More Details on Possible Immunotherapy for Glioblastoma

Liam Davenport

November 14, 2014

The mechanism of action of a promising experimental tumor-cell-derived vaccine for the treatment of glioblastomas has been revealed in a series of experiments conducted by American scientists.

The chamber-based vaccine triggers an immune response by inducing the release of antigen-bearing immunogenic glioma exosomes and an antisense oligodeoxynucleotide (AS-ODN) directed against the insulin-like growth factor type 1 receptor (IGF-1R).

The vaccine, which diffuses from the chambers in a slow, continual stream, has been shown to be protective against the development of tumors in mice. Moreover, immune reactions were observed in the sera of patients with recurrent glioblastomas.

"These results strongly suggest that some patients can mount an immune response to antigens that are shared by different glioblastomas and may benefit from our vaccination strategy," D. Craig Hooper, PhD, from the Department of Cancer Biology at Thomas Jefferson University in Philadelphia, and colleagues write.

Their study was published online November 14 in Cancer Immunology, Immunotherapy.

"Glioblastomas are the most common primary brain tumor, and they are also the most devastating," said Dr Hooper.

"Even with radiation, chemotherapy, and surgery — which are all standard of care — the life expectancy is about a year and a half," he told Medscape Medical News.

"It's very difficult to deliver therapeutics to the CNS; that's one of the problems," he added.

 
It's very difficult to deliver therapeutics to the CNS.
 

However, Dr Hooper pointed out, a number of cancers are mutagenic, and the immune system has the potential to act against them, "If we let the immune system escape some of the controls, we get a better outcome," he explained.

This study builds on previous work looking at antisense molecules directed at growth factors expressed by glioblastoma cells. David Andrews, MD, a neurologist at Thomas Jefferson University, was involved at that research and in the current study.

"The insulin-like growth factor receptor 1 is believed to be very important in terms of keeping these cells alive," Dr Hooper explained. In the previous work, the team had the idea that if they used "the antisense to deliver the message for this molecule, they would be able to kill the [tumor] cells."

Initial experiments in animals revealed that, although the AS-ODN had an effect, it took around a week, which is much longer than expected. Believing this could be related to the immune system, Dr Andrews and his colleagues conducted a pilot study (J Clin Oncol. 2001;19:2189-2200), in which autologous tumor cells were treated with an AS-ODN directed against IGF-1R ex vivo, encapsulated in a Lucite chamber to keep the tumor cells separate from the patient, and implanted into the rectus sheath for 24 hours.

Clinical and radiographic responses consistent with antitumor immunity were observed in eight of 12 patients.

Although these results were "pretty promising," Dr Hooper said that increasing oversight from the US Food and Drug Administration slowed the research. "We had to do a lot more work to understand how the vaccine worked," he explained, noting that that was really the genesis of the current study.

To determine whether the therapeutic effects seen in the pilot study were due to the release of immunostimulatory AS-ODN and exosomes from the treated tumor cells, Dr Hooper's team conducted a series of detailed experiments.

They established that the small antigenic particles released by glioma cells in culture could pass through the 0.1 µm pores of the Lucite chambers. Moreover, the particles expressed the glycoproteins CD63, CD71, and CD81, confirming that they were indeed exosomes.

"In addition, we found out that the antisense is not really killing the cells but perturbing them," Dr Hooper said. "The antisense itself has motifs that resemble some bacterial genetic material, so it triggers an immune response itself; it works like an adjuvant."

Next, the researchers implanted a single chamber of the vaccine into a glioma mouse model, and found that 85% of mice were protected against the development of glioblastoma after the implantation of GL261 tumor cells 14 days later.

For the final experiment, sera from 12 patients with recurrent glioblastoma was exposed to exosomes derived from three distinct primary glioblastoma cultures from unrelated individuals.

Immune responses were observed in six patients; four had significant immunoglobulin (Ig)M antibody binding to all three exosome preparations, and three of those patients plus two others had significant IgG antibodies levels reactive to the preparations.

In the six patients who did not respond, the "immune systems have been damaged by the standard of care," Dr Hooper explained. "There's a clear difference in the outcome between individuals who came in with more immune function than in ones who did not."

The team is undertaking another phase of their investigation with a study of patients who have yet to be treated. "They'll be in for their first diagnosis, first surgery, so their immune systems should be in much better shape when they enter the trial," Dr Hooper said.

"This will be the definitive arm of the trial. In a year or so from now, we'll be able to start judging whether or not this is going to be something that should be moved into the clinic a little bit faster," he noted.

"The reality is that we are beginning to understand more of the immunology of cancer," he said. "For many years, people never thought the immune system would be able to do anything, but now we know that that is wrong."

"We should be looking at keeping people's immune systems healthy and trying to direct them appropriately at the type of tumor they have. Once we understand antigens, we'll be able to make more universal vaccines. I think that's one of the sidelines to our recent work," he explained.

"There are ways, perhaps, to get the same sort of impact without using the chamber and antisense, but we like the fact that we have an antigen depot," said Dr Hooper. "We think that may help things out a bit, rather than just throwing in, for instance, dendritic cells that have been pulsed with antigen."

"It may well be worth trying it in other models, and we are certainly moving forward to do that in model systems," he added.

Dr Hooper has disclosed no relevant financial relationships.

Cancer Immunol Immunother. Published online November 14, 2014. Abstract

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