Human / Clinical Studies
This phase II trial had a number of weaknesses that could have influenced its outcome. The most important weakness is the fact that the patients were not randomly assigned to the two treatment groups. This lack of randomization raises the possibility of selection bias. In this regard, it is noteworthy that a larger percentage of patients in the NDV treatment group than in the placebo group received conventional therapy within the 3 months preceding the initiation of NDV therapy (82% vs. 58%). In fact, the average time between the completion of conventional therapy and the start of NDV therapy among the patients who had a either a complete response or a partial response was 1.8 months. Therefore, the contribution of NDV therapy to the observed clinical outcomes is difficult to determine.
In a phase I trial that was conducted in the United States, another lytic NDV strain, PV701, was tested in patients with various advanced cancers. In this trial, 79 patients whose tumors had not responded to conventional therapy were given intravenous injections of virus. Four different treatment regimens were evaluated as follows:
- A single dose of NDV given once every 28 days (17 patients).
- A single dose of NDV given 3 times during a 1-week period, repeated every 28 days (13 patients).
- Three injections of NDV given during a 1-week period, with the first injection containing a lower dose of virus than the remaining 2, repeated every 28 days (37 patients).
- Six injections of NDV given during a 2-week period, with the first injection containing a lower dose of virus than the remaining 5, repeated every 21 days (12 patients).
The researchers found that the use of lower initial doses of virus allowed the administration of higher subsequent doses. A complete response was reported for one patient, and partial tumor regression was observed in eight patients. Thirteen patients had stable disease for periods of time that lasted from 4 months to more than 30 months. Five patients died during the trial: four due to progressive disease and one due, possibly, to a treatment-related complication (refer to the Adverse Effects section of this summary for more information). Several patients experienced significant adverse side effects from NDV treatment, including fever, fatigue, dehydration, low blood pressure, shortness of breath, and hypoxia. Some patients who experienced these adverse effects required hospitalization. The researchers who conducted this trial have indicated that additional clinical studies are under way.
A major concern about the effectiveness of treating cancer patients by repeated administration of a lytic strain of NDV is the possibility that the immune system will produce virus-neutralizing antibodies. Virus-neutralizing antibodies would prevent NDV from reaching and infecting malignant cells, thereby blocking oncolysis. Impairment of NDV infection would also limit the ability of cytotoxic T cells that target virus antigens to kill virus-infected cancer cells. In addition, limiting the infection of cancer cells would lessen the likelihood that the immune system would become trained to better recognize tumor-specific antigens. The Hungarian investigators have shown that anti-NDV antibodies are produced in MTH-68-treated patients, but they apparently have not determined whether these antibodies are virus-neutralizing. However, the recent observation that immune system tolerance to viruses can be induced by repeated oral administration of virus proteins suggests that the concern about virus-neutralizing antibodies may not be entirely warranted. Reviewed in  It is conceivable that frequent inhalation (or injection) of NDV may lead to immune system tolerance of this virus. This possibility should be explored in future studies.