MTH-68/H oncolytic viral treatment in human high-grade gliomas.

Application of virus therapy to treat human neoplasms has over a three decade history. MTH-68/H, a live attenuated oncolytic viral strain of the Newcastle disease virus, is one of the viruses used in the treatment of different malignancies. Here we report on the administration of MTH-68/H to patients with glioblastoma multiforme, the most common and most aggressive neuroectodermal neoplasm with a poor prognosis, averaging six months to a year. Four cases of advanced high-grade glioma were treated with MTH-68/H after the conventional modalities of anti-neoplastic therapies had failed. This treatment resulted in survival rates of 5-9 years, with each patient still living today. Against all odds, each patient resumed a lifestyle that resembles their previous daily routines and enjoys a good quality of life, Each of these patients has regularly received MTH-68/H as their sole form of onco-therapy for a number of years now without interruption.

Induction of apoptosis by a Newcastle disease virus vaccine (MTH-68/H) in PC12 rat phaeochromocytoma cells.

The attenuated Newcastle Disease Virus (NDV) vaccine MTH-68/H has been found to cause regression of various tumors including certain types of human neoplasms (See Table 1 and References 86-88). The mechanism of its oncolytic action is poorly understood, but it appears to affect specific signaling pathways in the target cell. We studied the cellular effects of NDV employing PC12 rat phaeochromocytoma cells, a widely used model system to analyze differentiation, proliferation and apoptosis. The MTH-68/H vaccine was found to be cytotoxic on PC12 cells. It caused internucleosomal DNA fragmentation, the most characteristic feature of programmed cell death (PCD). A brief exposure (30 min) of P12 cells to the virus was sufficient to produce a full-blown apoptotic response. Major mitogen-activated protein kinase pathways (including the stress inducible c-Jun N-terminal kinase pathway and p38 pathway) or mechanisms regulated by reactive oxygen species appear to have no role in virus-induced cell death. The PCD-inducing effect of MTH-68/H could not be prevented by simultaneous treatment of the P12 cells with growth factors or second messenger analogs stimulating protein kinase C or Ca(++)-mediated pathways. In contrast, treatment with a cyclic AMP analog partially protected the them from virus-induced apoptosis. These experimental results suggests that MTH-68/H might disrupt a growth factor-stimulated survival pathway and that direct stimulation of protein kinase A-catalyzed phosphorylation events bypass this NDV-induced block.

Successful treatment of decompensated chronic viral hepatitis by bursal disease virus vaccine.

Three cases of women with chronic liver inflammation caused by hepatitis B (two) and C (one) viral infections, were followed up to twelve years after diagnosis. As conventional therapy was ineffective and the patients progressed into decompensated liver disease, they were superinfected with massive doses of an attenuated variant (MTH-68/B) of the apathogenic avian Bursal Disease virus (a double-stranded RNA virus from the Birnaviridae family). Clinical symptoms and biochemical abnormalities were resolved in two patients following few months of virus treatment. Cirrhosis was stabilized and significant clinical improvement was achieved in the third patient--who before the virus therapy was moribund with recurring, diuretic-resistant ascites, variceal bleedings, portal encephalopathy and renal failure. To our knowledge, these are the first recorded cases of decompensated chronic viral hepatitis which went to long-lasting remission or were stabilized by superinfection with an apathogenic virus.

Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H).

Newcastle Disease Virus Vaccine (MTH-68/H) was administered to patients suffering from advanced neoplastic diseases after non-efficient tumor-destructive treatment. Case reports of selected patients suggest promising effects of this treatment. A prospectively-randomized clinical study (phase III; in accordance with Good Clinical Practice, GCP) was proposed to confirm these results and is currently under consideration.

Preliminary report of a controlled trial of MTH-68/B virus vaccine treatment in acute B and C hepatitis: a phase II study.

Eighty four patients with viral hepatitis attributed to infection with hepatitis B virus (HBV) (n = 43) or hepatitis C virus (HCV) (n = 41) were included in this study employing the MTH-68/B vaccine, an attenuated variant of Bursal Disease Virus. Twenty of the 43 patients in the HBV group, and 22 of the 41 HCV patients were treated with MTH-68/B. The remaining patients received conventional therapy. Significantly more patients progressed into active chronic hepatitis on conventional therapy (13% of HBV and 26% of HCV cases respectively) than in the vaccine treated groups (0% and 9%). Relapses occurred less frequently in the vaccine treated groups (5% of HBV and 32% of HCV) than in the control groups (9% and 79%), while remissions within one month of treatment were observed more often in the vaccine treated groups (both 50% respectively) than in the control groups (26% of HBV and 21% of HCV patients respectively). The duration of hepatitis was also considerably shortened by MTH-68/B treatment in both HBV (from 7.5 +/- 3.7 to 5.9 +/- 3.0 weeks) and HCV patient groups (from 8.9 +/- 7.4 to 5.3 +/- 4.4 weeks). The data presented suggest that attenuated, non-pathogenic viruses may be of significant benefit for patients with viral hepatitis B and C infections.

Attenuated veterinary virus vaccine for the treatment of cancer.

Attenuated (nonpathogenic) avian viruses have been used as a form of nonspecific immunological treatment for advanced human cancer. For this study, we used Newcastle disease virus (NDV) vaccine MTH-68/N in an open phase II/B, placebo-controlled (26 patients), multicenter clinical trial for the treatment of 33 patients with advanced cancers. NDV (4000 U/day) or placebo was administered by inhalation twice weekly. During the 6-month trial, the size and presence of primary tumors and metastases were objectively monitored at five institutions by radiologists unaware of the type of treatment that was given. Regression of tumor(s) and/or metastases were observed in eight cases treated with virus (vs. none in the placebo group; p < 0.01). Ten additional patients treated with NDV had no further progression of their tumor sizes, whereas tumor stabilization was noted in only two control patients. Objective, favorable responses (regressions plus stabilization) to virus therapy thus occurred in a total of 18 patients (55%) compared to 2 patients in the placebo group (8%; p < 0.01). Two cases of complete remission were noted in the group treated with NDV. Patients receiving virus therapy had a higher rate of survival at 1 to 2 years. Of 33 patients receiving virus vaccine, 22 survived 1 year, compared to only 4 of 26 patients in the control group (p < 0.02). After 2 years, all seven survivors in the study were in the virus therapy group. There were no 2-year survivors in the control group (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

The course of LCMV infection in gnotobiotic and conventional adult mice pretreated with attenuated NDV vaccine.

A single intraperitoneal treatment with two different doses of live Newcastle Disease Virus (NDV) containing attenuated NDV vaccine one day before intracerebral inoculation with lymphocytic choriomeningitis virus (LCMV) had no influence on the ratio and time of deaths after infection with a 100 LD50 dose of LCMV either in gnotobiotic or in conventional mice. There was no difference either in the LD50 values determined on the basis of three parallel LCMV titration performed on mice pretreated with two different doses of vaccine or untreated. NDV vaccine pretreatment thus did not influence the cellular immune response to LCMV infection either in gnotobiotic or in conventional adult mice. As the NDV vaccine increased the cellular immune response to LCMV infection in suckling mice according to earlier results, the present results reinforce our earlier statement that the direction of immunomodulatory effects can be influenced by age.

Effect of chlorpromazine (CPZ) on the course of LCM virus infection in mice with developed and undeveloped immune system.

The cellular immune response to lymphocytic choriomeningitis (LCM) virus in germfree adult and conventional (Cv) suckling mice with undeveloped immune systems and in Cv adult mice with developed immune systems was suppressed by a single large, sublethal dose of the calmodulin antagonistic chlorpromazine and stimulated by a 100-times smaller dose administered intraperitoneally one day before the intracerebral virus infection. CPZ thus exerted a two-directional dose-dependent immunomodulatory effect in mice with both undeveloped and developed immune system.

Effect of attenuated viral vaccines on suckling mice infected with LCMV.

A single intraperitoneal treatment with live Newcastle Disease Virus (NDV) containing attenuated NDV vaccine, and with live infectious bursal disease virus (IBDV) containing attenuated IBDV vaccine, one day before intracerebral infection with lymphocytic choriomeningitis virus (LCMV) increased, whereas a similar treatment with inactivated NDV or IBDV vaccine did not influence the death rate of suckling mice from experimental lymphocytic choriomeningitis. Thus the attenuated live vaccine stimulated, whereas the inactivated ones failed to affect the cell-mediated immune response to LCMV. Control studies set up with the supernatant of plain tissue culture routinely used for the propagation of IBDV have shown that unlike the attenuated NDV vaccine, the immunostimulatory action is associated not so much with the virus itself, as with an as yet unidentified component of the tissue culture supernatant.

In vivo interference between pathogenic and non-pathogenic viruses.

The interference among viruses is a well-documented biological phenomenon, both in animals and tissue culture systems. In two of our previous in vivo experiments and in four independent animal experiments, which are described in this presentation, interferences were successfully used to influence the outcomes of viral diseases by using non-pathogenic viruses. In this study, four pathogenic viruses were studied in their natural hosts, and against these viruses, in different combinations, 15 non-pathogenic viruses were tested. There was great variation in mutual effects among pathogenic and non-pathogenic viruses. In our four experiments, the viruses were either simultaneously inoculated or the non-pathogenic viruses were preinoculated. Newcastle disease vaccine (Strain H) had remarkable effects in the development of mouse ascites-associated lymphoma virus. The 50% mortality rate in mice caused by a vaccine strain of rabies virus was reduced to 15% using avian encephalitis virus. The clinical manifestations of rabbit myxoma virus effects were significantly delayed by Newcastle disease vaccine (Strain H). The 72% mortality rate due to Rous sarcoma virus in chickens was decreased to 33.3% when the animals were preinoculated with avian bursa virus vaccine.

Interference between human hepatitis A virus and an attenuated apathogenic avian virus.

The effect of an attenuated apathogenic avian bursa virus on the course of human hepatitis A viral infection was studied in marmoset monkeys. The monkeys were infected with human hepatitis A virus, then superinfected with avian bursa virus one and three weeks after initial inoculation with human hepatitis A virus. The superinfected monkeys did not show the characteristic serum glutamic pyruvic transaminase (SGPT) elevation. Also their liver biopsies showed no pathologic changes. The virus control animals exhibited six times higher SGPT enzyme elevation than the superinfected groups, and hepatitis was detected by histopathology. This experiment, as known to us, is the first in which a definite interference was documented using a nonpathogenic virus against a highly pathogenic and clinically significant human virus. This should be considered a successful experiment demonstrating that the use of an apathogenic virus for the cure of a virus-induced disease is a realistic possibility.