Molecular Biology and Phase 1 Study of GM-CSF and Intrathecal Trastuzumab in Children with Recurrent Posterior Fossa Ependymoma

Abstract Background Ependymoma (EPN) is an aggressive pediatric CNS tumor with poor survival and significant morbidity. As immune factors are associated with outcome, the potential for effective immunotherapy in posterior fossa (PF) EPN has been suggested. Based on the success of immune stimulants combined with an anti-GD2 monoclonal antibody in high-risk pediatric neuroblastoma, we hypothesized that a similar approach would be a plausible immunotherapy strategy for recurrent PF EPN. Methods A phase 0/1 trial evaluating the safety and dosing of intrathecal (IT) trastuzumab combined with subcutaneous GM-CSF for pediatric patients with relapsed PF EPN was conducted. Results ErbB2/Her2, targeted by trastuzumab, was identified as a top therapeutic antibody target for EPN by in silico screening. In vitro co-culture assays with GM-CSF stimulated autologous PBMCs showed trastuzumab antibody-dependent cell cytotoxicity in PFA EPN cell lines. A phase 1 clinical study identified that IT delivery of trastuzumab in combination with subcutaneous GM-CSF was safe in children at both dose levels tested. Four patients (57%) successfully completed all planned therapy. The median progression-free survival was 2.4 years (95% CI, 0.47, not evaluable). Profiling of biological correlates identified that tumors of patients who did not progress on study had increased T-cell activity and decreased pro-tumor inflammatory myeloid gene expression compared to patients who progressed on study treatment. Conclusion IT trastuzumab in combination with GM-CSF is safe in recurrent pediatric PF EPN. A larger phase 2 study that includes both recurrent PFA and RELA-ST EPN is needed to determine the long-term efficacy of this immunotherapy strategy.