NEWCASTLE DISEASE VIRUS.

Introduction.
Newcastle disease virus (NDV) was the name given by Doyle to a highly contagious viral infection of poultry, also known as fowl pest, which was first reported on a farm near Newcastle upon Tyne, UK, in 1926. Shortly after the reported disease at Newcastle, two further outbreaks occurred in the UK, one in Somerset and the other in Staffordshire. At about the same time, a disease with similar symptoms was observed in Java (in the capital city now known as Jakarta), Indonesia, and shortly thereafter in other regions of Southeast Asia, notably around seaports of the Indian Ocean. Sub¬sequent cross-immunity tests showed that the viruses isolated in Southeast Asia and Newcastle upon Tyne were indistinguishable. The causative agent of the disease in Newcastle upon Tyne was identified as a virus, which was distinct from fowl plague (avian influenza virus), although the symptoms bore some resemblance. It is thought likely that the virus was transported to the port of Newcastle upon Tyne by ship from Southeast Asia. Whatever its origin, the new disease emerged and rapidly spread throughout the world [1,2,3].

The application of viruses for cancer treatment was based on anecdotal reports since the beginning of the 20th century on tempo¬rary improvement of cancer following natural viral infections or vaccinations against viral diseases, for example, rabies [4]. In 1965, Cassell and Garrett [5] first used live Newcastle disease virus (NDV) deliber¬ately to treat a human cancer, applying it intratumorally on one patient with cervical carcinoma. The application of NDV took importance after 1968 when a poultry farmer suffering from metastatic gastric cancer who had exhibited a spectac¬ular clinical improvement after having been exposed to a NDV poultry epidemic [6]. Following these reports on the anti-neoplastic effect of NDV, a few researchers have employed an attenuated NDV strain, designated MTH-68/H, to treat a variety of human malignancies [6,7].

Structure.
The virus is a membrane-enveloped virus non-segmented, negative-stranded RNA of roughly spherical structure. It contains a helical nucleocapside structure, with a central hole. The main protein subunit of the nucleocapside is the nucleocapside protein (NP). Two other proteins, the phosphoprotein (P) and the large (L) protein are also associated with the nucleocapside. The envelope is a lipid double layer derived from the host cell plasma membrane and has embedded in it, and protruding from it, the spike glycol-proteins hem agglutinin-neuraminidase (HN) and fusion (F). The matrix protein (M) is interposed between the nucleo¬capside and the viral envelope [1,2,3].
The virus is nonpathogenic to humans, except for rare transient respiratory infection among poultry workers. Some attenuated NDV strains have marked oncolytic properties in human tumors [2]. Attenuated NDV strains have been in use for over 40 years and have shown genetic stability, without anti-genie drift [3]. Following administration, oncolytic NDV strains, like MTH-68/H selectively replicate in human tumor cells, destroying them, whereas non-neoplastic cells remain unaffected [3,8,9,10]. Wild type NDV is the agent of the Newcastle Disease of chicken.

Mechanisms of action against cancerous cells.
Our knowledge of the mechanism of the tumor-destructive action of the oncolytic attenuated NDV strains is still growing. There are two ways, by which viruses can destroy their host cells: (1) by inducing necrosis or lysis by their excessive replication; (2) by inducing programmed cell death, apoptosis [7].

According to pilot studies on the interaction of NDV and tumor cells, both lysis and apoptosis are at work [8,12,13,14]. The apoptotic effect of MTH-68/H has been studied in the PC12 rat pheochromocytoma cell line [8,12]. PC 12 cells were found to be killed by MTH-68/H in a dose-dependent manner. Cell death was accompanied by internucleosomal DNA fragmentation, characteris¬tic of apoptosis. A very brief exposure to MTH-68/H was sufficient to induce full-blown apoptotic response. To induce oncolysis and apoptosis, an accurate targeting of tumor cells by the virus is of crucial importance. NDV envelope glycoproteins attach to sialic acid host cell membrane receptors . Since sialic acid receptors are widely distributed in different cell types, the targeting of NDV to human ectodermal, mesenchymal and neuro-ectodermal tumor cells is understandable . However, it is not sufficiently elu¬cidated why NDV targets selectively neoplastic cells, while normal cells also expressing sialic acid surface receptors remain uninfected. Nevertheless, it becomes increasingly clear that NDV's direct oncolytic and apoptosis-inducing effect is responsible for its clinical effectiveness. The immunomodulatory potency of the live attenuated NDV viral treatment may also play an important adjunctive role.
The beneficial effects and good applicability of live oncolytic attenuated NDV strains such as MTH-68/H are based on three important features:

(1) They selec¬tively target neoplastically transformed cells and leave normal cells uninfected [10,15] and Fabian Z et al., unpublished results)
(2) They are replication competent and destroy their host tumor cells
(3) The attenu¬ated NDV strains are stable, have an extensive safety database, and are well tolerated by patients with mini¬mal, if any, side effects.
MTH-68/H has been employed only once the other classical anti-neoplastic treat¬ments have failed. MTH-68/H proves to be a powerful weapon against the most malignant neuro-ectodermal tumor, Glioblastoma Multiforme, and its application has advantages not only with regard to current chemotherapy, but also to some novel therapeutic approaches. Controlled clinical trials using MTH-68/H are in preparation the efficacy of this virus therapy on a greater number of neuro-oncological and oncological patients.

Application. Application of oncolytic virus therapy to treat human neoplasms has over a three decade history. MTH-68/H, a live attenu¬ated oncolytic viral strain of the Newcastle disease virus, is one of the viruses used in the treatment of different malignancies. With regard to the unfavorable results of con¬ventional modalities in the treatment of human malignancies, novel therapeutic methods were tried as to their potential to inhibit tumor growth. One such method is the use of attenuated viruses to treat human malignancies [16,17,18]. The application of viruses for cancer treatment was based on anecdotal reports on tempo¬rary improvement of cancer following natural viral infections or vaccinations against viral diseases. Cassell and Garrett were the first in use the live Newcastle disease virus (NDV) deliber¬ately to treat a human cancer, applying it intratumorally [5].
The application of NDV took importance after 1968 with a patient who had exhibited a spectac¬ular clinical improvement after having been exposed to NDV poultry epidemic [6]. Following these reports on the antineoplastic effect of NDV, the a few researchers has employed an attenuated NDV strain, designated MTH-68/H, to treat a variety of human malignancies [6,7]. MTH-68/H has been developed into a highly purified, lyophilized product, containing live, replication com¬petent oncolytic viral particles, grown to standardized liters. A Phase II clinical trial using MTH-68/H was completed in 1991, where the inhalatory mode of administration was used, on patients suffering from a variety of advanced malignancies, no longer respon¬sive to conventional treatment modalities. The study demonstrated relative efficacy, an overall improved quality of life, and a benign side effect profile . The oncolytic potential of MTH-68/H has been char¬acterized under tissue culture conditions. MTH-68/H was found to be cytotoxic, as measured by the W cytotoxicity assay, on six tumor cell lines tested :

ƒÍ PC rat pheochromocytoma.
ƒÍ B16 mouse melanoma, Cos.
ƒÍ SV-40-transformed] monkey kidney tumor.
ƒÍ HeLa human cervical carcinoma.
ƒÍ MCF-7 human breast ade-nocarcinoma and 293T.
ƒÍ Adenovirus 5 DNA transformed human kidney cells.
ƒÍ Glioblastoma Multiforme.

Titer-dependence of the cytotoxic effect of MTH-68/H showed differences between these tumor cell lines. Replication of the virus in two of the tumor cell lines has been verified. In contrast, the non-neoplastic NIH3T3 mouse fibroblasts and Rat-1 rat fibroblasts were completely resistant to the cyto-cidal effect of MTH-68/H (Fabian Z and Szeberenyi J, unpublished results). In PC12 cells, a widely used model cell line for differentiation, survival and apoptosis signaling, MTH-68/H induced titer-dependent apoptotic DNA fragmentation [8,12]. The results of these cell culture studies strongly support the notion that MTH-68/H, besides a potential immunostimulatory effect, exerts its anti-cancer action by directly and selectively attacking and killing tumor cells.

Clinical Experience.
Pollak et al. described two cases with radical surgical approach and without recurrence for at least ten years and reviewed similar cases in the literature. Salvati et al. reported on 11 patients with GBM who lived at least 5 years after the diagnosis was first established. Yoshida et al. described two cases of 'decade survivors' after the removal of GBM from the frontal lobe, followed by chemotherapy and radiotherapy of these authors regard the radical surgical removal of the tumor and the relatively young age of the patient as the main factors determining long-term survival.

A special type of GBM, characterized histologically by a marked predominance of bizarre, multinucleated giant cells, represents a specific subgroup distinguished by a more favorable prognosis and long-term survival. Klein et al. reviewed the literature and added a case of a child who survived 11 years after operation until the time of publication. This special subgroup makes up about 5% of the GBMs . Giant cell GBMs form a distinct group according to molecular genetic studies . The question arises as to whether in the previous case reports in the literature, this specific histological type of giant cell GBM was recognized and whether at least part of the cases with long-term survival had not actually belonged to this subgroup.

Gene therapy aims at the introduction of additional genetic material which is transcribed and translated into proteins in the tumor cell and which counteracts uncontrolled prolifer¬ation. As vectors for gene transfer, genetically modified retro viruses, adeno viruses, coxsackie virusses and attenuated herpes sim¬plex virus have been used. As to gliomas, transfection of 'suicide' genes (e.g. herpes simplex virus thymidine kinase), of anti-angiogenic genes, tumor suppressor genes such as p53 andE2F-l, of cell surface receptors and of genes to induce apoptosis (e.g. box) has been in the foreground of research [25,26,27,28].

Therapy with oncolytic viruses is not a new con¬cept, although, there is increasing interest in this treatment modality among oncologists [4,29,30]. Sev¬eral virus strains, including retroviruses, adenoviruses, herpes viruses, parvo- and paramyxoviruses were described to have oncolytic properties [4,31]. Perhaps the most effective clinical experience has been achieved with a paramyxovirus, the attenuated NDV, upon which MTH-68/H treatment is based [6,7].

To investigate the anti-tumor effect of NDV, Xue LJ, found that the strong suppressive effect of NDV on the growth of these tumor cells was effective without dose dependence. They concluded that the NDV might be a potential anti-tumor agent Previously Zaitsev V showed that NDV had a protein called Hemagglutinin Neuraminidasa (HN) contained pliable sialic acid recognition. Presenting evidence of a binding site for its involvement in cell fusion .

Dolganiuc V explored the association of the NDV fusion (F) protein with cholesterol-rich membrane domains, founding that specific localization of the F protein in cholesterol-rich membrane domains is not required for cell-to-cell fusion . In basis of the results of Bar-Eli N, he demonstrates that NDV caused preferential damage to lymphoma cells as compared to non-cancerous normal cells The HN protein of the NDV plays a crucial role in the process of infection, Huang Z, established the hypothesis that the virulence of NDV is multigenic and that the cleavability of F protein alone does not determine the virulence of a strain .

Application of New Castle Disease Virus in the Cologne Model
In the Cologne Model, NCDV has recently been introduced for the treatment of solid tumors. The virus is made in the laboratory of Dendrimun Köln, the laboratory where also autologous dendritic cells, LAK cells, and stem cells for patients, who are being treated in the Medical Center Cologne, are being manufactured.

Patients who are eligible for treatment with NCDV will usually receive NCDV through an intra-arterial catheter to deliver the virus as close to the tumor as possible. For the implantation of intra-arterial catheters, close collaboration has been established with two extremely experienced doctors, specialized in implanting these catheters.

A second form of application is to deliver the NCDV intra-tumorally. Whether an intra-arterial catheter is used or whether the virus is injected directly into the tumor depends on several factors.

The first experiences are very positive and a clinical study is on its way to document efficacy and possible side effects.

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