Brain cancers are challenging enough to have to treat in adults, but when they recur in small children, treatment paradigms often become exponentially more difficult. However, now, a new study led by investigators at Baylor College of Medicine, Texas Children’s Hospital, and the Hospital for Sick Children (SickKids) describe a novel approach to treat medulloblastoma and ependymoma. The researchers were able to deliver appropriately targeted chimeric antigen receptor (CAR) T cell therapy directly into the cerebrospinal fluid that surrounds the tumor. Findings from the new study were published recently in Nature Medicine through an article titled “Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.”

“Recurrences of medulloblastoma and ependymoma can be disseminated throughout the lining of the brain and spinal cord, which are bathed in cerebrospinal fluid,” explained co-senior study investigator Nabil Ahmed, MD, associate professor of pediatrics and immunology, a section of hematology-oncology at Baylor and Texas Children’s Hospital. “This location offers the opportunity to deliver therapies into the cerebrospinal fluid compartment and could provide a better chance for the therapy to reach and eliminate the tumor than administering it through the bloodstream.”

The findings support further clinical studies to evaluate this strategy to treat pediatric brain cancers, the most common cause of cancer death in childhood. Indeed, a first-in-child clinical trial currently is recruiting patients at Texas Children’s Hospital and Baylor College of Medicine to test the safety and anti-tumor efficacy of this approach ( identifier: NCT02442297).

“The vast majority of children with recurrent metastatic medulloblastoma or ependymoma currently have a deadly prognosis, so it is very exciting to think we have identified a novel approach to treat this underserved patient population,” noted co-senior study investigator Michael Taylor, MD, a neurosurgeon and senior scientist in the developmental and stem cell biology program, chair in cancer research at SickKids, and professor in the departments of surgery and laboratory medicine and pathobiology at the University of Toronto.

The research team performed in-depth molecular studies of the target profile of recurrent medulloblastoma and ependymoma. These studies guided the design of CAR T cells engineered by Ahmed and colleagues at Baylor’s Center for Cell and Gene Therapy and Texas Children’s Hospital to target the most appropriate cancer molecules.

The researchers genetically engineered CAR T cells to recognize specific molecules on the surface of the tumor cells. When these CAR T cells encounter the tumor, they can fight it more effectively. CAR T cells have been impressively effective for patients with certain types of leukemia and are FDA-approved for this disease.

In mouse model studies, CAR T cells were administered into the cerebrospinal fluid around the tumor or into the bloodstream of mice harboring multiple patient-derived medulloblastoma and ependymoma tumors. The tumor size and animal survival were studied for about 200 days.

“We identified three cell-surface targets, EPHA2, HER2, and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain,” the authors wrote. “We validated 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 demonstrated 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.”

The results showed that administering tumor-specific CAR T cells into the cerebrospinal fluid was more effective than administering them via the blood. Moreover, the researchers combined CAR T cells with an approved cancer medication called azacytidine. The results showed that combining immunotherapy with azacytidine was significantly more effective than either treatment alone.

“As opposed to delivery through the blood, cerebrospinal fluid delivery overcomes the blood-brain barrier and also offers the advantage of minimizing exposure of other tissues of the body to the CAR T cells and, consequently, potential side effects,” concluded lead study investigator Laura Donovan, PhD, a post-doctoral fellow in the developmental and stem cell biology program at SickKids.


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