DDDR-40. TARGETING BCL-XL WITH MIRZOTAMAB CLETUZOCLAX (ABBV-155) AND STANDARD OF CARE THERAPIES OVERCOMES APOPTOTIC RESISTANCE IN GLIOBLASTOMA

Abstract Conventional GBM therapies (e.g., temozolomide (TMZ), irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce apoptosis, inevitably leading to disease progression and poor patient survival. Targeting apoptotic blocks with BH3 mimetics can be an efficacious strategy to trigger apoptosis; however, these therapies can prevent high exposures in patients due to on-target, off-tumor toxicity in normal tissues. Mirzotamab Cletuzoclax (ABBV-155) is a first-in-class antibody-drug conjugate (ADC) that is specific for the highly expressed cell surface protein B7-H3 (CD276) and delivers a selective and potent BCL-XL inhibitor warhead. Here we identified that both TMZ and IR leave p53 WT GBM tumors exclusively dependent on the apoptotic block, BCL-XL, for survival. ABBV-155 negated the BCL-XL apoptotic block in both cell culture and orthotopic xenograft GBM models. Consequently, ABBV-155 combined with TMZ or IR initiates apoptosis and is synergistically lethal in GBM cells. Moreover, these combinations decrease tumor burden and extend survival in patient derived orthotopic xenografts. Taken together, these results demonstrate that the combination of DNA damaging therapy and ABBV-155 can have a synergistic anti-tumor impact in p53 WT GBM.