For years, doctors have unsuccessfully battled the most malignant form of brain cancer: glioblastoma. A major problem is that the tumours can be hidden and the immune system detects them too late. Researchers have now succeeded in “heating” these immunologically “cold” tumours to fight them. Their first trial was so promising that they are preparing Phase 2 trials for developing immunotherapy. This method may prove to be even more effective in combating other types of cancer.
People with glioblastoma, a type of malignant brain cancer, have a poor prognosis today. They survive less than 18 months on average after diagnosis. Removing the tumour is insufficient, because the disease has already spread throughout the brain. Unfortunately, both these people’s immune systems and doctors have difficulty in detecting cancer cells, and attempts to combat the disease so far have been unsuccessful. A large international research consortium has now taken a decisive step towards achieving a breakthrough.
“We have decided to abandon the current principles guiding treatment. Instead of just treating the tumour itself, we try to treat the whole brain. We do this by adapting personalized treatment precisely to each person’s tumour. By targeting the treatment to the specific antigens in each person, we change the cancer from being immunologically “cold” to “warm” so that we can combat it with immunotherapy,” explains Hans Skovgaard Poulsen, Associate Research Professor and Chief Physician, Section for Neuro-oncology, Department of Radiation Biology, Rigshospitalet, Copenhagen.
Changing from cold to warm
The results of the Phase 1 trials conducted based on the new treatment principles are so promising that they have been published in Nature. The new type of treatment has two phases. First, doctors use tissue samples to identify some of the antigens (peptides or protein fragments) previous studies have shown are generally extensively expressed in brain tumours. Based on this, the first wave of treatment can include an immunotherapy cocktail called APVAC1 (actively personalized vaccine 1).
“This is broad-spectrum treatment, but the people treated with APVAC1 also get personalized treatment right away. Alongside this, we begin to monitor the most important changes in the antigens in each person’s tumours. If we find them, we can start producing vaccines against the specific antigens involved in this person’s cancer.”
While the personalized vaccine is being prepared, taking about 1 month, the brain cancer is combated with the broad-spectrum immunotherapy. Then the second phase of the treatment – APVAC2 – starts.
“The antibodies in the second treatment phase specifically target the changes that have taken place in each person’s tumour. The treatment therefore affects the cancer cells specifically and effectively and does not harm the person’s normal cells.”
The great challenge previously has been that the antigens in glioblastoma are expressed at a very low level. Creating an immune response that is powerful enough to effectively combat the cancer has therefore been difficult. Glioblastoma has therefore been considered “cold” immunologically, so previous attempts with immunotherapy have failed.
“We are only currently conducting Phase 1 trials, primarily examining whether the treatment is feasible and whether it is toxic. But we have already achieved a strong immune response, so we seem to have succeeded in making the “cold” tumours appear “warm” and are therefore very optimistic about the upcoming Phase 2 trials.”
Attenuated poliovirus can help
It is still too early to predict whether applying this treatment of a fatal type of brain cancer affecting nearly 200,000 people worldwide will be successful in the future. For now, the personalized vaccines have only been tested on 15 people at Rigshospitalet in the Phase 1 trials. Cautious optimism is therefore still needed.
“Most people had a strong immune response, and some survived longer than expected. We cannot yet determine whether the positive effects are random. We need to test the vaccine on a sample of more people before we can be sure that the vaccine is actually causing the effects.”
The research has been carried out as part of a large European Union consortium led from Germany that has been awarded about DKK 60 million in grants so far. The consortium is now planning Phase 2 trials on a much larger group of people in collaboration with Immatics, a pharmaceutical company headquartered in Germany, to determine whether the vaccine has the desired effectiveness. If this also succeeds, Phase 3 trials can be planned to compare this treatment with existing treatments for brain cancer.
“We have considerable work ahead of us before people can be treated. We are, however, optimists, because we achieve a substantial immune response, and we will probably be able to increase these effects through such means as programmed death-ligand 1 (PD-L1) inhibitors, which can further boost the human immune response. Phase 2 trials are also currently being conducted at Duke University in the United States, using the attenuated poliovirus to increase people’s immune response to cancer. So we are very optimistic that the survival rate will increase significantly in the coming years.”
“Actively personalized vaccination trial for newly diagnosed glioblastoma” has been published in Nature. A European Commission grant of DKK 45 million funded the study. In 2015, the Novo Nordisk Foundation awarded a grant to Hans Skovgaard Poulsen for the project Impact of Renin-angiotensin System Blockade on Clinical Outcome in Glioblastoma Patients.