Newcastle Disease Virus Tumor therapy with oncolytic virus Newcastle Disease Virus (NDV)

Summary With regard to the up to now unfavorable results of conventional therapy in the treatment of especially advanced tumors novel therapeutic methods have to be developed. Beside dendritic cell therapy another promising approach is the treatment with replication-selective viruses, also called oncolytic viruses. This approach is also known as virotherapy. The approach to virotherapy in our group is based on the Newcastle Disease Virus (NDV), one of the most promising candidates among the group of oncolytic viruses. NDV belongs to the family of the paramyxo viruses. NDV is not a pathogen for humans and is absolutely harmless causing only mild-flu-like symptoms or conjunctivitis in the worst of cases. NDV replicates efficiently in humans in tumor cells, only leading to complete destruction of the infected tumor cells within a short time. In clinical studies with NDV carried out so far, significant tumor remissions as well as prolonged survival periods have been observed with a very low rate of observed side effects. The Newcastle Disease Virus, which is used in our group for virotherapy, is propagated on human tumor cell lines and kept in high-pure form by means of a newly developed cleaning method by Prof. Dr. Dr. Lke from the German Primate Center in Gttingen (DPZ). The oncolytic potential of NDV is highly increased by the additional application of local hyperthermia before the administration of NDV, and by vaccination with Dendritic cells afterwards. Onkolytic viruses and lytic effect on cancer cells The application of viruses for cancer treatment is based on reports since the beginning of the 20th century on temporary improvement of cancer following natural viral infections or vaccinations against viral diseases. Using animal models the lytic effect of certain viruses on tumor cells was demonstrated at the beginning of the 1950. Modern techniques in molecular biology give rise for the development of oncolytic viruses as efficient treatment modality in human cancer. Base on the scientific knowledge an oncolytic virus should be based on three main features: 1. The virus selectively targets neoplastically transformed cells and leave normal cells uninfected. 2. The virus is replication competent and can destroy his host tumor cell.

3. The virus induces only mild to moderate side effects. Figure 1

Viruses with RNA as genetic material are potent candidates within the viruses tested for the above mentioned features. Especially NDV shows a natural distinct tropism for cancer cells based on the fact that the most of the tumor cells are more or less unable for an effective virus defense. NDV is an enveloped virus with two main virus specific glycoproteins found in the envelope, which are required for initial binding to and entering of NDV in the host cell. In humans, oncolytic NDV selectively replicates in human tumor cells whereas non neoplastic cells remain uninfected. Cancer cells infected with NDV can be killed directly by the virus within a short time after infection or leads to induction of a specific immunresponse against the virus infected cancer cell. The virus is non pathogenic in humans. The ability of NDV to infect and replicate efficiently in human cancer cells has been demonstrated by laboratory and animal studies. The ability of NDV to kill human cancer cells in vivo has also been shown. Clinical studies with NDV In 1965, Casell and Garett first used intratumorally on one patient with a regression was observed. Meanwhile reported to be of benefit in more than NDV to treat a human cervical carcinoma. A NDV-based anticancer a dozen clinical studies cancer, applying it remarkable tumor therapy has been concerning various

tumor types. The studies prove to be a powerful weapon especially against the most malignant brain tumor, glioblastoma multifome WHO IV. So far, two main different approaches for NDV based cancer therapy have been developed: 1. Treatment of cancer patients with NDV 2. Treatment of cancer patients with oncolysates, which are preparations containing plasma membrane fragments of NDV infected cancer cells (autologous or allogenic). The reported side effects associated with NDV exposure have generally been described as mild to moderate causing mild flu-like symptoms (fever), sometimes inflammation at the injection site and conjunctivitis in the worst of the cases. NDV can be administered intratumorally, intravenously as well as by inhalation.

Literature: a. reviews: 1. http://www.cancer.gov/cancertopics/pdq/cam/NDV/healthprofessional summary about NDV treatments 2. Kirn, Martuza, Zwiebel: Replication-selective virotherapy for cancer: Biological principles, risk management and future directions. Nature Medicine 7: 781-787 (2001). 3. Lorence, Williams, Rabin: Replication-competent, oncolytic Newcastle disease virus. In Hernaiz-Driever, Rabkin (eds): Replication competent viruses for cancer therapy. Monographs Virology, Basel, Karger, vol. 22, pp 160182 (2001). 4. Omar, Ideris, Ali, Othman, Yusoff, Abdullah, Shila, Wali, Zawawi, Meyyappan: An overview on the development of Newcastle disease virus as an anti-cancer therapy. Malaysian Journal of Medical Sciences 10: 4-12 (2003) 5. Shah, Benos, Gillespie, Markert: Oncolytic viruses: Clinical applications as vectors for the treatment of

malignant gliomas. Journal of Neuro-Oncology 65: 203-226 (2003).

b. Clinical trials: 1. Csatary, Moss, Beuth, Torocsik, Szeberenyi, Bakacs: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68). Anticancer Research 19: 635-638 (1999). 2. Csatary, Gosztonyi, Szeberenyi, Fabian, Liszka, Bodey, Csatary: MTH-68 oncolytic viral treatment in human high-grade gliomas. Journal of Neuro-Oncology 67: 83-93 (2004). 3. Freeman, Zackay-Rones, Gomori, Linetsky, Rasooly, Greenbaum, Rozenman-Yair, Panet, Libson, Irving, Galun, Siegal: Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Molecular Therapy 13: 221-228 (2005). 4. Lorence, Pecora, Major, Hotte, Laurie, Roberts, Groene, Bamat: Overview of phase I studies of intravenous administration of PV107, an oncolytic virus. Current Opinion in Molecular Therapeutics 5: 618-624 (2003).