ABSTRACT
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
Subject(s)
Brain Neoplasms/therapy , Cancer Vaccines/administration & dosage , Cerebrospinal Fluid/drug effects , Ependymoma/therapy , Immunotherapy, Adoptive/methods , Medulloblastoma/therapy , Animals , Brain Neoplasms/cerebrospinal fluid , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Cerebellar Neoplasms/cerebrospinal fluid , Cerebellar Neoplasms/immunology , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/therapy , Cerebrospinal Fluid/immunology , Child , Child, Preschool , Drug Delivery Systems/methods , Ependymoma/cerebrospinal fluid , Ependymoma/immunology , Ependymoma/pathology , Female , HEK293 Cells , Humans , Infant , Injections, Intraventricular , Male , Medulloblastoma/cerebrospinal fluid , Medulloblastoma/immunology , Medulloblastoma/pathology , Mice , Neoplasm Metastasis , Receptors, Chimeric Antigen/administration & dosage , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation , Treatment Outcome , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
Subject(s)
Medulloblastoma/blood supply , Medulloblastoma/pathology , Meningeal Neoplasms/blood supply , Meningeal Neoplasms/secondary , Allografts , Animals , Cell Line, Tumor , Chemokine CCL2/metabolism , Chromosomes, Human, Pair 10/genetics , Female , Humans , Male , Medulloblastoma/genetics , Mice, SCID , Neoplastic Cells, Circulating , ParabiosisABSTRACT
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.