Peptide Vaccine Shows Evidence of Immunological, Clinical Activity in Children With Gliomas

This abstract will be presented at an AACR press conference on Monday, April 2 at 7:30 a.m. CT in room CC20 A/B/C of the Hyatt McCormick Conference Center. Reporters who cannot attend in person may participate by calling in with the following information:U.S. & Canada: (888) 647-7462International: (201) 604-0169Newswise — CHICAGO — Peptide vaccination in children with gliomas was well tolerated with evidence of immunological and clinical responses, but some children experienced periods of immunological pseudoprogression, where tumors appeared larger than they actually were, according to results presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

“We’ve found that the vaccine is tolerated well with limited systemic toxicity, but we’ve also observed that there are some patients who have immunological responses to the vaccine target in the brain that can cause swelling and transient worsening, and subsequently, some of those children can have very favorable responses,” said Ian F. Pollack, M.D., Walter Dandy professor of neurological surgery and vice chairman for academic affairs in the department of neurological surgery at the University of Pittsburgh School of Medicine in Pittsburgh, Pa. “We’ve also demonstrated immunological responses in the majority of the kids.”

In the pilot study, Pollack, who is also chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh and co-director of the University of Pittsburgh Cancer Institute Brain Tumor Program in Pittsburgh, Pa., and colleagues enrolled 27 children, including 16 with newly diagnosed brain stem gliomas, five with newly diagnosed cerebral high-grade gliomas and six with recurrent gliomas.

Researchers assigned HLA-A2–positive children to subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes emulsified in Montanide-ISA-51 every three weeks for eight courses. They also administered intramuscular injections of poly-ICLC. The GAAs included EphA2, IL13Rα2 and survivin.

Among 22 evaluable cases, four children had rapidly progressive disease, 14 had stable disease for more than three months, three had sustained partial responses and one had prolonged disease-free status after surgery. ELISPOT analysis, which was completed in seven children, revealed responses in six children: to IL13Rα2 in five cases, EphA2 in three and survivin in three.

“These kids, who, for the most part, have intact and very robust immune systems, seem to mount an immune response against the vaccine very effectively at rates that may be even higher than have been noted in studies in adults,” Pollack said.

Pseudoprogression occurred in some cases and was similar to true tumor progression. For example, one child with a brain stem glioma had transient tumor enlargement and acute neurological deterioration four months after vaccine initiation. However, the tumor later regressed and the patient experienced a sustained partial response. Three other children with brain stem gliomas had symptomatic pseudoprogression, with transient neurological deterioration and tumor enlargement followed by stabilization on decreasing steroid doses.

“This was the first study of its type that examined peptide vaccine therapy for children with brain tumors like this,” Pollack said. “The fact that we’ve seen tumor shrinkage in children with very high-risk tumors has been extremely encouraging and somewhat surprising.”

The study was funded by the National Institutes of Health.

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Presenter: Ian F. Pollack, M.D.

Abstract Number: LB-131

Title: Peptide vaccine therapy for childhood gliomas: Interim results of a pilot study

Author Block: Ian F. Pollack, Regina I. Jakacki, Lisa H. Butterfield, Hideho Okada. Children's Hospital of Pittsburgh, Pittsburgh, PA, University of Pittsburgh Cancer Institute, Pittsburgh, PA

Introduction: Malignant astrocytomas of the brainstem and cerebral hemispheres and multiply recurrent low-grade gliomas carry a poor prognosis despite current treatments, and new therapeutic approaches are needed. Having gained significant experience with immunotherapy for adult gliomas, we extended these insights to childhood gliomas, based on our observations regarding their profiles of glioma-associated antigen (GAA) expression.Methodology: We initiated a pilot trial of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 given every 3 weeks for 8 courses along with intramuscular injections of poly-ICLC in HLA-A2+ children with newly diagnosed brainstem gliomas (BSG), cerebral high-grade gliomas (HGG), or recurrent gliomas. GAAs were EphA2, IL13Rα2, and survivin. Primary endpoints were safety and T cell responses against vaccine-targeted GAAs, assessed by ELISPOT and tetramer analysis. Treatment response was evaluated clinically and by MR imaging.Results: To date, 24 children have been enrolled, 13 with newly diagnosed BSG, 5 with newly diagnosed HGG, and 6 with recurrent gliomas. No dose-limiting non-CNS toxicity has been encountered. One child with a BSG had transient tumor enlargement in association with acute neurological deterioration 4 months after beginning vaccination that later regressed and culminated in a sustained partial response (PR), consistent with pseudoprogression. Two other children with BSG had symptomatic pseudoprogression, with transient neurological deterioration and tumor enlargement followed by stabilization on decreasing steroid doses. Among 22 patients evaluable for response, 4 had rapidly progressive disease, 14 had stable disease for > 3 months, 2 had PRs, 1 had an MR, and 1 had prolonged disease-free status after surgery. ELISPOT analysis, completed in seven children, showed response to IL13Rα2 in 5, EphA2 in 3, and survivin in 3.Conclusion: Peptide vaccination in children with gliomas is generally well tolerated, and has preliminary evidence of both immunological and clinical activity. Pseudoprogression can initially be difficult to distinguish from true tumor progression and aggressive management may be warranted.