Molecular biology and phase 1 study of GM-CSF and intrathecal trastuzumab in children with recurrent -posterior fossa ependymoma.
This phase 0/1 study reports target-selection and in-vitro evidence for trastuzumab-mediated cytotoxicity and found intrathecal trastuzumab plus subcutaneous GM-CSF safe at the two tested dose levels in children with recurrent posterior fossa ependymoma, with exploratory progression and immune-correlate findings.
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This phase 0/1 study reports target-selection and in-vitro evidence for trastuzumab-mediated cytotoxicity and found intrathecal trastuzumab plus subcutaneous GM-CSF safe at the two tested dose levels in children with recurrent posterior fossa ependymoma, with exploratory progression and immune-correlate findings.
Research significance
The record provides evidence that HER2/ErbB2 is a candidate ependymoma target, that trastuzumab can promote antibody-dependent cytotoxicity in PFA ependymoma co-cultures with GM-CSF-stimulated immune cells, and that the intrathecal combination was feasible and reported safe at tested doses; it remains an inference, requiring a larger controlled study, that this immune strategy improves disease control or survival.
Source abstract
BACKGROUND: Ependymoma (EPN) is an aggressive pediatric central nervous system 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 (s.c.) granulocyte-macrophage colony-stimulating factor (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 s.c. 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 the 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.