Enhanced therapeutic effect of anti-EGFR cetuximab antibody on glioblastoma by focused ultrasound in preclinical model (+ Running poster)

Abstract

Glioblastoma multiforme (GBM) is a very aggressive brain tumor, highly lethal. Overexpression of epidermal growth factor receptor (EGFR) and its mutant EGFR variant III are frequent in GBM [1] . They have shown to play a key role in the development and the growth of tumor cells. Several therapeutic strategies that target EGFR or its mutant have been developed, such as anti-EGFR monoclonal antibodies (mAb). One of them, the cetuximab (CTX) is interesting since it can block EGFR and EGFRvIII [2] . However, the blood-brain barrier (BBB) is one of the main limiting factor that restrains tumor penetration and decreases the efficacy of this immunotherapy. To overcome this issue, we have shown that the combination of injected microbubbles (MB) with low intensity focused ultrasound (FUS) transiently opened the BBB and enhanced CTX deliver in healthy brain, using immuno-PET imaging [3] , [4] . Here, we evaluated in mice the therapeutic benefits of repeated therapy (5 ×) combining the administration of CTX (40 mg/kg, iv.) with or without FUS-induced BBB opening. In vivo studies were performed on nude mice orthotopically grafted with human glioma cells (U251, 150,000 cells/injection) that overexpress EGFR. Survival rate has been investigated to evaluate the efficacy of the therapy on 4 different groups: sham with MB alone ( n = 5), FUS and MB ( n = 5), MB and CTX only ( n = 10), and MB + CTX + FUS ( n = 11). Furthermore, the delivery of radiolabeled CTX (89Zr, t1/2 = 3.3 days) into tumors has been quantified using PET imaging under two conditions: MB alone ( n = 6) or MB and FUS ( n = 5). As expected, CTX therapy alone without BBB opening in GBM model slightly improves median survival compared to the sham group (42 days vs. 29 days, not significant P = 0.1131). BBB opening helps to increase the significance of CTX therapeutic effect without improving drastically the immunotherapy efficacy. Maximal CTX therapeutic efficacy might be already achieved in the brain without FUS or anti-EGFR resistance might be developed overtime. Additional imaging and ex-vivo characterizations are ongoing to investigate this hypothesis.