Zurich team explores immunotherapy for brain tumors

Promising new approach emerges as researchers combine two compounds in preclinical studies

Jeffrey Bouley
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ZURICH, Switzerland—A team of researchers at the University of Zurich believes it may have discovered a new weapon in the paltry arsenal against glioblastoma, which  is one of the most ominous brain tumors. Even with aggressive surgery, radiation and chemotherapy, those with this particular form of brain cancer can generally expect to die from the disease, but the Zurich team, led by Dr. Burkhard Becher, has achieved preclinical success with a novel form of treatment that involves encouraging the body’s own immune system to recognize and eliminate cancer cells in the brain.
 
As Becher points out, animal experiments show that it is relatively easy to treat cancer in the early stages; however, it is far more difficult to successfully treat advanced cancer. Furthermore, treatment of brain tumors poses particular challenges, given that regulatory T cells accumulate in brain tumors and suppress immune attacks.
 
The initial objective of the University of Zurich research was to break through the tumor’s protective shield, with Becher explaining, “We wanted to establish whether we can actually elicit an immune response to a tumor growing within the brain.”
Interleukin-12 (IL-12) was the initial weapon the team chose, because when IL-12 is produced in a tumor, immune cells are stimulated locally in such a manner that the tumor is attacked and rejected. The approach worked well in the early stages of the tumor, so the researchers took the next step and in the second stage of work waited until the tumor was very large and the life expectancy of the untreated test animals was less than three weeks.
 
“We only began treatment when it was, in fact, already too late,” said the first author of the study, Dr. Johannes vom Berg, in the news release about the research—predictably, the success rate was low, and the team then injected biopharmaceutical IL-12 into the large brain tumor. “This did induce an immune response but only led to tumor rejection in one-quarter of the animals.”
 
The twist in their treatment approach came when the researchers took a cue from a new development in skin cancer treatment in their next stage and combined intra-tumoral IL-12 with the intravenous administration of a novel immunostimulating drug (a CTLA-4 blocker) that suppresses the regulatory T-cells, bringing them from a 25-percent success rate in tumor rejection to an 80-percent success rate.
 
“I have rarely seen such convincing data in preclinical glioma treatment,” said Michael Weller, a neuro-oncologist and director of the Clinic for Neurology at University Hospital Zurich, in the news release about the research, adding, “That’s why this development should be tested as soon as possible in clinical trials.”
 
In a joint trial, the team then tested the treatment in another tumor model that reportedly mimics the clinical situation of a human brain tumor patient even better, and once again they were successful.
 
In the research paper published Nov. 25 in The Journal of Experimental Medicine, “Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell mediated glioma rejection,” the team wrote, “Our data provide compelling preclinical findings warranting swift translation into clinical trials in GB and represent a promising approach to increase response rates of CTLA-4 blockade in solid tumors.”
 
In the announcement of the research results, Becher noted that they were seeking commercial partners and added, “We are cautiously optimistic but it’s time that we adopted completely new strategies to really get to grips with this fatal tumor.”
During a brief interview in late December, Becher updated the situation a bit, telling DDNews, “We are talking to potential commercial partners or investors to produce the compound in GMP quality. A clinical trial design draft exists and the clinical partners are enthusiastically on board.”
 
In other late 2013 brain tumor treatment news, Menlo Park, Calif.-based NewGen Therapeutics Inc. announced that data from a recent preclinical study demonstrate a high therapeutic potential for the company's targeted therapeutic candidate for brain cancer, NT-113. Data from in-vivo studies of the experimental drug reportedly demonstrated potent anticancer activity and improved survival in a mouse intracranial xenograft model implanted with both epidermal growth factor (EGFR)-amplified and EGFRvIII-mutated glioblastoma cell lines.
 
“Given NT-113's robust anticancer activity in multiple intracranial human glioblastoma xenograft studies, excellent pharmacokinetics and very high capacity to cross the blood-brain barrier, we plan to initially explore this potential targeted medicine for patients with glioblastoma and non-small cell lung cancer with brain metastases,” said Harry D. Pedersen, CEO of NewGen Therapeutics. “EGFR alterations drive many solid tumors to grow and spread.  Overexpression and/or mutations of EGFR occur in 40 percent to 60 percent of glioblastoma patients and 40 percent to 80 percent of non-small cell lung cancer patients, most of whom eventually develop brain metastases. Focusing on patients with EGFR over-expression or mutations in these studies should result in higher response rates, improved survival and more rapid approval timelines.”
NewGen plans to initiate Phase 1 studies with NT-113 in early 2015.

Jeffrey Bouley

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