Post-doctoral Fellowship Grant Awarded to Andrea Timpanaro

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric tumor occurring in the pons accounting for ~80% of brainstem gliomas. Each year, DIPG affects over 300 children in the U.S., with a median survival of only 11 months. Due to the tumor location, surgical resection is impossible, while resistance to current treatments makes the prognosis dismal. Chimeric antigen receptor (CAR) T cells are a new, targeted immunotherapy that has had remarkable success in curing children with hematological malignancies. This technology must now be translated to children with DIPG. B7-H3 is a protein expressed on nearly all DIPG but not on normal brain, enabling CAR T cells to selectively target tumor cells. Our Seattle Children’s team just completed BrainChild-03 (NCT04185038), a first-in-human phase 1 clinical trial for children with DIPG and found the planned highest dose, 100 million cells, to be safe. Some patients have also had remarkable clinical benefit, including two patients still on trial 2.5 years from their diagnosis without progression. Unfortunately, these encouraging results have not been universal, but a new era of combinatorial clinical trials is now possible.

ONC206 is a small molecule derived from ONC201, an allosteric agonist of the protease ClpP, that has shown even greater benefit in initial laboratory studies. ONC201 has had promising clinical efficacy against DIPG, but - as with CAR T cells - the positive outcome is not universal. While there is hope that ONC206 is more effective for children than ONC201, these agents will need to be combined with other therapies to reach a cure. Based on clinical success of B7-H3 CAR T cells, along with the advancement of ONC206 to clinical trials, in this project we will evaluate the combinatorial benefit of these agents together, determining their best time sequence for a future clinical trial for children with DIPG.