Immunotherapy for Head and NEC 3031292251, 9783031292255

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Cancer Immunotherapy  1

Anthony T. C. Chan Brigette B.Y. Ma  Editors

Immunotherapy for Head and Neck Cancer

Cancer Immunotherapy Volume 1 Series Editor Matthias Theobald III Department of Internal Medicine Johannes Gutenberg University of Mainz Mainz, Germany

Each volume of the series Cancer Immunotherapy will focus on one specific cancer covering scientific aspects as well as clinical applications including clinical trials and new drugs once immunotherapy for these cancers has reached the clinic.

Anthony T. C. Chan  •  Brigette B. Y. Ma Editors

Immunotherapy for Head and Neck Cancer

Editors Anthony T. C. Chan Sir YK Pao Centre for Cancer Hong Kong Cancer Institute The Chinese University of Hong Kong Hong Kong, China

Brigette B. Y. Ma Sir YK Pao Centre for Cancer Hong Kong Cancer Institute The Chinese University of Hong Kong Hong Kong, China

ISSN 2662-8384     ISSN 2662-8392 (electronic) Cancer Immunotherapy ISBN 978-3-031-29225-5    ISBN 978-3-031-29223-1 (eBook) https://doi.org/10.1007/978-3-031-29223-1 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Contents

 Immunological Landscape of Head and Neck Cancer: Mechanisms of Immune Escape and the Tumor Microenvironment����������������������������������������������������������������������������������������������   1 Nicole C. Schmitt, Brendan L. C. Kinney, and Robert L. Ferris  Drug Targets and Strategies in the Clinical Development of Immunotherapy for Head and Neck Cancer����������������������������������������������  17 Athénaïs van der Elst and Jean-Pascal Machiels  Immunotherapy in Locally Advanced Nasopharyngeal Carcinoma����������������������������������������������������������������������������������������������������������  41 Jun Ma and Yu-Pei Chen  Immunotherapy in Recurrent and Metastatic Nasopharyngeal Carcinoma����������������������������������������������������������������������������������������������������������  53 Brigette B. Y. Ma and Anthony T. C. Chan  Beyond PD-1/PD-L1 Immune Checkpoint Inhibitors: Other Targets and Approaches for Head and Neck Cancer��������������������������  63 Niki Gavrielatou, Panagiota Economopoulou, and Amanda Psyrri  Translational and Clinical Approach to Combining Immunotherapy with Radiotherapy in the Treatment of Head and Neck Cancer ������������������  83 Quaovi H. Sodji, Dhanya K. Nambiar, and Quynh-Thu Le  Clinical Application of Immunotherapy in the Perioperative Management of Head and Neck Cancer���������������������������������������������������������� 101 Frederick M. Howard, Nishant Agrawal, and Ari J. Rosenberg  The Role of Immune Checkpoint Inhibitors in the Treatment of Less Common Head and Neck Cancers������������������������������������������������������ 121 Stefano Cavalieri, Paolo Bossi, and Lisa Licitra  Development of Predictive Biomarkers to Immunotherapy in Head and Neck Cancer�������������������������������������������������������������������������������������� 135 Kedar Kirtane and Christine H. Chung

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Introduction

Head and neck cancer (HNC) is a heterogeneous group of cancers in terms of epidemiology, biology and treatment. Collectively, a total of 467,125 people died of cancers of the oral cavity, larynx, nasopharynx, oropharynx, hypopharynx and salivary glands, accounting for 4.7% of the 9.9 million cancer-related deaths recorded in 2021 [1]. Squamous cell cancer of the head and neck (HNSCC) is the most prevalent HNC subtype worldwide, where surgery, radiotherapy and chemotherapy have been the traditional therapeutic cornerstones. For many years, the treatment of patients with recurrent/metastatic (R/M) HNSCC that were without curative options had been limited to chemotherapy. Immunotherapy had never been regarded a ‘mainstream’ treatment for HNSCC until a historic breakthrough in 2006, when cetuximab—a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR)—was approved for the treatment of platinum-treated R/M HNSCC as a monotherapy, and in combination with radiotherapy in the treatment of locally advanced HNSCC [2, 3]. Cetuximab was the first immunotherapy that extends survival when combined with platinum-based chemotherapy (as the so called ‘EXTREME’ regimen) in the first-line treatment of R/N HNSCC [4]. However, this revival in immunotherapy started in 2006 was short-lived, as it would take another 10 years before the ‘Golden Period’ of immunotherapy for HNC began when the first antibody against the immune checkpoint protein programmed cell death receptor 1 (PD1), nivolumab, was approved in 2016 for the treatment of platinum-­ refractory R/M HNSCC in the CHECKMATE-141 study [5]. Since then, the survival of patients with R/M HNSCC has continued to improve from a historic median of less than 6 months with platinum chemotherapy alone, to over 10 months with the EXTREME regimen [4], and to nearly 15 months with the addition of pembrolizumab to platinum chemotherapy among biomarker-enriched population in the KEYNOTE-048 study [6]. This impact of immunotherapy on patients’ survival can also be observed in R/M non-keratinizing nasopharyngeal cancer, an Epstein-Barr virus-associated HNC that is endemic in Southern China and Southeast Asia. The therapeutic paradigm of HNC has been changed by this renaissance in immunotherapy, and hundreds of new clinical trials using immune checkpoint antibodies as therapeutic backbone are now ongoing in HNCs in various clinical settings. This book is a compendium of scientific highlights in immunotherapy for HNSCC, nasopharyngeal cancer (NPC) and other rarer HNCs such as salivary gland cancers. The multi-disciplinary team of authors are opinion leaders in their field

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who detailed the recent developments of immunotherapy in HNC in the nine chapters of this book. By retracing the journey from the bench to bedside, the book began with an overview in the mechanisms of immune escape in HNC, followed by concise summaries in the clinical development of immunotherapy and biomarkers in the palliative, curative and neoadjuvant setting. The scientific achievements outlined in this book are a testament to the people who have not given up hope on finding better treatments for HNC—patients who have participated in clinical trials of immunotherapy, and the researchers who have dared to challenge conventions and pushed the boundaries of knowledge. We would like to extend our heartfelt appreciation to all the contributors to this book who have worked tirelessly despite the challenges brought by the COVID pandemic globally. We wish to thank Ms Alice Kong for providing clerical support for this work. We would like to acknowledge the Charlie Lee Charitable Foundation which has supported this work in part through the Precision Immunotherapy Program, The Chinese University of Hong Kong. References 1. Sung H, Ferlay J, Siegel RL et  al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. doi: https://doi.org/10.3322/ caac.21660 2. Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578. doi: https://doi.org/10.1056/NEJMoa053422 3. Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11(1):21–28. doi: https://doi.org/10.1016/S1470-­2045(09)70311-­0 4. Vermorken JB, Mesia R, Rivera F et  al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127. doi: https://doi.org/10.1056/NEJMoa0802656 5. Ferris RL, Blumenschein G Jr, Fayette J et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867. doi: https://doi.org/10.1056/NEJMoa1602252 6. Burtness B, Harrington KJ, Greil R et al (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394(10212):1915–1928. doi: https://doi. org/10.1016/S0140-­6736(19)32591-­7 State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Charlie Lee Precision Immunotherapy Program The Chinese University of Hong Kong, Shatin, Hong Kong SAR 

Brigette B. Y. Ma Anthony T. C. Chan

Immunological Landscape of Head and Neck Cancer: Mechanisms of Immune Escape and the Tumor Microenvironment Nicole C. Schmitt, Brendan L. C. Kinney, and Robert L. Ferris

Contents 1  Introduction 2  Immunoediting and Tumor Mutational Burden 3  Antigen Processing Machinery 4  Immune Effector Cells 5  Immune Checkpoints 6  Immunosuppressive Cells and Cytokines 7  Mechanisms of Immune Escape Specific to HPV-Driven Disease 8  Conclusions References

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Abstract

In order for transformed cells to form tumors, they must escape from the ongoing pressure of the immune system. Distinct changes within tumor cells and within the composition of the tumor microenvironment comprise several mechanisms of immune escape. Despite a relatively high tumor mutational burden, head and neck cancers frequently possess defects in antigen processing machinery, which is required for presentation of neoantigens to immune cells. Immune effector cells may be few in number, functionally exhausted, or inhibited by the presence of immunosuppressive cells, cytokines, or chemokines within the tumor microN. C. Schmitt (*) · B. L. C. Kinney Winship Cancer Institute at Emory University School of Medicine, Atlanta, GA, USA e-mail: [email protected] R. L. Ferris University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA e-mail: [email protected]

Cancer Immunotherapy (2022) https://doi.org/10.1007/13905_2022_26, © The Author(s), under exclusive license to Springer Nature Switzerland AG Published Online: 15 October 2022

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environment. Although dysfunctional antitumor immunity is particularly prominent in human papillomavirus (HPV)-negative head and neck cancers, HPV-driven tumors have also developed distinct mechanisms of immune escape. Keywords

Antigen processing machinery · Head and neck cancer · Human papillomavirus · Immune escape · Myeloid-derived suppressor cells · Regulatory T cells

1 Introduction The antitumor immune response requires several key elements. Importantly, a tumor must be recognized as foreign or transformed by immune cells. In the innate immune response, natural killer (NK) cells recognize and kill tumor cells that express aberrant or stress signals, including low expression of major histocompatibility (MHC) molecules on the cell surface (Fig. 1). Recognition of tumor cells by T lymphocytes requires expression of tumor antigens. Such antigens can include mutated peptides (e.g., mutated p53) or viral oncoproteins such as those associated with the human papillomavirus (HPV). Tumor-associated antigens are proteins that are disproportionately expressed on tumor cells versus normal cells, such as epidermal growth factor receptor (EGFR). In order for these tumor antigens to be detected by immune cells, they must be presented on MHC molecules on the cell surface, which occurs after a series of antigen processing events (Fig. 2). The immune cells, particularly CD8+ cytotoxic T lymphocytes (CTLs), must be present and activated in order to react to these antigens. When any of these elements are missing, the result is a suboptimal or absent antitumor immune response. Further, the presence of immunosuppressive cells and cytokines can further inhibit the ability of CTLs to traffic into the tumor and kill transformed epithelial cells. Head and neck cancers have employed several of these methods of immune escape, which are discussed in detail in this chapter.

2 Immunoediting and Tumor Mutational Burden As described above, the adaptive antitumor immune response requires recognition of tumor neoantigens. Although some tumor mutations may be far more immunogenic than others, tumors with a high mutational burden (TMB) also tend to have higher infiltration by immune effector cells and respond more favorably to immunotherapy [1]. In fact, the process of immunosurveillance largely prevents transformed, mutated cells from forming tumors at all [2]. Over time, however, tumors may escape by inducing T cell tolerance to viral oncoproteins or mutated peptides that would otherwise serve as neoantigens [3]. Gradually, immune pressure results in escape populations of tumor cells, which may lack neoantigens or other factors critical for recognition by T cells and NK cells [2]. This process, known as

Fig. 1  Innate and adaptive antitumor immune responses. Natural killer cells detect cells that lack major histocompatibility (MHC) expression on the cell surface, resulting in the release of cytotoxic granules. The adaptive immune response depends on recognition of a tumor antigen presented on an MHC class I molecule, which is then recognized by an antigen-specific T cell receptor (TCR). Created with Biorender.com

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Fig. 2  Antigen processing and presentation requires a series of steps. First, cytosolic proteins are processed through the proteasome into peptides, which are then transported into the endoplasmic reticulum (ER) via transporter of antigen protein (TAP). A series of chaperones then assist with folding/assembly of the MHC class I molecule and loading of the antigenic peptide. The MHC-­ antigen complex is then transported to the cell surface for presentation to an antigen-specific T cell receptor (TCR). Created with Biorender.com

immunoediting, consists of three steps (Fig. 3) [2]. During the elimination stage, transformed cells are destroyed or suppressed by innate and adaptive immune cells. Transformed cells that survive the elimination stage enter the equilibrium stage, where they resist immune pressure and enter a dormant state. In the escape phase, cumulative suppression of the immune response results in expansion of the transformed cells, leading to tumor formation. Mechanisms contributing to this third

Fig. 3  The process of cancer immunoediting requires three main steps: elimination, equilibrium, and escape. In the elimination phase, transformed cells are suppressed or eliminated by immune effector cells. After adapting ways to resist immune pressure, transformed cells enter a state of equilibrium. Finally, further adaptations within the transformed cells or microenvironment allow these cells to escape immune pressures, leading them to divide rapidly and establish a tumor. NK natural killer; IL-12 interleukin 12; IFNγ interferon gamma; Treg regulatory T cell; MDSC myeloid-derived suppressor cell. Created with Biorender.com

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phase, in addition to loss of neoantigen expression, include dysfunction or absence of immune effector cells; dysfunction of antigen processing machinery; imbalance of co-inhibitory versus co-stimulatory checkpoints; and abundance of immunosuppressive cells and cytokines. These mechanisms as they pertain to head and neck cancer are discussed in more depth in the remainder of this chapter.

3 Antigen Processing Machinery The antigen processing machinery (APM) refers to the enzymes and chaperones tasked with the creation of antigenic epitopes and their translocation into the endoplasmic reticulum (ER), proper folding of MHC class I (also known as human leukocyte antigen or HLA in humans) and its association with beta-2-microglobulin (β2M), followed by loading of antigen onto MHC class I molecules, which are then shuttled to the cell surface for presentation to immune cells (Fig. 2). This process begins with the stimulation of conversion of the proteasome to the immunoproteasome by replacement of beta subunits β1, β2, and β5 with low molecular weight protein-2, 7, and 10 (LMP2, LMP7, and LMP10) [4–7]. With LMP2, 7, and 10 the immunoproteasome generates antigens of the correct size and with high affinity for the MHC class I binding cleft [4]. Following digestion, these epitopes are transported into the lumen of the ER by a heterodimer of transporter associated with antigen processing 1 and 2 (TAP1 and TAP2) [4–7]. Within the lumen of the ER, the antigenic peptide undergoes further processing to reach the ideal residue length of 8–11 amino acids by ER aminopeptidase 1 and 2 (ERAP1 and ERAP2); then, with the help of chaperones calreticulin, calnexin, ERp57, and tapasin, the antigen (Ag) is loaded and stabilized within the cleft of an MHC class I heavy chain- β2M light chain polymer [4–7]. The stable Ag-MHC class I-β2M trimer is finally transported to the cell surface via the Golgi apparatus for presentation to immune cells [4–7]. The correct function of this pathway is critical for recognition and clearance of malignant cells by CTLs [7–9]. The major induction pathway for the expression of most APM components is mediated by janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) with interferon gamma (IFN-γ) as the major signaling molecule [4–12]. IFN-γ stimulates the expression of LMP2, LMP7 (and subsequent conversion of the proteasome to the immunoproteasome), TAP1, TAP2, tapasin, HLA class I, and β2M [4–12] by two pathways: via the JAK/STAT phosphorylation cascade, which yields phosphorylated STAT1 (pSTAT1) homodimers capable of binding to gamma-activated sequences (GAS) in the promoter regions of the listed APM components [7], and via the expression and activation of nuclear protein NOD-like receptor family, caspase recruitment domain containing 5 (NLRC5), also known as class I transactivator (CITA) [11]. Independent of IFN-γ, TAP1 expression can also be induced by p53 and p73, either individually or in a synergistic fashion, in response to DNA damage [11]. Aside from this redundancy in the expression of TAP1, its importance in the proper presentation of antigen has been illustrated by in vitro experiments where cDNA for TAP1 was transfected into tumor cell lines;

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the resulting increased expression of TAP1 alone was able to induce CTL recognition and clearance of cells that had previously escaped immune clearance [9]. Inhibition and/or dysfunction of the APM is an essential mechanism for immune escape by malignant cells. Aside from β2M, of which there is minimal evidence of genetic alterations in head and neck squamous cell carcinoma (HNSCC) [5], genetic alterations in MHC/HLA class I and other APM genes are common. Complete and selective loss of HLA class I genes occur in about 15% and 37% of primary HNSCC lesions, respectively, and do account for functional abnormalities [4, 5]. Although loss of MHC class I may make tumor cells more susceptible to killing by NK cells, such alterations severely inhibit the ability of transformed cells to activate adaptive, antigen-specific immunity. The major contributor to the dysfunction of this pathway comes from deregulation of upstream transcription factors [10], especially STAT1. Baseline levels of pSTAT1 are markedly reduced in HNSCC due to an overexpression of epidermal growth factor receptor (EGFR), leading to aberrant expression of Src homology domain-containing phosphatase 2 (SHP2) [8]. SHP2 has been shown to actively dephosphorylate pSTAT1, leading to reduced expression of the IFN-γ-inducible components of the APM [8]. Interestingly, the overexpression of SHP2 also yields an immunosuppressive tumor microenvironment mediated by downregulation of RANTES and IP10 [8]. Literature regarding dysregulation of NLRC5 is scarce due to its recent discovery, though it has been shown to undergo copy number loss in approximately 20% of HNSCC lesions [11]. Alterations to p53 must also be considered regarding TAP1, because without functional p53, cells lose a layer of redundancy in the ability to upregulate this APM component in response to DNA damage [12]. Several members of the APM may be associated with survival outcomes. Aside from downregulation of HLA class I, downregulation of tapasin is also associated with reduced survival for patients with maxillary sinus squamous cell carcinoma tumors; additionally, LMP2, LMP7, TAP1, TAP2, and HLA class I have been negatively correlated with survival across anatomic subsites of the head and neck [5, 10]. One study found that downregulation of one or more of these components was present in 80% of the head and neck tumors analyzed [10]. This is a compounding issue, since downregulation of any one of these components may lead to insufficient surface presentation of functional Ag-HLA class I-β2M trimers [10]. A lack of sufficient presentation on HLA class I hinders the ability of CTLs to clear malignant cells [4–9], rendering many otherwise promising therapies such as immune checkpoint blockade ineffective for malignancies with diminished APM capacity.

4 Immune Effector Cells In the event that head and neck cancer cells fail to express and present antigen and also fail to produce damage-associated molecular patterns that induce inflammation and innate immunity, few immune effector cells will be recruited into the tumor microenvironment. Such “immunologically cold” tumors are associated with poor

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prognosis and poor responses to immunotherapy, whereas “hot” tumors with abundant immune effector cells tend to respond more favorably (Fig. 4). Using integrative genomic analyses, HPV-negative head and neck cancers have been classified into classical, basal, and inflamed/mesenchymal subtypes, with the latter subtype showing higher expression of genes associated with antigen presentation and T-helper cell differentiation [13]. The HPV-driven tumors could also be classified into classical and inflamed/mesenchymal types [13], which may in part account for the inferior prognosis seen in some “cold” HPV-positive tumors. Other immune escape mechanisms specific to HPV-driven head and neck cancers are discussed later in this chapter. Immune effector cells must not only be present but also functional in order to mount an effective antitumor immune response. The functions of immune effector cells can be severely impacted by some forms of therapy. For example, high-dose platinum chemotherapy can severely inhibit proliferation and cytokine production by T cells [14]. Repeated fractions of low-dose radiation can have a similar immunosuppressive effect [15]. Finally, expression of immune checkpoints can also dramatically impact the functions of immune effector cells.

5 Immune Checkpoints Co-inhibitory checkpoints, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), exist in order to prevent exaggerated immune responses such as autoimmunity. However, after chronic exposure to viral infection or tumor antigens, T cells may express increasing levels of inhibitory checkpoints over time, leading to functional “exhaustion.” Although PD-1 and CTLA-4 are the most widely studied so far, other co-inhibitory checkpoints, including TIM-3 and LAG3, also appear to play an important role in the pathogenesis of head and neck cancer [3]. T cells may also have decreased expression of co-­ stimulatory receptors including CD27, CD28, CD137, and OX40, which are necessary for optimal T cell function [16, 17]. The overall balance of co-inhibitory versus co-stimulatory checkpoints can determine the functional capacity of a T cell. For example, T cells from head and neck cancers that lose expression of co-stimulatory CD27/28 expression have been shown to gain expression of PD-1 and TIM-3 de novo, making them dysfunctional and suppressive to other T cells [17]. Targeting of co-inhibitory and/or co-stimulatory checkpoints as an immunotherapeutic strategy for head and neck cancer is further discussed in other chapters of this book.

6 Immunosuppressive Cells and Cytokines Just as immune effector cell function can be determined by the balance of co-­ inhibitory versus co-stimulatory checkpoints, the effects of the tumor microenvironment are largely influenced by the balance of immune stimulating versus immunosuppressive cells and cytokines (Fig.  5). Cytokines in the tumor

Fig. 4  Cold tumors lacking immune effector cells are associated with poor prognosis and poor responses to immunotherapy, versus hot tumors. Created with Biorender.com

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Fig. 5  Immune stimulating cells in the tumor microenvironment include natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), M1 macrophages, and dendritic cells (DC). M1 macrophages and DCs can phagocytose tumor cell fragments. Immunosuppressive cells include M2 macrophages, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), which secrete tumor-promoting cytokines and metabolites. Created with Biorender.com

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microenvironment may be classified as type 1, which promote effector T cell functions and include IFNγ and interleukins 2 and 12 (IL-2/IL-12); and type 2, including IL-4, IL-6, and IL-10, which inhibit T cell functions. Immunosuppressive cytokines, growth factors, and chemokines such as transforming growth factor beta (TGF-β), IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and prostaglandin E2 (PGE2) may be secreted by tumor cells and by immunosuppressive cells [18–20]. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells that are typically found in low numbers within the peripheral blood, maturing into macrophages, granulocytes, and dendritic cells under normal circumstances [21]. However, in cancer patients, MDSCs may accumulate in the blood and traffic into the tumor microenvironment, where they exert immunosuppressive effects. These cells consist of two subtypes with distinct functions and surface markers, called monocytic MDSCs and polymorphonuclear (formerly called granulocytic) MDSCs. These cells are recruited to the tumor microenvironment by cytokines and chemokines, including GM-CSF, MCP-1, CXCL1, IL-8, and CSF1; these cells can also be converted from other types of mononuclear cells into MDSCs within the tumor microenvironment [21]. Once they have accumulated within the tumor, MDSCs secrete substances including arginase 1, nitric oxide synthase, and reactive oxygen species, which inhibit the function of effector T cells either by direct damage or depletion of metabolic resources [21]. MDSCs isolated from head and neck cancer patients have been shown to produce arginase-1  in a STAT3-­ dependent fashion and dramatically inhibit T cell proliferation [22]. High levels of PMN-MDSCs have also been found to correlate with advanced cancer stage and poor survival outcomes in head and neck cancer patients [23, 24]. Tumor-associated macrophages (TAMs) typically develop one of two phenotypes in the tumor microenvironment: M1 (immune stimulatory) or M2 (immunosuppressive). TAMs can inhibit the function of T cells and NK cells by expressing HLA-E or HLA-G or by secreting immunosuppressive cytokines and metabolites, including arginase-1, TGFβ, and interleukins 6, 8, and 10 [21]. An abundance of M2 macrophages in the tumor microenvironment, which appears to be relatively common in head and neck cancer, correlates with metastasis and poor survival outcomes [25]. Similar to macrophages, CD4+ T-helper lymphocytes can differentiate into immune-stimulating TH1 or immunosuppressive TH2 subtypes. Regulatory T cells, also known as Tregs, are another important subset of tumor-­ promoting immune cells. Tregs are a subset of CD4+ T cells that also express Foxp3, CD25, and CTLA-4. Tregs can be recruited to the tumor microenvironment or induced into Tregs from undifferentiated CD4+ T cells by the cytokine milieu. Once in the tumor, Tregs can secrete immunosuppressive cytokines, similar to other immunosuppressive cells, but they can also directly kill immune effector cells by secreting cytolytic granules (perforin and granzyme) [21, 26]. The expression of CD39 on the surface of Tregs leads to conversion of ATP into adenosine, which is also immunosuppressive [27]. The CTLA-4 expressed on Tregs binds to CD80/ CD86, leading to limited availability of CD80/86 on dendritic cells for binding of the CD28 co-stimulatory receptor [21]. Although Tregs are generally considered to

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promote immune escape in several cancer types, studies on the prognostic role of Tregs in head and neck cancers have been mixed [21, 28–30], suggesting that the effects of Tregs on the immunological landscape of head and neck cancer may be more complex than previously thought.

7 Mechanisms of Immune Escape Specific to HPV-Driven Disease Currently, the majority of oropharyngeal squamous cell carcinoma (OPSCC) cases are driven by chronic HPV infection. In order to persist in the oropharynx and induce malignancy, the virus must first evade antiviral immunity. Several forms of immunosuppression, including infection with human immunodeficiency virus, congenital immunodeficiency, autoimmunity, and iatrogenic immunosuppression following organ transplantation, are associated with a high incidence of HPV-driven malignancies [31]. Secondly, high numbers of tumor-infiltrating lymphocytes (TIL) are associated with favorable outcomes in HPV-related OPSCC [32]. Thus, impaired immune responses appear to play a critical role in the pathogenesis of HPV-related cancers. The human papillomaviridae have a strategic life cycle that facilitates immune evasion. Infection occurs in the basal epithelial layers, where immune cells are present in higher number, but early gene products are limited. After replicating in these basal layers, E6/E7 oncoproteins are kept at low levels once viral DNA is incorporated as an intracellular episome [33]. As host cells approach the surface epithelium as mature keratinocytes, where immune cells are present in much lower numbers, viral replication and levels of E6/E7 are increased. Capsid proteins, which are highly immunogenic, are produced just prior to keratinocyte shedding, allowing limited exposure of these proteins to immune cells [34]. The virus sheds along with desquamating epithelial cells and does not require host cell lysis for release, thereby avoiding an inflammatory reaction that would typically facilitate an immune response [34–38]. In addition to a strategic life cycle, HPV oncoproteins can impair innate and adaptive immune responses in several distinct ways. Several prior studies have suggested that viral oncogenes can impair the production of interferons or interferon-­ responsive genes, which are critical for inducing a strong antitumor immune response [31, 33, 34, 36, 39, 40]. Approximately 20% of HPV-driven OPSCCs have inactivating mutations of TNF receptor-associated factor 3 (TRAF-3), which plays an important role in production of interferons and activation of NF-κB signaling during viral infection [41]. Toll-like receptor 9, also important in the immune response to HPV, may be downregulated by E6 and E7 oncoproteins [42, 43]. HPV oncoproteins can also inhibit the expression of several APM components (Fig. 2), including TAP-1, TAP-2, tapasin, MHC class I and II, and LMP-2 [34, 36, 42, 44, 45, 46]. HPV-positive tumors may also have a high number of Tregs and dysfunctional/exhausted CD8+ T cells [47, 48]. The role of immune checkpoint pathways in HPV-positive versus HPV-negative HNSCC is under debate, with previous studies on PD-1/PD-L1 expression in

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HPV-­positive versus negative disease showing mixed results [49]. In one study of HNSCC where PD-1 expression among TIL was classified as low, intermediate, or high, the TIL from HPV-positive tumors were more likely overall to be PD-1positive; however, TIL classified as PD-1-high were more abundant in HPV-negative tumors, with worse survival outcomes [49].

8 Conclusions In order for transformed cells to form a tumor and thrive, they must bypass or overcome several layers of immune pressure. Much has been learned in recent decades about the strategies used by tumor cells and the tumor microenvironment to escape immunosurveillance and immune killing. An improved understanding of these immune escape mechanisms has allowed the design of several different anticancer immunotherapies. These immunotherapeutic strategies will likely continue to expand and improve as we further characterize mechanisms of immune escape. Compliance with Ethical Standards Conflicts of Interest  NCS has received research funding for Astex Pharmaceuticals and has done consulting for Checkpoint Surgical. RLF has the following disclosures: Achilles Therapeutics: Advisory Board. Aduro Biotech, Inc.: Consulting. Astra-Zeneca/MedImmune: Clinical Trial, Research Funding. Bicara Therapeutics, Inc.: Consultant. Bristol-Myers Squibb: Advisory Board, Clinical Trial, Research Funding. EMD Serono: Advisory Board. Everest Clinical Research Corporation: Consultant. F. Hoffmann-La Roche Ltd.: Consultant. Genocea Biosciences, Inc.: Consultant. Instil Bio, Inc.: Advisory Board. Kowa Research Institute, Inc.: Consultant. Lifescience Dynamics Limited: Advisory Board. MacroGenics, Inc.: Advisory Board. Merck: Advisory Board, Clinical Trial. Mirati Therapeutics, Inc.: Consultant. Nanobiotix: Consultant. Novasenta: Consulting, Stock, Research Funding. Numab Therapeutics AG: Advisory Board. OncoCyte Corporation: Advisory Board. Pfizer: Advisory Board. PPD: Consultant. Rakuten Medical, Inc.: Advisory Board. Sanofi: Consultant. Seagen, Inc.: Advisory Board. Tesaro: Research Funding. Zymeworks, Inc.: Consultant. Funding  Supported in part by Winship Cancer Institute of Emory University.

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References 1. Mandal R, Samstein RM, Lee KW et al (2019) Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 364:485–491. https://doi.org/10.1126/science.aau0447 2. Dunn GP, Ikeda H, Bruce AT et  al (2005) Interferon-gamma and cancer immunoediting. Immunol Res 32:231–245. https://doi.org/10.1385/ir:32:1-­3:231 3. Ferris RL (2015) Immunology and immunotherapy of head and neck cancer. J Clin Oncol 33:3293–3304. https://doi.org/10.1200/JCO.2015.61.1509 4. Concha-Benavente F, Srivastava R, Ferrone S et al (2016) Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells. Oral Oncol 58:52–58. https://doi.org/10.1016/j.oraloncology.2016.05.008 5. Ferris RL, Hunt JL, Ferrone S (2005) Human leukocyte antigen (HLA) class I defects in head and neck cancer. Immunol Res 33:113–133. https://doi.org/10.1385/IR:33:2:113 6. Lee MY, Jeon JW, Sievers C et al (2020) Antigen processing and presentation in cancer immunotherapy. J Immunother Cancer. https://doi.org/10.1136/jitc-­2020-­001111 7. Leibowitz MS, Andrade Filho PA, Ferrone S et al (2011) Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother 60:525–535. https://doi.org/10.1007/s00262-­010-­0961-­7 8. Leibowitz MS, Srivastava RM, Andrade Filho PA et  al (2013) SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. Clin Cancer Res 19:798–808. https://doi. org/10.1158/1078-­0432.CCR-­12-­1517 9. Lopez-Albaitero A, Nayak JV, Ogino T et al (2006) Role of antigen-­processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 176:3402–3409. https://doi.org/10.4049/jimmunol.176.6.3402 10. Meissner M, Reichert TE, Kunkel M et  al (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11:2552–2560. https://doi.org/10.1158/1078-­0432. CCR-­04-­2146 11. Yoshihama S, Roszik J, Downs I et al (2016) NLRC5/MHC class I transactivator is a target for immune evasion in cancer. Proc Natl Acad Sci U S A 113:5999–6004. https://doi.org/10.1073/ pnas.1602069113 12. Zhu K, Wang J, Zhu J, Jiang J et al (1999) p53 induces TAP1 and enhances the transport of MHC class I peptides. Oncogene 18:7740–7747. https://doi.org/10.1038/sj.onc.1203235 13. Keck MK, Zuo Z, Khattri A et al (2015) Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res 21:870–881. https://doi.org/10.1158/1078-­0432.CCR-­14-­2481 14. Tran L, Allen CT, Xiao R et  al (2017) Cisplatin Alters antitumor immunity and synergizes with PD-1/PD-L1 inhibition in head and neck squamous cell carcinoma. Cancer Immunol Res 5(12):1141–1151. https://doi.org/10.1158/2326-­6066.CIR-­17-­0235 15. Morisada M, Clavijo PE, Moore E et al (2018) PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Onco Targets Ther. https://doi.org/10.1080/2162402X.2017.1395996 16. Baruah P, Lee M, Odutoye T et al (2012) Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients. Immunobiology 217:669–675. https://doi.org/10.1016/j.imbio.2011.11.005 17. Pfannenstiel LW, Diaz-Montero CM, Tian YF et  al (2019) Immune-­checkpoint blockade opposes CD8(+) T-cell suppression in human and murine cancer. Cancer Immunol Res 7:510–525. https://doi.org/10.1158/2326-­6066.CIR-­18-­0054 18. Camacho M, Leon X, Fernandez-Figueras MT et  al (2008) Prostaglandin E(2) pathway in head and neck squamous cell carcinoma. Head Neck 30:1175–1181. https://doi.org/10.1002/ hed.20850

Immunological Landscape of Head and Neck Cancer: Mechanisms of Immune Escape…

15

19. Dasgupta S, Bhattacharya-Chatterjee M, O'Malley BW et al (2005) Inhibition of NK cell activity through TGF- 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 175:5541–5550. https://doi.org/10.4049/jimmunol.175.8.5541 20. Pak AS, Wright MA, Matthews JP et al (1995) Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res 1(1):95–103 21. Davis RJ, Van Waes C, Allen CT (2016) Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer. Oral Oncol 58:59–70. https://doi.org/10.1016/j.oraloncology.2016.05.002 22. Vasquez-Dunddel D, Pan F, Zeng Q et al (2013) STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest 123:1580–1589. https://doi.org/10.1172/ JCI60083 23. Zhong LM, Liu ZG, Zhou X et  al (2019) Expansion of PMN-myeloid derived suppressor cells and their clinical relevance in patients with oral squamous cell carcinoma. Oral Oncol 95:157–163. https://doi.org/10.1016/j.oraloncology.2019.06.004 24. Lang S, Bruderek K, Kaspar C et  al (2018) Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res 24:4834–4844. https://doi. org/10.1158/1078-­0432.CCR-­17-­3726 25. Costa NL, Valadares MC, Souza PPC et  al (2013) Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol 49:216–223. https://doi.org/10.1016/j.oraloncology.2012.09.012 26. Cao X, Cai SF, Fehniger TA et al (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27:635–646. https://doi. org/10.1016/j.immuni.2007.08.014 27. Deaglio S, Dwyer KM, Gao W et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265. https://doi.org/10.1084/jem.20062512 28. Badoual C, Hans S, Rodriguez J et  al (2006) Prognostic value of tumor-­infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472. https://doi. org/10.1158/1078-­0432.CCR-­05-­1886 29. Qi Z, Liu Y, Mints M et al (2021) Single-cell deconvolution of head and neck squamous cell carcinoma. Cancers (Basel). https://doi.org/10.3390/cancers13061230 30. Strauss L, Bergmann C, Gooding W et al (2007) The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13:6301–6311. https://doi.org/10.1158/1078-­0432. CCR-­07-­1403 31. Frazer IH (2009) Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology 384:410–414. https://doi.org/10.1016/j.virol.2008.10.004 32. Nasman A, Romanitan M, Nordfors C et al (2012) Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS One. https://doi.org/10.1371/journal.pone.0038711 33. Stanley MA, Pett MR, Coleman N (2007) HPV: from infection to cancer. Biochem Soc Trans 35:1456–1460. https://doi.org/10.1042/BST0351456 34. Kanodia S, Fahey LM, Kast WM (2007) Mechanisms used by human papillomavi ruses to escape the host immune response. Curr Cancer Drug Targets 7:79–89. https://doi. org/10.2174/156800907780006869 35. Bodily J, Laimins LA (2011) Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 19:33–39. https://doi.org/10.1016/j.tim.2010.10.002 36. O'Brien PM, Saveria Campo M (2002) Evasion of host immunity directed by papillomavirusencoded proteins. Virus Res 88:103–117. https://doi.org/10.1016/s0168-­1702(02)00123-­5 37. Stanley M (2008) Immunobiology of HPV and HPV vaccines. Gynecol Oncol 109(Suppl. 2):S15–S21. https://doi.org/10.1016/j.ygyno.2008.02.003

16

N. C. Schmitt et al.

38. Vu HL, Sikora AG, Fu S, Kao J (2010) HPV-induced oropharyngeal cancer, immune response and response to therapy. Cancer Lett 288:149–155. https://doi.org/10.1016/j.canlet.2009.06.026 39. Chang YE, Laimins LA (2000) Microarray analysis identifies interferon-­inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31. J Virol 74:4174–4182. https://doi.org/10.1128/jvi.74.9.4174-­4182.2000 40. Nees M, Geoghegan JM, Hyman T et  al (2001) Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-­associated and NF-kappaB-responsive genes in cervical keratinocytes. J Virol 75:4283–4296. https://doi. org/10.1128/JVI.75.9.4283-­4296.2001 41. Hayes DN, Van Waes C, Seiwert TY (2015) Genetic landscape of human papillomavirusassociated head and neck cancer and comparison to tobacco-related tumors. J Clin Oncol 33:3227–3234. https://doi.org/10.1200/JCO.2015.62.1086 42. Bhat P, Mattarollo SR, Gosmann C et  al (2011) Regulation of immune responses to HPV infection and during HPV-directed immunotherapy. Immunol Rev 239:85–98. https://doi. org/10.1111/j.1600-­065X.2010.00966.x 43. Zhou Q, Zhu K, Cheng H (2013) Toll-like receptors in human papillomavirus infection. Arch Immunol Ther Exp 61:203–215. https://doi.org/10.1007/s00005-­013-­0220-­7 44. Albers A, Abe K, Hunt J et  al (2005) Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 65:11146–11155. https://doi.org/10.1158/0008-­5472.CAN-­05-­0772 45. Gildener-Leapman N, Ferris RL, Bauman JE (2013) Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral Oncol 49:1089–1096. https://doi.org/10.1016/j. oraloncology.2013.09.009 46. Vambutas A, DeVoti J, Pinn W et al (2001) Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport. Clin Immunol 101:94–99. https://doi.org/10.1006/clim.2001.5094 47. Allen CT, Lewis JS Jr, El-Mofty SK et al (2010) Human papillomavirus and oropharynx cancer: biology, detection and clinical implications. Laryngoscope 120:1756–1772. https://doi. org/10.1002/lary.20936 48. Badoual C, Hans S, Merillon N et  al (2013) PD-1-expressing tumor-­infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 73:128–138. https://doi.org/10.1158/0008-­5472.CAN-­12-­2606 49. Kansy BA, Concha-Benavente F, Srivastava RM et al (2017) PD-1 Status in CD8(+) T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer. Cancer Res 77:6353–6364. https://doi.org/10.1158/0008-­5472.CAN-­16-­3167

Drug Targets and Strategies in the Clinical Development of Immunotherapy for Head and Neck Cancer Athénaïs van der Elst and Jean-Pascal Machiels

Contents 1  I ntroduction 2  Anti-PD-1 Treatment for Recurrent and/or Metastatic SCCHN 2.1  Anti-PD-1: From Platinum Failure to First-Line Therapy 2.2  Treatment Selection 3  Management of Patients Treated with Immune Checkpoint Inhibitors (ICIs) 3.1  Hyperprogression 3.2  Pseudoprogression and Treatment Beyond Progression 3.3  Specific Toxicities for Head and Neck Cancers 4  Optimization of Anti-PD-1 Treatment in R/M SCCHN 4.1  Other Anti-PD-1/L1 Inhibitors, Alone or Combined with Anti-CTLA-4 4.2  Chemotherapy in Combination with or Sequential to Immunotherapy 5  Conclusion References

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A. van der Elst Institute for Experimental and Clinical Research (IREC, pôle MIRO), Université catholique de Louvain (UCLouvain), Brussels, Belgium e-mail: [email protected] J.-P. Machiels (*) Institute for Experimental and Clinical Research (IREC, pôle MIRO), Université catholique de Louvain (UCLouvain), Brussels, Belgium Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium e-mail: [email protected] Cancer Immunotherapy (2022) https://doi.org/10.1007/13905_2022_27, © The Author(s), under exclusive license to Springer Nature Switzerland AG Published Online: 15 October 2022

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Abstract

Recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a challenging disease with poor prognosis. Until recently, the EXTREME regimen (cis/carboplatin-5-fluorouracil-cetuximab) was standard treatment for R/M SCCHN considered sensitive to platinum. For patients pretreated with platinum, second-line options (methotrexate, cetuximab, or taxanes) have been unsatisfactory with a median survival of less than 6 months. Thanks to the CHECKMATE-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040 clinical trials, nivolumab and pembrolizumab, two PD-1 inhibitors, are approved in patients with R/M SCCHN who progress after platinum therapy. The results of KEYNOTE-048 also enabled pembrolizumab to be approved as first-line treatment for R/M SCCHN either as monotherapy or in combination with platinum and 5-fluorouracil. Different regimens are thus available and treatment selection should mainly be based on the PD-L1 expression combined positive score, patient symptoms, the need for rapid tumor shrinkage, possible autoimmune comorbidities, and contraindications to chemotherapies. While PD-1 inhibitors have shown impressive long-term responses in some R/M SCCHN patients, overall response rates remain moderate. To improve their efficacy, different strategies are under investigation including immunotherapy combinations and combinations with targeted therapies or other treatment modalities. Keywords

Anti-CTLA-4 · Anti-PD-1 · Recurrent and/or metastatic SCCHN · Treatment indications

1 Introduction Squamous cell carcinoma of the head and neck (SCCHN) arises from epithelial cells and presents in the oral cavity, the oropharynx, the hypopharynx, and the larynx. It is the seventh most common cancer worldwide, accounting for approximately 700,000 new cases annually and 350,000 deaths in 2018 [1]. The carcinogenesis processes are multifactorial. Main risk factors are smoking and alcohol consumption, responsible for 75–85% of SCCHN [2]. Human papillomavirus (HPV) infection is another risk factor for oropharyngeal cancers. The prevalence of oropharyngeal cancer attributable to HPV is increasing and varies widely across the globe but is estimated at around 30% [3]. HPV-positive patients with oropharyngeal cancer have a significantly better outcome than patients diagnosed with HPV-negative disease. HPV-positive SCCHN outside of the oropharynx is rare (