5T4-targeted therapy ablates cancer stem cells and prevents recurrence of head and neck squamous cell carcinoma.

Purpose: Loco-regional 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, i.e. cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency. Experimental Design: 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. Results: Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4high tumors displayed lower overall survival than those with 5T4low tumors (p=0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) 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) in vitro. Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in 3 patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by 5-fold in the PDX-SCC-M1, and 2-fold in the PDX-SCC-M11 model. Importantly, mice (n=12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for over 200 days, while the control group had 7 recurrences (in 12 mice) (p=0.0047). Conclusions: Collectively, these findings demonstrate that an anti-5T4 antibody-drug conjugate reduces the fraction of cancer stem cells and prevents local recurrence, and suggest a novel therapeutic approach for patients with HNSCC.