Aug
13
2022

New Immunotherapy Approach against Cancer

By | Cancer, immune system

A recent publication reported about a new immunotherapy approach against cancer. The model it dealt with was a very vicious brain cancer with the name glioblastoma. The results of this research were subsequently transferred to another vicious cancer, osteosarcoma, which is a form of bone cancer with a very poor prognosis. Researchers have to do further clinical experiments to establish this new immunotherapy in osteosarcoma patients. Physicians completed the following experiments and clinical studies.

Oncolytic virus Delta-24-RGD can lead to remission in glioblastoma patients

Researchers at the University of Navarra, Pamplona, Spain together with The University of Texas MD Anderson Cancer Center in the US investigated glioblastoma patients. They found that treatment of glioblastoma patients with oncolytic viruses Delta-24-RGD led to a greater than 3-year remission in 20% of cases. Normally, patients with a glioblastoma survive only 9 months on average. 12% had a greater than 95% reduction in the size of the tumor. This was a phase 1 clinical study with 37 patients who had recurrent malignant glioblastoma. The authors said: “Oncolytic adenoviruses are attractive therapeutic agents because they can kill tumor stem cells and induce cell death by several mechanisms, including direct lysis, expression of toxic proteins, induction of cytokines, and T-cell–mediated immunity.” The particular oncogenic virus that the researchers used was an adenovirus Delta-24-RGD.

Transferring glioblastoma results to a cure for osteosarcoma

The same researchers wanted to see whether the cure rates of treating patients with glioblastoma was transferable to other cancer patients. In particular they were interested in patients with osteosarcoma, which is a similarly vicious cancer. Advanced osteosarcoma has a survival rate of 27% after 5 years. The researchers first did experiments with a human osteosarcoma cell line in tissue culture and at the same time a murine osteosarcoma cell line. Later they tested the action of oncolytic viruses Delta-24-RGD in a mouse model.

Experiments with osteosarcoma cells in tissue culture

The advantage of such experiments is that you can control all the parameters easily in a Petri dish. But critics say that this is far removed from osteosarcoma behavior in humans. Researchers found that the oncolytic virus Delta-24-RGD killed many osteosarcoma cells in vitro. They also were able to insert a new gene into the oncolytic virus, which was equally effective in killing osteosarcoma cells. They called this virus Delta-24-ACT.

Curing osteosarcoma in a mouse model

Next the researchers tested effectiveness of the oncolytic viruses, Delta-24-ACT and Delta-24-RDG in mice. They injected osteosarcoma cells from tissue culture into the tibia of mice. Tumor growth was subsequently measured. The experimental groups were given two oncolytic virus infections, the control group did not. On day 10 and 18 the researchers could see that controls had faster growing tumors compared to the experimental groups. The experimental groups had less tumor side effects. And the experimental mice survived longer than the controls. Further research showed that the oncolytic viruses produced a 4-1BBL protein, which stimulated the animals’ immune system to fight the osteosarcoma.

New immunotherapy approach against cancer: Effector T cells

Researchers could prove that in mice treated with oncolytic viruses it was the special protein (4-1BBL) that stimulated T lymphocytes to become killer T cells. They in turn attacked the osteosarcoma cells.

New immunotherapy approach against cancer: The need for human research

Doing research in humans is more complicated than in a mouse model. But in order to improve survival rates in patients with osteosarcoma human research is absolutely essential. However, research is complex and the effects of oncolytic viruses is only in the 20% range with regard to increasing survival. This requires more research. It may be that instead of oncolytic viruses a stimulatory protein would arm T cells to become killer T cells that fight the cancer.

New Immunotherapy Approach against Cancer

New Immunotherapy Approach against Cancer

Conclusion

Glioblastoma patients had a better survival after treatment with oncolytic viruses Delta-24-RGD. Researchers translated this type of research to another cancer, osteosarcoma. This also has a poor prognosis, Researchers did experiments in tissue culture and in a mouse model. They were able to show that oncolytic viruses produced a 4-1BBL protein, which stimulated the animals’ immune system to fight the osteosarcoma. Specifically, the protein armed T lymphocytes and turned them into killer T lymphocytes. These destroyed osteosarcoma cells in tissue culture or in the mouse model. It is encouraging to see positive results in a laboratory setting of a tissue culture. The step further in an animal experiment is also a positive achievement. More research will improve the cure rates of osteosarcoma. The effective treatment of osteosarcoma in humans is still far away! The next step is human research that shows improvements in patients’ survival rates.

Jul
27
2018

Modified Poliovirus Effective Against Brain Cancer

By | Cancer, immune system

A clinical trial found modified poliovirus effective against brain cancer. 61 patients with glioblastoma, the most deadly brain cancer there is, have been enrolled in this trial since 2012.

Glioblastoma treatment with genetically modified poliovirus

Dr. Gromeier, one of the lead cancer researchers at Duke University, Durham, North Carolina has done animal experiments. Unlike poliovirus, he found that genetically modified poliovirus was harmless for the central nervous system and yet he found modified poliovirus effective against brain cancer. This genetically modified poliovirus was attacking glioblastoma cells in cell cultures and in human brains. Dr. Annick Desjardins, a co-author of the study explained that the researchers had to take a piece of RNA away from the poliovirus and replace it with a neutral piece of RNA. This way it is still attracted to the numerous poliovirus receptors, which are expressed on many human cancers. The genetic sequence that allows poliovirus to reproduce in normal cells was taken out with the genetic modification. An inert RNA piece from the rhinovirus, the cause of the common cold was replacing this.

Effect of the genetically modified poliovirus

This way the modified poliovirus is no longer destroying nervous tissue. But the virus can still multiply in the glioblastoma cells, release toxins and kill these cancer cells.

Dr. Bryan Choi is a fellow in the Cellular Immunotherapy Program at Massachusetts General Hospital Cancer Center. He also works at the Department of Neurosurgery at Harvard Medical School. Although he was not part of this study he stated that this study was a giant step forward. “Perhaps the most promising aspect is the ability for this genetically modified virus to not only directly kill brain cancer cells, but to release tumor antigens,” Choi said. Antigens are toxic substances that stimulate the immune system to mount an immune response against the cancer. This immunotherapeutic effect is an important aspect of this new treatment modality.

Some human statistics of the pilot study showing modified poliovirus effective against brain cancer

Here are the highlights.

  1. 21% of the poliovirus patients are still alive three years after treatment; this compares to just 4% of the control patients who only received chemotherapy.
  2. The average survival time for the 61 patients who have received the genetically modified poliovirus therapy was 12.5 months. This compares with 11.3 months for a control group of matched patients. These had received standard treatment (chemotherapy).
  3. Some patients were much better responders than others. A 20-year old man a 60-year-old man survived 69 months (nearly 6 years). They are still alive today. This was unthinkable of in the past for patients with glioblastoma.

Repeat modified poliovirus therapy for glioblastoma recurrence

Dr. Darell D. Bigner, a co-author of the study, a professor of pathology and emeritus director observed the following. Some patients experienced initial reduction of the glioblastoma, and when the cancer came back they received repeat modified poliovirus treatments. To the surprise of the investigators the tumors shrank again and again. This was never the case with conventional chemotherapy. Once a glioblastoma is chemotherapy-resistant, chemotherapy will not work again.

Experience with modified poliovirus therapy

  1. In this trial treatment for glioblastoma started with implanting a catheter right into the center of the glioblastoma. An infusion of the engineered poliovirus followed, a process that could take up to 6.5 hours. Removal of the catheter was next.
  2. In the beginning researchers used higher doses of the genetically engineered poliovirus. Some people developed severe inflammation causing seizures, which needed treatment. Confusion and language difficulties were also side effects. Others developed pronounced nausea. The researchers decided to lower the dosage of the genetically engineered poliovirus, and the patients still had good clinical results.
  3. “We are presently enrolling in a phase 2 trial combining the genetically modified poliovirus with one dose of chemotherapy,” Desjardins said. “We are also enrolling in a trial for pediatric brain tumor patients.” In addition studies using genetically engineered poliovirus against breast cancer and against skin cancer are also in the planning stage.
  4. There are other new approaches where there the doctor injects the photosensitizer indocyanine into breast cancer tissue. Next the doctor points a laser beam near the infrared frequency of light to the cancer area. You find details about this procedure here.
Modified Poliovirus Effective Against Brain Cancer

Modified Poliovirus Effective Against Brain Cancer

Conclusion

A new approach to treating glioblastoma, one of the deadliest brain cancers, has shown promising results. A genetically engineered poliovirus is no longer making the person sick with polio, but instead destroys glioblastoma cells and prolongs patients’ lives. Some patients lived up to 6 years while controls lived less than one year. The effect of this new treatment occurs from the release of toxins within the glioblastoma cancer. This leads to cancer cell death and the release of these toxins. The immune system receives stimulation to recognize and destroy the remaining glioblastoma cells. At this point the basic steps of this new therapy are in place.

Future direction of research

But the same method will one day likely be in use for other cancers. There are plans for new clinical trials to examine this further. The researchers also want to test cure rates of a combination of chemotherapy and genetically engineered poliovirus therapy. This will answer the question whether the combination treatment will be better than genetically engineered poliovirus therapy alone.