Can we inject viruses into the computer

Oncolytic viruses: "drugs" with a domino effect

After infection with CD133-specific measles viruses, CD133-positive tumor cells (green) fuse and die, a few hours later only holes can be seen in the cell layer. Photo: Paul Ehrlich Institute

Tumor therapy with oncolytic viruses - so-called virotherapy - is currently being tested in several clinical studies.

Fighting malignant tumors with viruses is not a new idea. Chance observations in the last century laid the foundation for this unusual form of therapy. A four-year-old boy in San Francisco temporarily recovered from severe leukemia after contracting cowpox. And a young woman with cervical cancer felt better for a short time after being vaccinated against rabies. But for a long time one tried in vain to convert these observations into an effective form of treatment. Some of the attempts to help people with cancer by giving them viruses failed miserably, so that the experiments were stopped entirely (1).

Only when it became possible to genetically modify viruses in such a way that they harm the tumor but not the entire organism (box) did virotherapy come back into focus. Different types of virus are and have been tested against different types of tumors in clinical trials.

In China, an altered adenovirus has been approved for the treatment of cancer of the head and neck for eight years. Oncolytic viruses are not yet approved in Europe or the USA. But that could soon change after the completion of further clinical studies (2).

Scientists at the University Hospital of Tübingen are pursuing a promising treatment option for peritoneal carcinosis (3). The team around Prof. Dr. med. Ulrich Lauer has so far treated six cancer patients with genetically modified smallpox vaccine viruses as part of a phase I / II study. So far, neither a cure nor a life extension has been achieved, says Lauer: "But we are seeing a cell-biological effect: cancer cells perish because the viruses multiply in the tumor tissue."

Three marker genes inserted

The smallpox virus (vaccinia) used has been optimized for its oncolytic use (GL-ONC1 from Genelux): three viral genes have been removed and three marker genes have been inserted. This allows virus-infected cells to be visualized and the number of dead tumor cells can be quantified.

The patients - who had been fully treated according to traditional methods - were treated via a permanent catheter up to four times every 28 days 107 or 108 Virus particles administered directly into the abdominal cavity. “The amount of viruses should be up to 5 × 109 can be increased, ”says Lauer, explaining the next steps. So far, the patients have tolerated the virus administration well, it remains to be seen how they react to higher doses.

It is possible that the direct application of the virus to the tumor can overcome a serious hurdle that previously stood in the way of oncolytic therapy. If the viruses are passed through the bloodstream, they often do not reach their destination because they are quickly caught in the lungs, liver or spleen.

If a person has already had contact with the virus that is used for the therapy, there is a possibility that the immune system has already been sensitized and antibodies quickly recognize the oncolytic virus and intercept it on the way to the tumor. Therefore, virotherapy has not been particularly effective so far.

Like the people of Tübingen, Jeong Heo from the Pusan ​​National University Hospital in Busan, South Korea, and an international team of researchers have now tried to inject oncolytic viruses directly into the tumor. The virus JX-594 (Jennerex Inc., San Francisco) used is also a modified smallpox vaccine virus that lacks virulence factors, but instead incorporates the gene for the human growth factor GM-CSF (granulocyte macrophage colony-stimulating factor). With this modification, the aim is to direct the body's immune system to the virus activity in the tumor in order to attack the cancer cells.

As the research group reported in February (4), a phase II study in 30 patients with liver cancer was quite successful. The virus was applied directly to the tumor three times at an interval of 14 days in two different doses. An increase in the number of viruses in the tumor was observed even at the low dose. An immune response against the virus or the tumor cells started. The patients who had received a larger amount of virus survived an average of 14.1 months after therapy, while the survival of the seriously ill could only be increased by an average of 6.7 months due to the lower amount of virus. For the first time, according to the study's authors, survival was significantly and dose-dependently prolonged with oncolytic therapy.

According to von Lauer, cancer therapy with viruses offers decisive advantages as a supplement to classic tumor therapies. “This is a biological therapy that, compared to chemotherapy, is accompanied by far fewer side effects than chemotherapy.” In addition, the viruses are able to multiply in the body. The organism therefore produces its own medication for a certain period of time.

In all of this, however, it is of crucial importance that the viruses not only have a direct effect on the cancer cells. "When the virus lyses the cancer cells, tumor antigens are released against which, in the context of the immune response against the viruses, a defense reaction of the immune system can also start," explains Lauer.

It is true that on the one hand there is fear of the immune system because it could prematurely “take the therapeutic viruses out of circulation”, on the other hand the immune defense makes a decisive contribution to the anti-tumor effect of the oncolytic viruses. If the viruses multiply in the tumor tissue, certain mechanisms with which the cancer cells would otherwise inhibit the immune defense in their immediate vicinity are suspended. And once an immune response against cancer has been initiated with the support of the virus, it continues to have an effect even after the oncolytic viruses have long since disappeared from the body, so the researchers hope. In the best-case scenario, there is a lasting effect that could protect against progression or relapse.

In addition to the vaccinia viruses mentioned, therapeutic viruses based on Reo- or Herpes simplex viruses (HSV-1) have the greatest chances of early approval. Reoviruses (Reolysin) are harmless human viruses that are used unchanged. Several phase II studies are currently ongoing to test the effectiveness of the virus in combination with chemotherapy in patients with head and neck cancer, ovarian or pancreatic cancer (5).

Metastases also infected

Previously, in a phase I study, 33 patients with various solid tumors and metastases had been administered multiple times via the bloodstream. The side effects were significantly lower than those of classic chemotherapy. The viruses accumulate in both the primary tumor and the metastases. The disease stabilized temporarily in eight patients, and the tumor volume shrank in some.

About 20 years ago, Prof. Dr. Robert Martuza from Massachusetts General Hospital in Boston came up with the idea of ​​using herpes simplex viruses to fight cancer. But first attempts in the mouse model failed because the animals developed encephalitis. Genetically modified HSV-1 viruses are now available that can only multiply in tumor cells.

Boost immune response

The most advanced in clinical studies is Talimogene laherparepvec (T-VEC) from Amgen. The messenger substance GM-CSF was incorporated into this modified HSV-1 virus in order to increase the immune response against the tumor cells. Results of the phase III study have just been reported at the American Society of Clinical Oncology congress in Chicago. Thereafter, 436 melanoma patients (stage IIIB, IIIC, IV) were administered either intralesional T-VEC (n = 295) or subcutaneous GM-CSF (n = 141).

A statistically significant difference was observed with regard to the sustained response rate (DRR): it is 16 percent in the T-VEC group and 2 percent in the GM-CSF arm (6). The overall survival time also tended to increase in the verumarm.

Researchers at the Paul Ehrlich Institute in Langen recently even used virotherapy in animal experiments against cancer stem cells. To this end, they have succeeded for the first time in generating oncolytically effective measles viruses that specifically infect and kill CD133-positive cancer stem cells. In this way, tumor foci of the test animals could be partly completely eliminated (7).

Dr. rer. nat. Ulrike Gebhardt

@Literature on the Internet:
www.aerzteblatt.de/lit2713

Rationale of Virotherapy

Oncolytic viruses are viruses that infect and lyse tumor cells, generate a specific immune response or introduce toxins and tumor suppressor genes into tumor cells. Most oncolytic viruses are genetically engineered and provided with toxic, angiogenesis-inhibiting, immunogenic, immunomodulatory or tumor suppressor transgenes.

If successful, thousands of progeny viruses are formed per tumor cell, which at the end of the infection process ends in a massive burst of the infected tumor cells (oncolysis). The newly released progeny viruses then infect other tumor cells that have not yet been infected (domino effect).

Since healthy cells have an intact immune defense, they are usually only infected to a low degree or they are able to suppress a higher degree of virus replication.

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