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.
Methods: 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, IL13Ra2, 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, 27 children have been enrolled, 16 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 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 tumor enlargement followed by stabilization on decreasing steroid doses. Among 23 patients evaluable for response, 15 had stable disease for > 2 months, 3 had PRs, 1 had an MR, and 1 had prolonged disease-free status after surgery. Only 3 had progressive disease during the first two vaccine courses. ELISPOT analysis in 12 children, showed responses in 11: to IL13Ra2 in 9, EphA2 in 6, and survivin in 7. 8 of 11 BSG patients exceeded the historical median survival and 5 others remain on therapy.
Conclusions: Peptide vaccination in children with gliomas is well tolerated, and has preliminary evidence of both immunological and clinical activity.
Patient Care: We have observed unprecedented disease regression in patients with brainstem glioma, metastatic low-grade glioma, and a thalamic GBM, as well as prolonged disease stabilization in a substantial percentage of the cohort. This work will be translated to a multi-institutional study for children with high-risk gliomas.
Learning Objectives: The role of vaccine therapy as a promising new adjunct for childhood gliomas will be discussed.
These results will be presented in the context of the current therapeutic options for these tumors
References: Okada H, Low KL, Kohanbash G, McDonald HA, Hamilton RL, Pollack IF. Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J Neuro-Oncol 88: 245-250, 2008, PMCID: PMC2561257.
Okada J, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Barlett DL, Brown C, Zeh H, Holtzmann MP, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS. Induction of CD8+ T cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with a-type-1-polarized dendritic cells and poly-ICLC in patients with recurrent malignant glioma. J Clin Oncol 29: 330-336, 2011.