Roxanne Nelson

April 09, 2012

April 9, 2012 (Chicago, Illinois) — A novel peptide vaccine was well tolerated and showed evidence of immunologic and clinical responses in children with gliomas, according to the results of a small pilot study.

Among the 22 children who were available for evaluation, 4 had rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 achieved prolonged disease-free survival after surgery.

However, there were also 7 cases of pseudoprogression, which is an effect of treatment and not related to tumor progression, explained lead author Ian F. Pollack, MD, chief of pediatric neurosurgery at Children's Hospital of Pittsburgh and codirector of the University of Pittsburgh Cancer Institute Brain Tumor Program in Pennsylvania.

"Pseudoprogression is a concern that warrants close monitoring and intervention," he said during a press briefing here at the American Association for Cancer Research 103rd Annual Meeting.

The prognosis for children with diffuse brain stem gliomas and other high-grade glioma tumors is dismal with current therapies, explained Dr. Pollack, adding that the only treatment that has any sort of effect on these tumors is radiation.

"Numerous chemotherapy and radiation approaches are used, but 1-year survival is still only in the range of 15% to 20%, and overall survival in the range of 35% to 50%," he said, so there is a strong rationale for novel treatment approaches, such as immunotherapy.

Pediatric Trial Based on Adult Results

This pediatric trial builds on extensive experience with a cocktail of novel glioma-associated antigen (GAA) epitope peptides that are overexpressed in the tumors of adults. These include EphA2 and IL13Rα2, with immunoadjuvant poly-ICLC added to promote the immune response. The regimen was well tolerated in adults and showed clinical and immunologic activity.

The researchers found that more than 75% of pediatric gliomas express at least 1 of these antigens, and that provided the rationale for a pediatric trial, explained Dr. Pollack.

In this pediatric trial, 27 children with human leukocyte antigen–A2-positive gliomas have been enrolled to date — 16 with newly diagnosed brain stem gliomas, 5 with newly diagnosed cerebral high-grade gliomas, and 6 with recurrent gliomas.

The primary end points of the study were safety and tolerability; secondary end points included T cell responses against vaccine-targeted GAAs that were assessed with enzyme-linked immunosorbent spot (ELISPOT) assay and tetramer analysis. The response to treatment was evaluated clinically and with magnetic resonance imaging.

The pediatric vaccine used in this study was similar to the one evaluated in adults, and consisted of EphA2, IL13Rα2, and survivin, with a tetanus toxoid added.

The vaccine was emulsified in Montanide-ISA-51 and given every 3 weeks for 8 courses, along with intramuscular injections of poly-ICLC.

Survival Beyond Historic Median

Overall, the vaccine was well tolerated. The most common reactions were flu-like symptoms and mild injection-site reactions, according to Dr. Pollack. There were no grade 3 or 4 systemic toxicities.

The only major toxic effects observed were in several patients with tumor pseudoprogression, which is a transient enlargement of the tumor with neurologic worsening. Two patients became fairly ill, he explained, 1 had very mild pseudoprogression that was detected only in retrospect, and 1 was entirely asymptomatic.

"But it appears to be an efficacy signal," he said.

To date, 19 of the 22 evaluable patients have had stable disease or response through at least 2 vaccine cycles, which is quite good in this poor-risk population, Dr. Pollack noted. "Eight of our 11 brain stem glioma patients have survived beyond the historic median for these tumors, which is about 10.5 months, and many remain on therapy."

From an immunologic standpoint, 11 of 13 children with a completed ELISPOT analysis have shown a positive response — to IL13Rα2 in 9 cases, to EphA2 in 6, and to survivin in 7.

He noted that 5 tumors have been evaluated to date, and all of them overexpress at least 1 of the glioma antigens.

In conclusion, said Dr. Pollack, immunologic and clinical evidence of activity has been obtained; in some cases, it has been very dramatic. More extensive analyses of safety and efficacy are warranted in a multi-institutional setting.

This study is important on several levels, said Olivera Finn, PhD, distinguished professor and chair of the Department of Immunology at the University of Pittsburgh. "This is clearly helping the children, but also because immunotherapy depends on activating your own immune system," she told Medscape Medical News.

"When an adult is diagnosed with cancer, we don't know how long that cancer has been there — it could have been slowly growing for decades," she pointed out. "But with a 2-year-old child, there's no question of how long it's been there. It's a very different setting, and the immune systems of children are very robust and recover quickly. There is a lot of promise...making these results really significant in the pediatric population."

The study was funded by the National Institutes of Health.

American Association for Cancer Research (AACR) 103rd Annual Meeting: Abstract LB-131. Presented April 2, 2012.

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