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

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...

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Bibliographic Details
Published in:Clinical cancer research 2017-05, Vol.23 (10), p.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: Article
Language:English
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
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Summary: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. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-16-1834