A Novel Immunotherapy: LYC-55716, a Small-molecule RORγ Agonist, in Clinical Trials for Head and Neck Squamous Cell Carcinoma

This review highlights the evidence-based data to support current best management practices for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Current limitations and areas of emerging therapeutics are also emphasized. The cornerstone of palliation for patients with R/M HNSCC is a platinum-based backbone. Platinum doublets induce higher response rates than single agents but do not demonstrate a survival advantage and are associated with increased toxicity. The only regimen to demonstrate survival superiority is platinum, fluorouracil, and cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). EGFR inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have achieved only modest success in R/M HNSCC, illustrating the importance of identifying predictive biomarkers and finding ways to overcome mechanisms of resistance. Although phosphoinositide 3-kinase pathway alterations are present at a high rate in HNSCC, the identification of efficacious agents in patients with activating alterations has yet to be discovered. Immunotherapy represents an attractive treatment strategy for R/M HNSCC, with promising preliminary data from studies involving immune checkpoint blockade and toll-like receptor agonists. Human papillomavirus has a prognostic role in R/M disease; therefore, stratification of patients by human papillomavirus status in clinical trials is indicated. Although under-represented in clinical trials, elderly patients experience similar survival outcomes compared with younger patients, albeit with increased toxicity. Despite therapeutic advances, prognosis nonetheless remains poor for patients with R/M HNSCC. Enrollment of patients onto clinical trials to investigate novel therapeutics and identify predictive biomarkers is necessary to further refine and improve outcomes.

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Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040)

Journal for ImmunoTherapy of Cancer ◽

10.1186/s40425-019-0578-0 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Sara I. Pai ◽

Sandrine Faivre ◽

Lisa Licitra ◽

Jean-Pascal Machiels ◽

Jan B. Vermorken ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Clinical Trials ◽

Comparative Analysis ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Phase Iii ◽

Phase Iii Clinical Trials

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HNC0014, a Multi-Targeted Small-Molecule, Inhibits Head and Neck Squamous Cell Carcinoma by Suppressing c-Met/STAT3/CD44/PD-L1 Oncoimmune Signature and Eliciting Antitumor Immune Responses

Cancers ◽

10.3390/cancers12123759 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3759

Author(s):

Jih-Chin Lee ◽

Alexander T.H. Wu ◽

Jia-Hong Chen ◽

Wen-Yen Huang ◽

Bashir Lawal ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Growth ◽

Cell Carcinoma ◽

Head And Neck ◽

Small Molecule ◽

Squamous Cell ◽

Xenograft Model ◽

Neck Squamous Cell Carcinoma ◽

Treatment Modalities ◽

Mouse Xenograft Model

Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exosp- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development.

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