Multi-Ganglioside Targeting to Overcome Antigen Heterogeneity in DMG

Early phase trials of GD2 and B7-H3 CAR T cells have demonstrated the potential for this modality in treating diffuse midline glioma (DMG), an otherwise highly lethal tumor. However, convincing evidence of CAR T cell efficacy has been limited to select patients. Antigen expression is a critical factor for anti-tumor response to CAR T cells, and antigen heterogeneity and loss under immune pressure can drive therapeutic resistance. In preliminary data, we have found that although ganglioside GD2 is present in all DMG tumors, it is expressed at heterogeneous levels, which may limit the efficacy of GD2 CARs in these patients.

This study aims to optimize  GD2 CAR T cell therapy for DMG patients by 1) Characterizing GD2 heterogeneity 2) Identifying alternative targets in GD2-low tumors 3) Correlating ganglioside expression with transcriptomic signatures to understand underlying biology and inform our therapeutic approach 4) Engineering CAR T cells capable of overcoming antigen heterogeneity by targeting multiple antigens.