Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer.

Autor:	Jacobs MT; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri., Wong P; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Zhou AY; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri., Becker-Hapak M; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Marin ND; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Marsala L; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Foster M; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Foltz JA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Cubitt CC; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Tran J; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Russler-Germain DA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri., Neal C; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Kersting-Schadek S; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Chang L; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Schappe T; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Pence P; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., McClain E; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Zevallos JP; Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Rich JT; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri., Paniello RC; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri., Jackson RS; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri., Pipkorn P; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri., Adkins DR; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri., DeSelm CJ; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri., Berrien-Elliott MM; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri., Puram SV; Alvin J. Siteman Cancer Center, St. Louis, Missouri.; Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri.; Department of Genetics, Washington University School of Medicine, St. Louis, Missouri., Fehniger TA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Alvin J. Siteman Cancer Center, St. Louis, Missouri.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Oct 13; Vol. 29 (20), pp. 4196-4208.
DOI:	10.1158/1078-0432.CCR-23-0156
Abstrakt:	Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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