Ependymomas: development of immunotherapeutic strategies

Abstract

Ependymomas are among the most challenging childhood brain tumors. Although 50–70% of ependymomas are cured with surgery and irradiation, a significant percentage of tumors recur. Ependymomas that are not amenable to complete resection at diagnosis have a particularly poor prognosis, and the vast majority of affected children experience tumor recurrence. Although transient responses have been observed in recurrent tumors treated with re-irradiation and several chemotherapy regimens, long-term disease control is rarely achieved. Children with recurrent disease commonly experience cumulative neurological morbidity from repeated surgical and adjuvant therapy interventions and almost universally succumb to refractory tumor progression. Accordingly, conceptually new treatment approaches are needed, both to decrease the risk of tumor recurrence and to enhance disease control in those children who experience recurrent disease. This article reviews the current application of risk-based treatment stratification at diagnosis, the rationale for exploring the role of novel therapeutic strategies such as immunotherapy at recurrence and the concept behind a vaccine-based trial for these tumors.

Keywords::

• brain tumor
• ependymoma
• immunotherapy
• pseudoprogression

Acknowledgements

The authors would like to thank Andres Salazar (Oncovir, Inc.) for providing poly-ICLC for the glioma trials.

Financial & competing interests disclosure

This work and the relevant preliminary studies were supported in part by NIH grants (P01NS40923, R01CA174858 and R21CA149872); the UPCI Immunological Monitoring Core, supported in part by award P30CA47904; grants from the Pediatric Low-Grade Glioma Initiative via the National Brain Tumor Society and the Ellie Kavalieros Fund of the Children’s Hospital of Pittsburgh Foundation; the Pediatric Clinical and Translational Research Center, supported by grants from the NIH (UL1 RR024153 and UL1TR000005). H Okada was supported by the following grants: 2R01NS055140, 1P01 CA132714, 1R21 CA117152 and 1R21CA133859. H Okada is an inventor in the US Patent Application No. 60,611,797 (Utility Patent Application): ‘Identification of an IL-13 Receptor Alpha2 Peptide Analogue Capable of Enhancing Stimulation of Glioma-Specific CTL Response’. An exclusive licensing agreement has been completed on this application between University of Pittsburgh and Stemline, Inc. Due to the potential conflicts of interest, H Okada did not solely interpret any data in the pediatric astrocytoma study referred to in this submission. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • The initial management of ependymomas has to take into account known prognostic factors, such as extent of tumor resection, histology and location, as well as other clinical factors such as patient age and metastatic stage.

• • Advances in surgical techniques and the use of conformally delivered irradiation have improved the overall prognosis for children with ependymomas, but a substantial percentage of patients still experience disease progression, which is difficult to control with current therapies.

• • Immunotherapy represents a novel treatment approach that has recently been explored in astrocytic tumors in both adults and children.

• • Ependymomas express high levels of several tumor-associated antigen that are overexpressed in astrocytomas and have been incorporated in astrocytoma immunotherapy.

• • Because the development of an immune response within brain tumors can lead to immunological pseudoprogression with resultant neurological deterioration, careful monitoring and management are required to minimize the risk of potentially dangerous adverse effects.