Abstract

<div>Abstract<p><b>Purpose:</b> Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.</p><p><b>Experimental Design:</b> Here, we evaluated the efficacy of MEDI0641, a novel antibody–drug conjugate targeted to 5T4 and carrying a DNA-damaging “payload” (pyrrolobenzodiazepine) in preclinical models of HNSCC.</p><p><b>Results:</b> Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4<sup>high</sup> tumors displayed lower overall survival than those with 5T4<sup>low</sup> tumors (<i>P</i> = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDH<sup>high</sup>CD44<sup>high</sup>) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B) <i>in vitro</i>. Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (<i>n</i> = 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice; <i>P</i> = 0.0047).</p><p><b>Conclusions:</b> Collectively, these findings demonstrate that an anti-5T4 antibody–drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC. <i>Clin Cancer Res; 23(10); 2516–27. ©2016 AACR</i>.</p></div>

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