were by the same group of researchers. Some positive results were found in these studies. The fourth trial was led by different researchers and showed no benefit. The same type of NDV was used to make the vaccines in all 4 studies, but the 2 groups of researchers used different methods to make them. Results from these studies need to be confirmed by randomized controlled trials that enroll larger numbers of people.

   Two other phase II trials of NDV oncolysates were done in Germany. One of the studies showed that people in the trial had longer disease-free survival when compared with published information on similar patients who were treated with surgery alone. Because these studies were not controlled and the patients received other treatments, it is not clear if it was the treatment with NDV oncolysates that caused the responses reported.

   Studies Using Whole-cell Vaccines

   All published clinical studies of whole-cell vaccines with NDV have been done in Germany. Most of these studies involved patients with colorectal cancer, breast cancer, ovarian cancer, or renal cell (kidney) cancer. The same type of NDV was used to make the vaccines in all of the studies.

   Some of these studies found improved disease-free survival or improved overall survival in patients treated with whole-cell vaccines. The lack of control groups and other weaknesses in study design and reporting made it unclear if benefits were caused by the whole-cell vaccine or by something else. Overall, the results showed that these vaccines may help the immune system kill more cancer cells during the vaccination program but may not provide long-term cancer immunity.

   Studies Involving Infection with NDV (Including MTH-68)

   Most research on the treatment of cancer by infecting patients with NDV has been done in Hungary, using the NDV strain MTH-68. The published findings include the following types of studies:

   • An anecdotal report (incomplete descriptions of the medical and treatment history of one or more patients).
   • A case report (a detailed report of the diagnosis, treatment, and follow-up of an individual patient).
   • A small case series (a group of case reports involving patients who were given similar treatment).
   • A phase II clinical trial.

   According to the researchers, the MTH-68 treatment was helpful for most of the patients in these studies. The number of patients in the studies was small, however, and the patients in the clinical trial were not randomly assigned. The patients also received other treatments. For these reasons, it is not known if the patients were helped by the MTH-68 or by something else.

   In the United States, a phase I clinical trial tested PV701, another type of NDV. In this trial, 79 patients with advanced cancers that were not helped by conventional therapy were given PV701 by injection into a vein. Some patients had partial responses to the treatment, while others did not have any change in their condition. More studies are planned.

   One major concern is that repeated injections of NDV may cause a person's immune system to form antibodies against the virus. These antibodies would prevent NDV from infecting and killing cancer cells. More research is needed to study this.

7. Have any side effects or risks been reported from NDV?

   The side effects caused by NDV exposure have been mild to moderate. As noted in Question 1, NDV causes mild flu-like symptoms, conjunctivitis, and laryngitis in humans. Other side effects vary with how the virus is given.

   • The most commonly reported side effect after treatment with the virus alone is fever, which usually goes away within 24 hours. In one study, inflammation and swelling were seen near some tumors. These complications may have contributed to the death of one patient.
   • The most common side effects of treatment with NDV-infected whole-cell vaccines are minor:
     • Mild headache.
     • Mild fever on the day of the vaccination.
     • Itching, swelling, and redness of the skin at the injection site.
   • The only negative effect of treatment with the NDV oncolysate vaccine is inflammation at the injection site.

   Studies that combined treatment with NDV oncolysates or whole-cell vaccines with substances called cytokines reported flu-like symptoms, fever, and swelling. The side effects seen in these studies have been linked to the cytokine portion of the treatment.

8. Is Newcastle disease virus approved by the US Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The US Food and Drug Administration (FDA) has not approved Newcastle disease virus as a treatment for cancer.

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