Sheila Singh, MD, PhD

ACGT – Barbara Netter Collaboration Award, 2024

The long-term vision of this collaboration is to develop T cell-based immunotherapies for pediatric brain tumors with the potential to become standards of care.

Globally, there are more than 400,000 children that are diagnosed with cancer each year, and in developed countries cancer remains the most common cause of death by disease for children. While cure rates for pediatric patients with leukemias and lymphomas have improved significantly, outcomes for pediatric patients with malignant brain tumors lag behind with an overall 5-year survival rate of approximately 65% in developed countries. However, depending on brain tumor type, survival rates can be much lower, including for group 3 and 4 medulloblastoma (MB) and ependymoma (EPN). 

Pediatric brain tumors are in desperate need of a transformative therapeutic approach since current approaches are often not curative and are associated with significant acute and long-term associated toxicities. Radiation, one of the cornerstones of current treatment approaches, has significant long-term side effects to the developing brain leading to “pyrrhic victories” in which long-term survivors suffer from learning disabilities, behavioral issues, and an inability to fully integrate into our society and fast-paced social networks. 

The bold vision of this ACGT-funded collaboration is to develop a curative Synthetic T-cell Therapy for pediatric brain tumors. The high specificity of such T-cell therapies would make them less toxic than current standard-of-care therapies, reducing acute and long-term adverse effects and the risk of late recurrences.

Several pieces of evidence suggest that researcers are at a propitious time for success in delivering novel Synthetic T cell-based therapies for pediatric brain tumors, and in this collaborative research proposal the focus is on chimeric antigen receptor (CAR) T-cell therapy. First, CAR T-cell targets for pediatric brain tumors have already been identified by the research collaborators (B7-H3, GD2, GPC2) and data is already available to credential them as safe for early phase clinical trials. Second, locoregional and/or intravenous delivery of CAR T cells has demonstrated significant antitumor activity in children with diffuse midline gliomas and glioblastoma and in adults with glioblastoma multiforme. Third, the research group has deep expertise in developing next-generation CAR therapeutics with enhanced potency compared to first-generation CAR immune cells created a decade ago. This expertise will be fully leveraged by our team to enhance the potency and durability of effect. Fourth, the group brings experts in syngeneic murine models and patient-derived orthotopic xenografts that allow interrogation of the tumor microenvironment of brain tumors and to use these models to develop evidence-based CAR T-cell products for future clinical testing.

“The best way to describe this collaboration is that the whole is much greater than the sum of the parts. Good science like this is done as a team.”