Neuro-oncology · 2026
Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma.
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Timpanaro Andrea, Song Edward Z, Toumi Ryma, Elena-Sanchez Leonel, Piccand Caroline, Nemec Kelsey M, Kordowski Anja, Lau Davina, Johnson Scott, Winter Lily, Rajendran Ashmitha, Ronsley Rebecca, Oda Shannon K, Gustafson Joshua A, Wendler Jason P, Koschmann Carl, Evans Myron, Pattwell Siobhan, Jensen Michael C, Foster Jessica B, Dun Matthew D, Meechan Michael, Biery Matthew C, Vitanza Nicholas A
Аннотация
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against central nervous system (CNS) tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation.
METHODS: We tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models.
RESULTS: B7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (P < .003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells extended survival in DIPG xenograft mouse models.
CONCLUSIONS: B7-H3 CAR T cells combined with ONC206 are a feasible and efficacious multi-agent approach against multiple DIPG models.
METHODS: We tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models.
RESULTS: B7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (P < .003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells extended survival in DIPG xenograft mouse models.
CONCLUSIONS: B7-H3 CAR T cells combined with ONC206 are a feasible and efficacious multi-agent approach against multiple DIPG models.