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 Table of Contents  
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 199-203

Immunotherapy and its advances in the management of head-and-neck cancer

Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India

Date of Submission19-Nov-2018
Date of Decision06-Jan-2019
Date of Acceptance23-Jul-2019
Date of Web Publication21-Nov-2019

Correspondence Address:
Sajad Ahmad Buch
Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya (Deemed to be University), Deralakatte, Mangalore - 575 018, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjhr.cjhr_155_18

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Head-and-neck squamous cell carcinoma (HNSCC) consists of biologically aggressive tumors of a heterogeneous group. Despite the advances made in the surgical and radiological treatment methods for HNSCC, the limitations in the control of the disease and the treatment-associated toxicity have kept the 5-year overall survival at a dismal rate. The multifactorial methods used for the treatment of HNSCC bring their deleterious effects on patient's quality of life due to lasting xerostomia, sensorineural hearing loss, and diminished swallowing function. The inadequate improvement in the survival rate and associated side effects with the existing treatments have shifted the attention in HNSCC research toward the finding of less toxic and more effective treatments. The outstanding improvements in the survival outcomes of certain advanced cancers treated with immunotherapy have encouraged extensive interest in the field. Cancer surveillance is maintained by a competent immune system, and hence, activation of immune system is included as an overall goal against the cancer. This review explores recent advances in the treatment of HNSCC focusing on immunotherapy describing briefly the developing areas of immunotherapy research, challenges, and future actions for the comprehensive application of immunotherapy in HNSCC.

Keywords: Head-and-neck squamous cell carcinoma, immunotherapy, monoclonal antibody, nivolumab, pembrolizumab

How to cite this article:
Buch SA, Chatra L. Immunotherapy and its advances in the management of head-and-neck cancer. CHRISMED J Health Res 2019;6:199-203

How to cite this URL:
Buch SA, Chatra L. Immunotherapy and its advances in the management of head-and-neck cancer. CHRISMED J Health Res [serial online] 2019 [cited 2021 Mar 6];6:199-203. Available from: https://www.cjhr.org/text.asp?2019/6/4/199/271326

  Introduction Top

Head-and-neck squamous cell carcinoma (HNSCC) is one of the most widely common cancers affecting the upper aerodigestive tract and is the second most common cancer in India with 77,000 cases diagnosed every year.[1] HNSCC causes more than 550,000 cases and 380,000 deaths each year throughout the world.[2] It originates from the mucosal lining of the upper aerodigestive tract and involves anatomical sites such as the nasopharynx, oropharynx, larynx, hypopharynx, and the oral cavity.[3] Although historically associated with tobacco and alcohol use, there has been emergence of human papillomavirus (HPV) implicated subset of HNSCC affecting the region of oropharynx.[4] HPV types 16, 18, and 33 are mainly the causative agents of this subset of HNSCC and are considered as a distinct clinical and biological type and carry a marginally better prognosis than HPV-negative HNSCC.[5] The tumor site, its stage and the status of HPV dictate the selection of treatment for HNSCC in addition to the treatment preferences and the medical status of the patient. HNSCC can be successfully managed with either surgery or radiotherapy when encountered at an early stage. When HNSCC patients are encountered, most of them are seen with locally advanced disease and thus warrant a multimodal treatment approach. Locally advanced HNSCC type usually leads to relapse causing poor survival rate; the relapse can occur as a result of either, the growth of one more carcinoma, remaining even after management of the primary cancer or due to the histopathologically undetected outgrowth of residual tumor cells.[6] A combination therapy is employed in cases with local regionally advanced HNSCC comprising surgery or chemoradiotherapy, radiation, and chemotherapy. Despite this curative approach, a significant subset of these patients will develop locoregional failure and/or distant metastases. The prognosis for the patients with recurrent and/or metastatic (R/M) HNSCC is meager with transitory response to palliative chemotherapy and few other available agents, regardless of consequential improvement in the treatment and subsequent prognosis of locally advanced HNSCC.[7] The 5-year progression-free survival (PFS) rate of advanced HNSCC has continued to remain still at 40%–50% and the average time to relapse as <2 years regardless of the combination of various treatment modalities.[8] The 3-year overall survival (OS) and disease-free survival (DFS) with HPV-positive HNSCC is significantly higher than HPV negative, HNSCC (3-year OS rates: 90% vs. 65%, P = 0.001 and 3-year DFS rates: 85% vs. 49%, P = 0.005).[9] To improve the quality of life and explore the means of achieving a favorable prognosis for HNSCC, the focus of the contemporary research has been to excerpt more effective and less harmful treatments.

  Discussion Top

Since the time of achieving unparalleled clinical benefits in advanced melanoma, immunotherapy has continued to be a pioneer and has with time changed the therapeutic concept of different type of cancers.[8] The American Society of Clinical Oncology identified immunotherapy based on its tremendous effect and promising potential as “Advance of the Year” for the 2nd year in succession.[10] The US Food and Drug Administration (FDA) after approving just one targeted therapy for HNSCC in nearly a decade changed the clinical spectrum of head-and-neck cancer by approving two immunotherapy drugs, namely pembrolizumab and nivolumab for the treatment of R/M cases in 2016. A variety of modifications involving immune system in HNSCC causes truncated antitumor immunity. Cancer immunotherapy works on the principle of restoring the functions of the pathways of immune signaling of the host, and thus, tumors are prevented from escaping restrictive actions.[11] The immune system of the host thus in a revived fashion functions to neutralize a variety of cellular and molecular tumor escape stratagems, which include the impairment of tumor antigen (TA) processing and presentation, establishment of an immunosuppressive microenvironment, secretion of tumor-promoting cytokines, mediation of tumor escape through regulatory Treg cells (T-cells) or myeloid-derived suppressor cells, and induction of T-cell anergy through an increase in co-inhibitory receptors, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) or a decrease in co-stimulatory receptor expression.[12],[13] Much of the progress among the treatments countering the tumor escape mechanisms has been done against components which target the co-inhibitory receptor pathway, i.e., PD-1 and CTLA-4 (immune checkpoints). Evidence through various sources indicates HNSCC to be a disease of immunosuppression. The changes that follow involve expression of immune checkpoint molecules, which intensify the percentage of immunosuppressive regulatory T-cells in the circulation and in the tumor microenvironment, amend cytokine production, lead to the dysregulation of myeloid dendritic cell (DC) function and T-cell function, and decrease the number of natural killer cells.[14] There is an association of co-inhibitory receptor PD-1 expression in tumor-infiltrating lymphocytes (cluster of differentiation 4-positive [CD4+] and CD8+ T-cells) and HPV-positive viral infection.[3] PD-1 ligand (PD-L1) is overexpressed often in HNSCC irrespective of the HPV status.[11] The outcome of these findings offers a strong credence to the use of immunotherapy in HNSCC, the mechanism of which involves immune dysregulation.

Immunotherapy entered a revolutionary phase in 2016 with the approval of two anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab for the treatment of R/M HNSCC.[3],[13] The US FDA approved nivolumab and pembrolizumab based on nivolumab's superior OS shown with its monotherapy against cetuximab and achievement of a healthy response rate with pembrolizumab.[8] These outcomes supported the concept that the host immune system has a vital role in regulating HNSCC and giving creditable validation for targeting immune system of the host during HNSCC treatment. The two agents interfere with the communication between PD-L1 and PD-1, whose unobstructed collaboration downregulates T-cells letting cancer cells to escape surveillance of immune system.[15],[16],[17] Nivolumab is a fully human, immunoglobulin (Ig) G4 anti-PD-1 mAb that is approved by FDA for the treatment of Hodgkin lymphoma, non-small cell lung carcinoma, melanoma, urothelial carcinoma, renal cell cancer, and recently for HNSCC.[7] Ferris et al. recently carried an open-label Phase III trial employing nivolumab in R/M HNSCC patients with a primary endpoint of OS and secondary endpoints having PFS, safety, rate of objective response, and patient-reported quality of life.[18] Nivolumab group showed a median OS of 7.5 months (95% confidence interval [CI] = 5.5–9.1) while as the median OS in the standard therapy group was 5.1 months (95% CI = 4.0–6.0) (hazard ratio: 0.70, P = 0.01). Nivolumab resulted in 19% points higher 1-year survival rate than the group treated with standard therapy, with the median PFS of 2 months in the nivolumab group against 2.3 months (95% CI = 1.9–3.1) with standard therapy group. The rate of PFS (6 months) and the response rate were both higher for nivolumab at 19.7% and 13.3%, respectively, against PFS of 9.9% and response rate of 5.8% in standard therapy group. These results lead to the approval of nivolumab by FDA for the treatment of R/M HNSCC on November 10, 2016.[7] Pembrolizumab, a monoclonal antibody, was approved for the treatment of melanoma and R/M HNSCC in August 2016 and acts on PD-1 and is also effective in some advanced solid tumors.[19] The patients with R/M HNSCC expressing PD-L1 were given pembrolizumab, 10 mg/kg intravenously/2 weeks in an open-label, multicenter Phase Ib trial.[20] A total of 60 patients who expressed PD-L1 positivity were treated with 23 of them being HPV positive and 37 HPV negative. Forty-five percent of patients (27/60) developed serious adverse events (AE), but no drug-related death was reported. Furthermore, 8/45 (18%) patients demonstrated an objective response (OR) by central imaging review (95% CI = 8–32); the objective response rate (ORR) was 4/16 (25%) in HPV-positive patients and 4/29 (14%) in HPV-negative patients.

Although single-agent immunotherapy has led to a significant response rate in several R/M HNSCC settings, several others have shown either an inadequate or total absence of response.[18],[21],[22] The expression of checkpoint receptors can be altered by the cytotoxic and targeted agents, but the effect of these agents is not well understood on the immune system and HNSCC tumor cells. For instance, CTLA-4+ Foxp3+ Treg suppressor cells are increased in both the circulation and microenvironment by the action of cetuximab signifying that the adding ipilimumab may remove this suppressive effect and boost antitumor immunity.[23] The combinations of anti-PD-1/PD-L1 and anti-CTLA-4 treatments have been introduced in HNSCC keeping in mind the good results achieved in advanced melanoma cases.[24] Tremelimumab is an anti-CTLA-4 monoclonal antibody, and durvalumab is a high-affinity engineered human IgG1 monoclonal antibody that obstructs binding of PD-L1 to PD-1 and CD80. The KESTREL study, a Phase III trial (NCT02551159), is presently assessing the effectiveness of durvalumab alone or tremelimumab plus durvalumab against the standard-of-care EXTREME regimen (cetuximab, 5-fluorouracil, and cisplatin) for the first-line treatment of R/M HNSCC. The efficacy of durvalumab alone and its combination with tremelimumab is being evaluated at present against the standard-of-care regimen in platinum refractory HNSCC in EAGLE, a Phase III trial (NCT02369874). Another Phase III trial CheckMate-651 (NCT02741570) evaluating the efficiency of nivolumab alone or in combination with ipilimumab (anti-CTLA-4 monoclonal antibody) is being carried out, against the EXTREME regimen in the first-line R/M HNSCC. CONDOR trial (NCT02319044) is currently evaluating durvalumab alone, tremelimumab alone, and durvalumab plus tremelimumab in PD-L1 negative, platinum-refractory HNSCC patients. Few of the trials with combination of anti-PD-1 + anti-CTLA-4 being conducted are shown in [Table 1].[25]
Table 1: Few anti-programmed cell death 1 + anti-cytotoxic T-lymphocyte-associated protein-4 combination immunotherapy trials

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The recent advances in the treatment for HNSCC have been employing oncolytic viruses either as single agents or in association with standard or immunotherapy. Talimogene laherparepvec (T-VEC) an attenuated herpes simplex virus 1 is the only oncolytic virus till date, approved for the treatment of cancer, specifically for advanced melanoma.[26] Oncolytic viruses modify various important steps in the cancer-immunity cycle and thus enjoy several advantages against cancer.[27] A combination of T-VEC and pembrolizumab was checked for safety and efficacy in 36 patients of R/M HNSCC with results showing a practicable safety outline and preliminary ORR showing clinical activity.[28] Follow-up of this study for PFS/OS in R/M HNSCC is currently underway (NCT02626000). In addition to the T-VEC virus, the other oncolytic viruses under investigation for HNSCC, namely recombinant vaccine virus JX-594 and the recombinant avian fowlpox virus TRICOM (NCT00625456 and NCT00021424), are currently being evaluated in early-phase clinical trials.[3],[24]

Vaccines in cancer immunotherapy have generated a lot of interest in the recent times with several studies being carried on their efficacy in HNSCC. Cancer vaccines stimulate the adaptive immune system through the presentation of TAs by antigen-presenting cells, and the vaccines that target tumor specific antigen are ideal as autoimmune response to normal cells can be evaded.[29] The various cancer vaccine stratagems tried earlier, including peptide or protein vaccines, recombinant vector-based vaccines containing TA-encoding DNA in viral or bacterial vector DNA-based vaccines, and delivery of protein- or peptide-activated DCs or delivery of whole killed tumor cells. Numerous cancer vaccine trials have been explored in HNSCC patients. DCs were used with wild-type p53 peptide in a Phase Ib trial and were well tolerated in HNSCC cases increasing p53-specific T-cell frequencies in around 69% (11/16) of the patients, and 2-year DFS was 88%.[30] A Phase II trial evaluated a peptide vaccine against IMP3, CDCA1, and LY6K for locally advanced HNSCC displayed a median OS of 4.9 months in the vaccinated arm against 3.5 months for the unvaccinated group.[31] A modified vaccinia virus Ankara vaccine expressing p53, in a blend with pembrolizumab (NCT02432963), is currently being tested in R/M setting. INO-3112 is a DNA vaccine which combines two previously developed DNA vaccines (plasmids encoding HPV16 and HPV18 E6/E7) which results in an HPV-specific CD8+T-cell response.[32] The Hespecta vaccine family (the acronym is derived from HPV E Six Peptide Conjugated to Amplivant) includes ISA101 and ISA201, which are peptide vaccines derived from HPV16 E6 and E7 proteins. ISA01 is currently being evaluated as monotherapy and in combination with nivolumab for HPV16+ tumors in a Phase II trial (NCT02426892). Two E6 peptides of HPV16 are conjugated to a toll-like receptor 2 agonist in a second-generation vaccine, namely ISA201. HPV-positive tumors that were treated definitely are being evaluated currently in a Phase I trial (NCT02821494) of ISA201. Although these studies are reassuring, uncertainty remains on the inclusion of cancer vaccines for the management of HNSCC due to lack of any further clinical trial data.

  Conclusion Top

Oncologic diseases have always warranted clinical trials for the development of new drugs and explore novel therapeutic approaches. Only two agents, cetuximab and docetaxel, were approved and in use for R/M HNSCC in the past 10 years. Since investigators have established a concrete role of immune system in tumor mechanics, immunotherapy has advanced with two agents approved recently in 2016 by the FDA for R/M HNSCC. This has been a vital step forward for the clinical control of the process of tumorigenesis in R/M HNSCC. Further research of immune dysfunction, plus additional understanding about growing incidence of HPV + HNSCC, might explore pathways for newer therapeutic agents for HNSCC. The substandard performance of immunotherapies in certain R/M setting has been mainly due to dearth of vision into the features controlling clinical responses. To uncover such deficiencies, further studies are required to investigate the complexities of tumor response to immunotherapy agents. Due to the insights gained through new data evolving from studies, and more awareness into combinations of immunotherapeutic agents, it is plausible to think about future advances in the therapeutic results of patients with HNSCC, and immunotherapy will become a standard for the treatment of head-and-neck cancer.

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