5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

• Published in: Clinical cancer research Vol. 23; no. 10; pp. 2516 - 2527
• Main Authors: Kerk, Samuel A, Finkel, Kelsey A, Pearson, Alexander T, Warner, Kristy A, Zhang, Zhaocheng, Nör, Felipe, Wagner, Vivian P, Vargas, Pablo A, Wicha, Max S, Hurt, Elaine M, Hollingsworth, Robert E, Tice, David A, Nör, Jacques E
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.05.2017
• Subjects: Animal models; Animals; Benzodiazepines - administration & dosage; Cancer; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Self Renewal - genetics; Cell Self Renewal - immunology; Cell self-renewal; Chemotherapy; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA microarrays; Drug development; Drug Resistance, Neoplasm - immunology; Experimental design; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - immunology; Intravenous administration; Membrane Glycoproteins - immunology; Mice; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - pathology; Patients; Pyrroles - administration & dosage; Regression analysis; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Stem cell transplantation; Stem cells; Surgery; Tissue Array Analysis; Treatment Outcome; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1834

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. 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. Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4 tumors displayed lower overall survival than those with 5T4 tumors ( = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDH CD44 ) 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) 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 ( = 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; = 0.0047). 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. .