P12.10 In vivo dynamics and anti-tumor effects of B7-H3-directed CAR T-cells in an orthotopic medulloblastoma mouse model

Background

The majority of solid tumors in pediatric patients occurs in the central nervous system, with medulloblastoma accounting for approximately 20% of pediatric brain tumors. Current treatment, involving resection, radiotherapy, and chemotherapy, improves long-term survival but is associated with significant adverse effects. Hence, there is an urgent need for novel therapeutic approaches. Chimeric Antigen Receptor (CAR) T-cell therapy has shown promise in treating hematologic malignancies. Its potential suitability for medulloblastoma remains uncertain. Initial preclinical and clinical studies suggest efficacy, but the dynamics of CAR-T recruitment, their interactions with tumor cells, optimal administration routes (intravenous, intraventricular, intratumoral), and mechanisms of potential treatment failure are unclear. To address these gaps, we aimed to establish an in vivo model for further investigation of CAR T-treatment in medulloblastoma.

Materials and Methods

Three weeks after the microsurgical implantation of a chronic cerebellar window in immunodeficient Fox^N1 mice, red fluorescent human medulloblastoma cells (DAOY^tdt; SHH) were injected into the cerebellum. After 20 days solid tumor had formed, and CAR T-cells^GFP directed against the surface antigen B7-H3 were injected at a distance of 1mm adjacent to the tumor. As control, we used antiCD-19 CAR T-cells^GFP. Intravital two-photon laser scanning microscopy was used to longitudinally monitor tumor growth and CAR T-cells at a cellular level.

Results

We successfully established a xenogeneic orthotopic medulloblastoma model which allows repetitive in vivo microscopy on a cellular resolution. Our preliminary results show, that following intracranial injection CAR T-cells were recruited to the tumor site and reduced tumor growth.

Conclusions

Our mouse model can be used to evaluate the efficacy of CAR T-treatment for medulloblastoma and analyze CAR T-biology at a cellular level. Preliminary data showed a possible efficacy of antiB7-H3 CARs. In further experiments, we plan to dissect the efficacy of different application routes on the treatment efficacy.

J.J. Herold: None. N. Teske: None. N.N. Kutlu: None. L. Dengler: None. C. Eberle: None. E. Nikolaishvili: None. P. Karschnia: None. J. Blobner: None. K. Müller: None. S. Langer: None. V. Buschinger: None. L. Warmuth: None. D.H. Busch: None. V.R. Buchholz: None. N. Thon: None. J.C. Tonn: None. T. Feuchtinger: None. L. von Baumgarten: None.