Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...National Institute of General Medical Sciences (NIGMS)
United States Department of Health and Human Services
Find out more...National Institute of Allergy and Infectious Diseases (NIAID)
United States Department of Health and Human Services
Find out more...National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Dental and Craniofacial Research (NIDCR)
Alvin J. Siteman Cancer Center (Siteman Cancer Center)
ASCO Young Investigator Award via Conquer Cancer Foundation
Washington University Division of Physician-Scientists
Paula C and Rodger O. Riney Blood Cancer Initiative
Lymphoma Research Foundation (LRF)
Barnes Jewish Hospital Foundation
Doris Duke Fund to Retain Clinician Scientists and Clinician Scientist Development Award
ARTICLE ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy–refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC.
We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells.
Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets.
These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.
