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Viruses against cancer: complete regression of malignant brain tumours after treatment with parvoviruses

Studies by scientists from the German Cancer Research Centre (DKFZ) have shown that advanced glioblastomas regressed completely in rats after treatment with parvoviruses, thus significantly increasing the survival time compared with untreated animals. Parvoviruses do not cause any disease symptoms in humans and the rats treated did not show any undesired side effects, either. A clinical phase I trial on parvovirus treatment of patients with advanced glioblastoma is being prepared in collaboration with the Department of Neurosurgery at the Heidelberg University Hospital.

Computer simulation of the surface structure of a parvovirus

Although particular parvoviruses normally infect rodents, they can also infect human cells. However, they do not cause any disease symptoms in humans. Most importantly, these viruses have an astonishing property: They kill infected tumour cells without causing any damage to healthy tissue. This is why scientists in the teams of Prof. Dr. Jean Rommelaere and Prof. Dr. Jörg Schlehofer at the German Cancer Research Centre (Deutsches Krebsforschungszentrum, DKFZ) have spent the last few years investigating whether these viruses can be used as weapons against cancer.

Many different viruses have already been tested for use in cancer therapy, especially in the treatment of cancers for which no effective established treatment methods are available. The DKFZ researchers realized early on that parvovirus H-1 has important advantages over other viruses. In association with Dr. Karsten Geletneky of the Department of Neurosurgery at the Heidelberg University Hospital, the researchers have become the first to prove that malignant glioblastomas completely regress as a result of parvovirus treatment.

The experiments were conducted in rats in which brain tumour cells had been implanted. Once the resultant brain tumours had reached a specified size, the animals were given parvoviruses, either by direct injection into the tumour or by intravenous injection into the bloodstream. In the animals that had had the viruses injected directly into the tumour, the tumours shrank visibly after only three days, disappearing completely in eight out of the twelve animals treated. The rodents survived without any symptoms, while untreated control animals suffered from severe disease symptoms within three weeks of tumour cell implantation. In the intravenously treated group, tumours regressed completely in six out of nine animals. The animals have survived for more than one year now without any symptoms or late side effects caused by the therapy.

The researchers found no infection-related damage in the nervous tissue surrounding the tumour. The viruses did not spread to the rest of the organism. Although parvovirus DNA was detectable in all organs several days after virus transfer, this was only temporary. Although the viruses had infected healthy cells, this did not result in a new virus generation. However, in the tumour tissue, the viruses reproduced and viral protein production was detected only in these cells. In rats that had no tumours, the viruses did not reproduce. Thus, it appears that the presence of cancer cells is a necessary condition for the parvoviruses to reproduce.

Prof. Dr. Jean Rommelaere © DKFZ

The positive results of these experiments have convinced the DKFZ researchers that parvoviruses are suitable candidates for cancer treatment. Professor Jean Rommelaere summarises the reasons why: "Parvovirus H-1 does not cause any disease symptoms in humans. Since we are normally not immune to rodent viruses, Parvovirus H-1 is not immediately eliminated by the human immune system after injection. Since parvoviruses use their natural properties to kill tumours their genetic material does not need to be genetically manipulated like herpes viruses, polioviruses or adenoviruses, which have been used in other studies. Moreover, they do not incorporate their genetic material into the host cell's genome, so there is no risk of them ‘accidentally' boosting growth-promoting genes."

Rommelaere's colleague, Jörg Schlehofer, adds two more qualities that could be decisive for the therapy of glioblastomas, in particular: "Parvoviruses pass the blood-brain barrier, which means that they can be administered via the bloodstream. In addition, they reproduce in cancer cells, which is particularly important for successful treatment of diffusely growing glioblastomas. Thus, the second-generation viruses reach and eliminate even those cancer cells that have already settled at some distance from the primary tumour."

Parvovirus therapy to be tested in clinical trial

Dr. Karsten Geletneky, University Hospital Heidelberg

The promising results in the animal model have encouraged the DKFZ scientists, along with Dr. Karsten Geletneky of the Neurosurgery Department of Heidelberg University, to plan a clinical trial on the treatment of advanced glioblastomas. Glioblastoma is considered the most dangerous type of brain tumour; only about half of those affected survive the first year after diagnosis. Even innovative drugs that have been made available recently have only been able to prolong survival for very short periods. Therefore, new treatment approaches for this type of cancer are urgently needed.

Preparing such a trial involves a great deal of work. Large quantities of virus have to be produced under controlled conditions for toxicological tests. Therefore, even a large institute like DKFZ could not afford to finance a transfer of these results into clinical practice. Continuation of viral therapy development was only made possible thanks to funds from the Munich-based company Oryx. The company is planning to provide funds for the early phase of the development of therapeutically effective substances into clinically applicable drugs.

As the researchers have already obtained and submitted to the drug approval authority many of the required toxicological data, they expect to be able to admit the first patients to the trial by the end of the year. In addition, DKFZ and Oryx have recently signed another agreement: Oryx will also be involved in the development of a parvovirus therapy against pancreatic cancer.

Literature:

Karsten Geletneky, Irina Kiprianova, Ali Ayache, Regina Koch, Marta Herrero y Calle, Laurent Deleu, Clemens Sommer, Nadja Thomas, Jean Rommelaere und Jörg R. Schlehofer: Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models. Neuro-Oncology 2010, DOI: 10.1093/neuonc/noq023

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/viruses-against-cancer-complete-regression-of-malignant-brain-tumours-after-treatment-with-parvoviru