Immunotherapy for Head and Neck Squamous Cell Carcinoma

Purpose of Review

Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the current challenges with immunotherapy and future goals for treatment using these agents.

Recent Findings

Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy.

Summary

ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy.

     

Molecular Targets in Squamous Cell Carcinoma of the Head and Neck

Opinion statement Worldwide more than a half million people develop Head and Neck cancer annually. Despite a significant decrease in smoking, about 40,000 new patients are diagnosed with carcinoma of the head and neck annually in the United States, and 11,000 of them succumb to their disease. More than 90% of these cancers are squamous cell carcinoma. The survival rates of patients with squamous cell carcinoma of the head and neck (SCCHN) have not improved significantly despite multimodality therapy including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In SCCHN the epidermal growth factor receptor (EGFR) antibody cetuximab has shown promising results in a phase III trial in combination with radiation. How best to integrate these agents with the traditional treatment modalities of surgery, radiotherapy, and cytotoxic chemotherapy is of vital importance but has yet to be determined. This article will discuss the biology of molecular targeted agents as well as current clinical trials and future directions of these agents in SCCHN.     

铁死亡在头颈部鳞状细胞癌中的研究进展

头颈部鳞状细胞癌(HNSCC)作为全球发病率极高的癌症之一,由于晚期HNSCC手术治疗后易发生术后复发及对部分化疗药物的耐药性,患者预后情况并不乐观.因此,提高化学药物治疗HNSCC的效率,改善HNSCC患者预后成为目前亟需解决的问题.最新研究发现铁死亡对部分类型的肿瘤细胞的生长增殖具有调节作用,一定程度上降低了肿瘤治...     

Tumor Evolution and Intratumor Heterogeneity of an Oropharyngeal Squamous Cell Carcinoma Revealed by Whole-Genome Sequencing

Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genomic instability that could lead to clonal diversity. Intratumor clonal heterogeneity has been proposed as a major attribute underlying tumor evolution, progression, and resistance to chemotherapy and radiation. Understanding genetic heterogeneity could lead to treatments specific to resistant and metastatic tumor cells. To characterize the degree of intratumor genetic heterogeneity within a single tumor, we performed whole-genome sequencing on three separate regions of an human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma and two separate regions from one corresponding cervical lymph node metastasis. This approach achieved coverage of approximately 97.9% of the genome across all samples. In total, 5701 somatic point mutations (SPMs) and 4347 small somatic insertions and deletions (indels)were detected in at least one sample. Ninety-two percent of SPMs and 77% of indels were validated in a second set of samples adjacent to the discovery set. All five tumor samples shared 41% of SPMs, 57% of the 1805 genes with SPMs, and 34 of 55 cancer genes. The distribution of SPMs allowed phylogenetic reconstruction of this tumor''s evolutionary pathway and showed that the metastatic samples arose as a late event. The degree of intratumor heterogeneity showed that a single biopsy may not represent the entire mutational landscape of HNSCC tumors. This approach may be used to further characterize intratumor heterogeneity in more patients, and their sample-to-sample variations could reveal the evolutionary process of cancer cells, facilitate our understanding of tumorigenesis, and enable the development of novel targeted therapies.     

头颈部鳞状细胞癌免疫治疗预测指标及分子标志物的研究进展

鳞状细胞癌是头颈部最常见的恶性肿瘤,严重威胁患者生命。继传统的手术治疗和放、化疗后,免疫治疗为患者带来了新的希望。临床上应用程序性死亡配体-1(programmed death-1 ligand 1,PD-L1)免疫检查点抑制剂单药或联合靶向、化疗方案可以改善患者生存率,因此被多项国内或国际指南推荐。肿瘤免疫微环境中三级淋巴结构（tertiary lymphoid structure,TLS）、高肿瘤突变负荷（tumor mutation burden,TMB）、OX40激活性抗体以及淋巴细胞活化基因-3(lymphocyte-activation gene 3,LAG-3)蛋白的表达,以及它们与肿瘤良好预后之间的相关性,意味着它们可能成为新的预测指标,同时对人乳头状瘤病毒（human papilloma virus,HPV）在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）中的探索也有望为临床医生提供新的治疗思路。     

头颈鳞癌的术前化疗效果

[目的]研究术前化疗能否提高手术切除率,降低局部复发率。［方法］104例头颈鳞癌病人分成试验组（58例）：术前化疗 手术 术后放疗组;对照组（46例）：手术 术后放疗,但不用术前化疗。手术方式为原发癌切除 颈淋巴结清扫术,用或不用肌皮瓣修复头颈部组织缺损。术后放疗剂量50Gy～60Gy。术前化疗用PFP方案即DDP＋5－Fu＋PYM。［结果］试验组部分缓解67.2%,微效17.2%。试验组和对照组3年局部复发率分别为27.6%、52．2％（P＜0.01）;但3年内远处转移率无差异,分别为34．5%、34．8%,中位生存期分别为23个月和22个月,3年生存率分别为65．5%和56．5%（P＞0.05）。［结论］术前新辅助化疗,可以缩小瘤体,提高手术切除率,减少局部复发。     

Vascular Targeting and Therapeutics for Squamous Cell Carcinoma of the Head and Neck

Close to 38 500 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. Traditional therapy for SCCHN has involved a multimodality approach of radiotherapy, surgery, and chemotherapy. More recently, novel therapeutic targets for solid tumors, including SCCHN, have been subject to preclinical and clinical applications. One of these newer approaches is antiangiogenic therapy. The mechanism of angiogenesis and the role it plays in tumor growth has been the subject of extensive investigation over the last 3 decades. As new antiangiogenic agents are being approved for the treatment of various solid tumors this critical review, using current preclinical and clinical evidence available thus far, examines the possible future role this new modality will have in the management of SCCHN. The different steps of angiogenesis and the corresponding targets are discussed, with a focus on vascular endothelial growth factor, as well as the preclinical and clinical evidence for the role of angiogenesis in SCCHN.     

Mechanisms of Tumor Growth and Metastasis in Head and Neck Squamous Cell Carcinoma

Opinion statement The formation and progression of head and neck squamous cell carcinoma (HNSCC) is multisystemic and involves the immune system, vascularization, and dissemination. Immune involvement includes the subversion of anti-tumor defenses. Vascularization involves both angiogenesis and vasculogenesis. Dissemination involves local tumor invasion as well as distant metastasis through processes including angiogenesis and lymphangiogenesis. Current studies in the dysregulation of various processes, including genetic stability, angiogenesis, lymphangiogenesis, immune regulation, and immune function, are opening opportunities for the development of targeted tumor therapies. The interrelationship of these processes in HNSCC development will be explored in this review.     

Epidemiology of Esophageal Lesions in Patients with Head and Neck Squamous Cell Carcinoma

Background: Esophageal squamous cell carcinoma (ESCC) is disturbing because of its aggressive clinical path and high mortality rate. The aim of this study was to investigate the characteristics of premalignant lesions and cancer of the esophagus in patients with a history of head and neck SCC. Methods: One hundred consecutive patients were investigated for diagnosis of superficial esophageal SCC. Lesions and their invasive depth for determination of the optimal method of treatment, and endoscopic examinations were carried out using Lugol chromoendoscopy. During endoscopy all abnormalities were investigated using approximately 10 ml of a 2% Lugol iodine solution sprayed over the entire esophageal mucosa using a spray catheter. Results: The mean±SD of age was 59.1±11.0 years. The tumor location in most patients (in both men and women)was the glottis. The statistical analysis showed significant differences between male and female in glottis and tongue. Twenty percent of patients reported the history of alcohol consumption and 22 percent were smokers, with 20.3% of men and 28.6% of women having digestive symptoms. The most common symptom in men was dysphagy and in women was odynophagy. Conclusion: In common, men are at high risk for ESCC and a high percent of current tobacco smokers, passive smokers and the history of alcohol intake were observed. In conclusion people in these high-risk groups would greatly benefit by acquisition of knowledge about and participating in a screening program.     

免疫治疗头颈部鳞状细胞癌的预后因素分析

[目的]评估免疫治疗头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)患者疗效及预后影响因素。[方法]回顾性收集接受PD-1单克隆抗体治疗的HNSCC患者的临床和生存资料。采用Kaplan-Meier法分析基线特征(患者临床病理特征、联合治疗方案)和预后之间的关系。基于患者的生存状况和生存时间,使用X-tile软件找到预后营养指数(PNI)的最佳截断值使之成为二分类变量。采用Cox回归模型进行单因素和多因素分析,单因素分析中显著的变量包含在多因素Cox回归模型中,确定独立预后因素。P<0.05为差异有统计学意义。[结果]研究人群中位无进展生存期(PFS)为9.0个月(95%CI:7.6～10.4)。患者的性别、吸烟、饮酒、肿瘤分化程度、HPV感染、原发部位、临床分期均不是生存危险因素。年龄在60岁及以下的患者有较好的PFS(10.7个月vs 6.6个月,P=0.024)。64例患者接受免疫治疗作为一线治疗,接受一线治疗的患者有较高的总缓解率(ORR,57.8%)。73例患者接受免疫联合化疗,18例患者接受免疫联合化疗加抗血管...