NK Cell-Dependent Antibody-Mediated Immunotherapy Is Improved In Vitro and In Vivo When Combined with Agonists for Toll-like Receptor 2 in Head and Neck Cancer Models

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression.

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Correction: In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-20-0602 ◽

2020 ◽

Vol 19 (9) ◽

pp. 1955-1955

Author(s):

Abu Syed Md Anisuzzaman ◽

Abedul Haque ◽

Dongsheng Wang ◽

Mohammad Aminur Rahman ◽

Chao Zhang ◽

...

Keyword(s):

Head And Neck Cancer ◽

Antitumor Activity ◽

Head And Neck ◽

Neck Cancer ◽

Synergistic Antitumor Activity

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PO-0942 EXPRESSION OF THE EGFR/HER2/PAKT PATHWAY IN VITRO AND IN VIVO IS AFFECTED BY HYPOXIA IN HUMAN HEAD AND NECK CANCER

Radiotherapy and Oncology ◽

10.1016/s0167-8140(12)71275-6 ◽

2012 ◽

Vol 103 ◽

pp. S371

Author(s):

J. Bussink ◽

J.H.A.M. Kaanders ◽

D.L. Wheeler ◽

A.J. van der Kogel ◽

M. Iida ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Human Head

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Tyrosine kinase profiling guides combined therapeutic strategies in head and neck cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6078 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6078-6078

Author(s):

R. Rodríguez-Barrueco ◽

M. Ortíz-Ruiz ◽

J. J. Cruz ◽

A. Ocana ◽

A. Pandiella

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Cell Lines ◽

Neck Cancer ◽

Tyrosine Kinases ◽

Egf Receptor ◽

Drug Combinations ◽

Metastatic Setting

6078 Background: Squamous cell carcinoma of the head and neck (SCCHN) is still an incurable disease in the metastatic setting. A particular subgroup of proteins implicated in the head and neck cancer are the tyrosine kinases (TK). Therapeutic inhibition of several of them including the EGF receptor with cetuximab in combination with radiotherapy or chemotherapy has shown to be clinically useful. Beyond EGFR, oncogenic activation of other TKs may be implicated in the genesis/progression of SCCHN. In this context, the identification of the TKs activated in SCCHN is a must in order to adequately target these kinases with already available inhibitors. Methods: Here we have investigated activated tyrosine kinases in head and neck cancer tumors derived from patients using a human phospho protein array for 42 receptor tyrosine kinases (RTK). Western-blot experiments were performed to validate each phospho RTK in tumors from patients. The same approach was followed in a series of head and neck cancer cell lines. In vivo xenografted models were used to study the antiproliferative effect of the combination of specific TK inhibitors against them. Results: TK receptors of the EGF and the VEGF family were the mostly activated in tumors derived from patients. 90% of patients revealed high pEGFR content. In addition, other EGFR/HER family receptors, such as HER3, were also activated (phosphorylated) in samples from patients. These data were corroborated in the SCCHN cell lines. In these cells, other RTK signalling intermediates were also active. Particularly, the Akt and FAK kinases. Combination of the anti-EGFR-HER2 TK inhibitor lapatinib with dasatinib (that targets FAK) was synergistic in vitro. Combination of lapatinib with the anti-VEGFR TK inhibitor pazopanib was inefficient in vitro, but resulted in a better trend in response in the in vivo xenografted models, as compared to the action of the single agents. Conclusions: Rational target drug combinations should be based on the identification of activated TK receptors or downstream signalling molecules. In head and neck cancer combination strategies using anti-EGFR/HER, anti-FAK, and anti-VEGFR compounds increases the action of individual treatments. These results open the door for future clinical development of these drug combinations. No significant financial relationships to disclose.

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Targeted Photodynamic Therapy and Photochemical Internalization of Human Head and Neck Cancer: a preclinical study in vitro and in vivo

10.33612/diss.167799500 ◽

2021 ◽

Author(s):

◽

Wei Peng

Keyword(s):

Head And Neck Cancer ◽

Photodynamic Therapy ◽

Head And Neck ◽

Neck Cancer ◽

Human Head ◽

Preclinical Study ◽

Photochemical Internalization ◽

Targeted Photodynamic Therapy

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Abstract 3046: Combining Chk1/2 inhibition with cetuximab and irradiation enhances in vitro and in vivo cytotoxicity of head and neck cancer models

10.1158/1538-7445.am2016-3046 ◽

2016 ◽

Author(s):

Ling Zeng ◽

Reena Beggs ◽

Tiffiny Cooper ◽

Eddy Shih-Hsin Yang.

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Cancer Models ◽

In Vivo Cytotoxicity

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The Cancer Stem Cell Concept in Progression of Head and Neck Cancer

Journal of Oncology ◽

10.1155/2009/894064 ◽

2009 ◽

Vol 2009 ◽

pp. 1-8 ◽

Cited By ~ 22

Author(s):

Zhuo (Georgia) Chen

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Solid Tumors ◽

Neck Cancer ◽

Human Head ◽

Short Review ◽

Cancer Type ◽

Progression Model

Human head and neck cancer (HNC) is a highly heterogeneous disease. Understanding the biology of HNC progression is necessary for the development of novel approaches to its prevention, early detection, and treatment. A current evolutional progression model has limitations in explaining the heterogeneity observed in a single tumor nest. Accumulating evidence supports the existence of cancer stem cells (CSCs) as small subpopulations in solid tumors, including HNC. These CSCs can be selected by appropriate cell surface markers, which are cancer type specific and have been confirmed by uniquein vitroandin vivoassays. Selected CSC populations maintain a self-renewal capability and show aggressive behaviors, such as chemoresistance and metastasis. In addition to introducing the CSC concept in solid tumors, this short review summarizes current publications in HNC CSC and the prospective development and application of the CSC concept to HNC in the clinic.

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