GPC2 as an Immunotherapeutic Target in Medulloblastoma and other Pediatric Brain Tumors

Children with brain tumors such as medulloblastoma continue to have poor outcomes despite maximal intensification of existing radiation and chemotherapeutic regimens. Consistent with their embryonal origins, medulloblastomas and other brain tumors differentially express lineage-specific cell surface molecules, raising the possibility that immunotherapeutic approaches can be developed. The recently FDA-approved chimeric antigen receptor (CAR) T cell therapy for acute lymphoblastic leukemia that was pioneered at the Children's Hospital of Phildadelphia provides proof that immunotherapies can combat otherwise fatal childhood cancers. However, challenges remain in identifying molecules that meet optimal immunotherapeutic safety and efficacy criteria in most childhood cancers, including pediatric brain tumors. An ideal immunotherapeutic target should be cell surface localized and robustly differentially expressed between tumor and normal tissues. We have recently discovered that the signaling co-receptor glypican-2 (GPC2) meets these criteria in both medulloblastomas and neuroblastomas (Bosse et al., Cancer Cell, 2017). GPC2 is a highly expressed medulloblastoma and neuroblastoma cell surface molecule that is not detectable at significant levels on normal pediatric tissues. To therapeutically leverage GPC2’s differential expression, we have developed a GPC2-directed antibody-drug conjugate ADC; D3-GPC2-PBD), that links a GPC2-specific antibody (D3) with DNA damaging pyrrolobenzodiazepine (PBD) dimers.

This ADC potently inhibits the growth of neuroblastoma patient-derived xenografts (PDXs). However, the efficacy of this ADC in medulloblastoma models remains undefined. Furthermore, in additional preliminary work, we have also found that GPC2 may be overexpressed in other lethal pediatric brain tumors, such as high-grade gliomas (HGGs), CNS peripheral neuroectodermal tumors (PNETs) including the universally lethal embryonal tumors with multilayered rosettes (ETMRs), and atypical teratoid rhabdoid tumors (ATRTs). Our central hypothesis is that targeting GPC2 with the D3-GPC2-PBD ADC in medulloblastoma and other GPC2-expressing pediatric brain tumors will evoke potent tumor cytotoxicity.