A Review of Immunotherapy for Head and Neck Cancer

Abstract

The introduction of immune checkpoint inhibitors (ICIs) to oncological care has transformed the management of various malignancies, including head and neck squamous cell carcinoma (HNSCC), offering improved outcomes. The first-line treatment of recurrent and malignant HNSCC for many years was combined platinum, 5-fluorouracil, and cetuximab. Recently, the ICI pembrolizumab was approved as a first-line treatment, with or without chemotherapy, based on tumor and immune cell percentage of programmed-death ligand 1 (PD-L1). Multiple head and neck (HN) cancer trials have subsequently explored immunotherapies in combination with surgery, chemotherapy, and/or radiation. Immunotherapy regimens may be personalized by tumor biomarker, including PD-L1 content, tumor mutational burden, and microsatellite instability. However, further clinical trials are needed to refine biomarker-driven protocols and standardize pathological methods to guide combined regimen timing, sequencing, and deescalation. Gaps remain for protocols using immunotherapy to reverse oral premalignant lesions, particularly high-risk leukoplakias. A phase II nonrandomized controlled trial, using the ICI nivolumab, showed a 2-y cancer-free survival of 73%, although larger trials are needed. Guidelines are also needed to standardize the role of dental evaluation and care before, during, and after immunotherapy, specifically in regard to oral immune-related adverse events and their impact on cancer recurrence. Standardized diagnostic and oral care coordination strategies to close these gaps are needed to ensure continued success of HN cancer immunotherapy.

Introduction

Head and neck (HN) cancers affect the oral cavity, pharynx, larynx, and, less frequently, the salivary glands, sinuses, and nasal cavity. More than 90% of HN cancers are HN squamous cell carcinoma (HNSCC). HNSCC of the oropharynx and nasopharynx are often associated with human papillomavirus (HPV) and Epstein-Barr virus (EBV) infections, respectively; however, tobacco and alcohol consumption, especially for nonoropharyngeal HN cancers, remain major risk factors (Cohen, Bell, et al. 2019). The increasing incidence of HPV-related oropharyngeal cancers has prompted a growing partnership among dentists, oral medicine clinicians, and researchers toward medical and oral health strategies to optimize the care of patients with HN cancers (D’Souza et al. 2022). This integration has been bolstered by advances in the use of immunotherapy for HNSCC, including its Food and Drug Administration (FDA)–approved indications for recurrent or metastatic HNSCC (R/M HNSCC) (Ferris et al. 2016; Cohen, Soulières, et al. 2019; Harrington, Burtness, et al. 2023) and its multiple ongoing trials for locally advanced HNSCC (LA HNSCC) (Rao et al. 2023). Although standardized guidelines have been published from the Society for Immunotherapy of Cancer and the American Society of Clinical Oncology (ASCO) for the use of immunotherapy in HNSCC (Cohen, Bell, et al. 2019; Yilmaz et al. 2023; Orland et al. 2024), little has been discussed and reported in the scientific literature from a dental perspective.

Therefore, we provide here an overview of the immunotherapy studies in HNSCC and the management of oral immune-related adverse events (oral-irAEs), including the value of dental and oral care before, during, and after HN cancer treatment.

The Concept: Therapies for the Immune System to Fight Cancer

The tumor microenvironment (TME) in solid tumors, including HNSCC, consists of a complex network of neoplastic stromal cells. These cells have developed mechanisms to evade apoptotic and anti-tumor signals from the immune system. To counteract these mechanisms, a range of immunotherapies has been developed. These therapies aim to inhibit tumor cells and their cytokines from suppressing the immune system, thereby enabling macrophages, regulatory T cells, and other tumor-infiltrating immune cells to eliminate the neoplastic cells and restore tissue function.

The most prominent immunotherapy, the immune checkpoint inhibitor (ICI), functions by blocking immune checkpoints (ICs) within the TME stroma. ICs, including cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligands (PD-L1 and PD-L2), when activated, lead to immune system downregulation and tolerance. In cancer-free tissue, this prevents autoimmunity. However, in tumor tissue, it results in tumor tolerance, local invasion, and metastasis. ICIs, by preventing such evasion, have become instrumental in maintaining immune cell focus on cancer elimination (Fig. 1, left).

Figure 1.

Immune checkpoint inhibitors and associated adverse events. Abbreviations: CD80, cluster of differentiation 80; CTLA-4, cytotoxic T lymphocyte–associated protein 4; IL-10, interleukin 10; MHC I, major histocompatibility complex 1; PD-1, programmed death protein 1; PD-L1, programmed death protein ligand 1; SS, Sjögren’s syndrome; TCR, t-cell receptor; T-reg cell, T-regulatory cell; TGF-β, transforming growth factor–beta.

A Brief History

ICIs first emerged as cancer therapy in March 2011 with the FDA approval of the anti-CTLA-4 antibody ipilimumab for advanced-stage melanoma. Subsequently, the anti-PD-1 antibodies nivolumab and pembrolizumab were approved for the same condition. Multiple ICIs have since been approved for various cancers, including HNSCC (Cohen, Bell, et al. 2019).

Besides ICIs, many non-ICI anti-TME immunotherapies exist and have been approved for other malignancies (Parmar et al. 2022), including oncolytic virus therapy, CAR T-cell therapy, and therapeutic vaccines. This review, however, will focus primarily on ICIs, reflecting their predominance in the landscape of HN cancer immunotherapy.

Overview of ICI Approaches to HNSCC

HNSCC is a complex and challenging disease to treat, often requiring surgery, chemotherapy, and/or radiation therapy (RT) through a multimodal approach. Treatment algorithms are typically categorized by whether the tumor is localized, locally advanced (LA), or recurrent or metastatic (R/M). Regarding curative intent, patients with localized HNSCC often receive single-modality therapy (surgery or RT), while those with LA HNSCC often receive a combination of chemoradiation therapy (CRT) or surgery followed by adjuvant RT or CRT. For many years, the first-line treatment for patients with incurable R/M HNSCC consisted of a combination of platinum, 5-fluorouracil (5FU), and cetuximab (a monoclonal antibody against epidermal growth factor receptor), known as the EXTREME regimen (Vermorken et al. 2008). More recently, ICIs have been incorporated into the management of patients with LA and R/M HNSCC (Orland et al. 2024).

Single-Modality ICIs for R/M HNSCC

In 2016, the FDA approved 2 ICIs as second-line treatment of patients with unresectable R/M HNSCC: the PD-1 monoclonal antibodies nivolumab, based on the results of CheckMate 141 (NCT02105636) (Ferris et al. 2016), and pembrolizumab, based on the results of KEYNOTE-040 (NCT02252042) (Cohen, Soulières, et al. 2019). Multiple trials have subsequently explored their use in combination with other therapies (Table 1).

Table 1.

Review of Completed Clinical Trials in Head and Neck Cancer Immunotherapy.

Completed Clinical Trial	Phase	Protocol/Immunotherapy	Highlights
R/M HNSCC (single ICI regimens)
CheckMate 141 (NCT02105636)	III	Nivolumab versus methotrexate, docetaxel, or cetuximab	Supported 2016 FDA approval of nivolumab as second-line treatment (Ferris et al. 2016)
KEYNOTE-040 (NCT02252042)	III	Pembrolizumab versus methotrexate, docetaxel, or cetuximab	Supported 2016 FDA approval of pembrolizumab as second-line treatment (Cohen, Soulières, et al. 2019)
KEYNOTE-048 (NCT02358031)	III	Pembrolizumab alone or combined with a platinum/5FU versus EXTREME	Supported 2019 FDA approval of Pembrolizumab as first-line alone (when CPS <1%) or combined with platinum/5FU when CPS ≥1% (Harrington, Burtness, et al. 2023)
R/M HNSCC (multiple ICI regimens)
CheckMate 651 (NCT02741570)	III	Nivolumab + ipilimumab versus EXTREME	Showed no statistically significant difference in OS but showed nivolumab/ipilimumab with a better safety profile compared with EXTREME (72.2% any-grade AE and 28.2% grade 3/4 TRAE versus 97.5% any-grade AE and 70.7% grade 3/4 TRAE), respectively (Haddad et al. 2023)
CheckMate 714 (NCT02823574)	II	Nivolumab + ipilimumab versus nivolumab + placebo	Nivolumab + ipilimumab had no clinical benefit over nivolumab alone as first-line treatment for R/M HNSCC (Harrington, Ferris, et al. 2023)
R/M HNSCC (IRT regimens)
NCT02684253	II	Nivolumab alone versus nivolumab and SBRT	Showed no improved abscopal effect, PFS, OS, or response duration with IRT over ICI alone (McBride et al. 2021)
LA HNSCC (definitive immunotherapy regimens)
NCT02586207	I	Pembrolizumab, cisplatin, and RT (70 Gy)	Showed pembrolizumab can be safely combined with CRT (Powell et al. 2020)
KEYNOTE-412 (NCT03040999)	III	Pembrolizumab or placebo + cisplatin and RT (70 Gy)	Showed no benefit of adding pembrolizumab to CRT (Schnellhardt et al. 2023)
JAVELIN HN 100 (NCT02952586)	III	Avelumab or placebo + cisplatin and IMRT (70 Gy)	Showed no benefit of adding avelumab to CRT (Lee et al. 2021)
Debio 1143-201 (NCT02022098)	II	Xevinapant or placebo + cisplatin and RT	Showed benefit of adding xevinapant to CRT (locoregional control at 18 mo of 54% versus 33%, P = 0.026) (Sun et al. 2020)
LA HNSCC (induction immunotherapy)
CheckRad-CD8 (NCT03426657)	II	Induction (durvalumab/tremelimumab + cisplatin/docetaxol) then definitive durvalumab/tremelimumab + RT	Showed feasibility of dual ICI (anti-PD-L1 and anti-CTLA-4) as part of a quadruple ICT induction/definitive IRT regimen based on pathological complete response or 20% increased intratumoral CD8+ T cells (Hecht et al. 2022)
High-risk HPV-negative LA HNSCC (neoadjuvant immunotherapy)
NCT02641093	II	Neoadjuvant pembrolizumab followed by surgery and then pembrolizumab + either RT (intermediate risk) or CRT (high risk)	Survival improved for intermediate-risk group but not high-risk group (Wise-Draper et al. 2022)
High-risk HPV-related OPC (neoadjuvant immunotherapy)
Checkmate 358 (NCT02488759)	I/II	Neoadjuvant nivolumab given days 1 and 15 with surgery by day 29	Results showed pathologic regression in HPV-positive (23.5%) and HPV-negative (5.9%) tumors, encouraging future trials on neoadjuvant immunotherapy (Ferris et al. 2021)
OPL
NCT03692325	II	IV nivolumab, once every 2 wk (4 administrations)	First immunotherapy trial for oral potentially malignant lesions, suggesting potential clinical activity for nivolumab in high-risk OPL (Hanna et al. 2024)

Abbreviations: 5FU, 5-fluorouracil; AE, adverse event; CPS, combined positive score; CRT, chemoradiation therapy; CTLA-4, cytotoxic T lymphocyte–associated protein 4; DFS, disease-free survival; EXTREME, combined platinum/5FU/cetuximab; HPV, human papillomavirus; HNSCC, head and neck squamous cell carcinoma; IRT, immunoradiation therapy; ICI, immune checkpoint inhibitor; ICT, immunochemotherapy; IMRT, intensity-modulated radiation therapy; IV, intravenous; LA, locally advanced; OPC, oropharyngeal cancer; OPL, oral premalignant lesion; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death protein ligand 1; PFS, progression-free survival; PR, pathological response; R/M, recurrent and metastatic; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SoC, standard of care; TRAE, treatment-related adverse event.

Combined ICIs for R/M HNSCC

CheckMate 651 (NCT02741570) and CheckMate 714 (NCT02823574) evaluated the combination of the ICIs nivolumab and ipilimumab against standard chemotherapy regimens for R/M HNSCC. In CheckMate 651, nivolumab/ipilimumab was compared to the EXTREME regimen in the first-line setting of patients with R/M HNSCC. The results revealed no statistically significant difference in overall survival (OS), the primary endpoint of the study. However, the safety profile of nivolumab/ipilimumab (72.2% any-grade adverse event [AE] and 28.2% grade 3/4 treatment-related AE [TRAE]) in comparison to EXTREME (97.5% any-grade AE and 70.7% grade 3/4 TRAE) was favorable (Haddad et al. 2023).

In CheckMate 714, nivolumab/ipilimumab was compared with nivolumab as first-line treatment (no prior systemic therapy) for patients with R/M HNSCC. No statistically significant difference was seen between arms with regard to the objective response rate, the primary endpoint of this study (Harrington, Ferris, et al. 2023). Based on these results, combination ICIs alone for HNSCC remain experimental.

ICI-Chemotherapy for R/M HNSCC

Combined immunochemotherapy (ICT), like combined immunotherapies, aims to enhance the therapeutic efficacy and overcome the limitations of an individual modality. ICT aims to align the direct cytotoxic effects of chemotherapy with the antitumor immune benefits of immunotherapy.

KEYNOTE-048 (NCT02358031) investigated how the percentage of PD-L1–positive tumor and immune cells in patients’ tumors (measured as combined positive score [CPS]) might predict their benefit from pembrolizumab alone or combined with chemotherapy compared with EXTREME. Results showed improved OS with pembrolizumab alone (for patients with tumor PD-L1 CPS ≥1%) and when combined with platinum/5FU (for patients with any PD-L1 CPS result) (Harrington, Burtness, et al. 2023). The results led to the FDA approval of single-agent pembrolizumab for patients with R/M HNSCC with PD-L1 CPS ≥1 and pembrolizumab plus chemotherapy for patients with R/M HNSCC regardless of PD-L1 CPS results (Cohen, Bell, et al. 2019; Yilmaz et al. 2023).

ICI Radiotherapy for R/M HNSCC

RT can have immunostimulatory effects, making immuno-RT (IRT) an attractive treatment option for HN cancer. Numerous studies exploring the synergy between the in-field effect of RT and the systemic effect of immunotherapy (Qian and Schoenfeld 2020) suggest RT’s abscopal effect (i.e., the systemic antitumor response outside the irradiated field). Although the abscopal effect has been documented in a case report of R/M HNSCC treated by IRT (Forner et al. 2020), a phase II trial (NCT02684253) comparing nivolumab alone to nivolumab with RT in R/M HNSCC showed no abscopal effect (McBride et al. 2021). Multiple trials (Table 2) with IRT are ongoing to confirm these results and to define optimal RT dose, timing, and sequence with immunotherapy (De Felice et al. 2023; Rao et al. 2023).

Table 2.

Review of Ongoing Clinical Trials in Head and Neck Cancer Immunotherapy.

Ongoing Clinical Trial	Phase	Protocol/Immunotherapy	Highlights
R/M HNSCC
CONFRONT (NCT03844763)	I/II	Avelumab, cyclophosphamide, and RT (8 Gy single shot)	ICRT regimen exploring abscopal effect
NCT03474497	I/II	Pembrolizumab, intralesional IL-2, and RT (8 Gy × 3 fx)	IRT regimen with intralesional IL-2 exploring abscopal effect
Keynote-717 (NCT03386357)	II	Pembrolizumab ± concurrent radiotherapy (12 × 3 Gy) of 1, 2, or 3 metastases	IRT regimen exploring relationship between predictive biomarkers (PD-L1 and tumor-infiltrating lymphocytes) and abscopal effect
NCT03283605	I/II	Durvalumab/tremelimumab and SBRT followed by durvalumab alone	IRT regimen exploring benefit from dual ICI (anti-PD-L1 and anti-CTLA-4)
PembroMetaRT (NCT04747054)	III	First-line SoC (pembrolizumab ± platinum/FU) ± hypofractionated locoregional RT (54 Gy/8 fx)	IRT regimen exploring addition of RT to SoC first-line treatment regimen
LA HNSCC
NCT05930938	III	Induction xevinapant (or placebo) + cetuximab and RT	Potential to add xevinapant to SoC cetuximab/RT
XRAY VISION (NCT05386550)	III	Induction xevinapant (or placebo) + IMRT (66 Gy/2 fx)	Potential to add xevinapant to SoC RT
TrilynX (NCT04459715)	III	Induction xevinapant (or placebo) + cisplatin and IMRT (70 Gy/35 fx)	Potential to add xevinapant to SoC CRT
NCT02296684	II	Neoadjuvant pembrolizumab (1 dose, 1 or 2 cycles) + SoC (resection + adjuvant RT ± cisplatin ± pembrolizumab (if high risk by surgical pathology (positive margins or ENE)	Potential to guide neoadjuvant ICI dose (1 dose, 1 or 2 cycles) and addition of adjuvant ICI to SoC regimen by tumor marker/surgical pathological response (Shibata et al. 2021)
KEYNOTE-689 (NCT03765918)	III	Neoadjuvant pembrolizumab (1 dose, 2 cycles) + SoC (resection + adjuvant RT ± cisplatin) ± pembrolizumab (if high risk by surgical pathology) compared with SOC	Potential to add neoadjuvant ICI to SoC resection/adjuvant CRT and addition of adjuvant ICI to SoC regimen by surgical pathological response
High-risk HPV-positive OPC
IMMUNEBOOST (NCT03838263)	II	Induction nivolumab + SoC (IMRT + cisplatin) compared with SoC	Feasibility not reached due to toxicity; PFS and OS results are pending (Mirghani et al. 2022)
NCT03829722	II	Induction/concurrent/adjuvant nivolumab with SoC RT/carboplatin/paclitaxel	Assessing feasibility and tolerance of nivolumab as induction/concurrent/adjuvant to SoC CRT
CompARE (NCT04116047)	III	Induction/adjuvant durvalumab + SoC (cisplatin + IMRT ± neck dissection) compared with SoC	Multicenter phase III study assessing if induction/adjuvant nivolumab + SoC CRT will improve overall survival and quality of life over CRT alone
Low-risk HPV-positive OPC
NCT03952585	II/III	Induction nivolumab (or cisplatin) + reduced-dose RT (60 Gy IMRT or IGRT) compared with SoC CRT (cisplatin + 70 Gy [IMRT or IGRT])	Novel ICI + reduced dose RT deintensification strategy with potential to replace ICI with cisplatin in SoC regimen
NCT03799445	II	Induction nivolumab/ipilimumab + reduced-dose RT (50 to 6 Gy IMRT)	Novel deintensification strategy measuring safety, tolerability, and feasibility of induction anti-PD-1/CTLA-4 + reduced-dose RT
NCT03410615	II	Induction + concurrent durvalumab/ RT (70 Gy) + adjuvant (durvalumab or durvalumab/tremelimumab) compared with SoC CRT (cisplatin + 70 Gy RT)	Novel deintensification strategy exploring replacement of cisplatin in SoC regimen with anti-PD-L1 + adjuvant (anti-PD-L1 or anti-PD-L1/CTLA-4)
NCT04867330	II	Induction ICT (toripalimab/docetaxel/cisplatin) followed by standard CRT (cisplatin + RT [70 Gy]) (when pathology <50% partial response) or reduced-dose RT (60 Gy) alone (when ≥50% partial response)	Novel induction IRT strategy followed by decision to deintensify definitive CRT to reduced-dose RT based on tumor partial response (>50%)
NCT02827838	II	Neoadjuvant durvalumab (1 dose, 2 cycles) followed by resection	Exploring effect of durvalumab on local/systemic immune activation (measured by level of immune-regulatory miR in plasma and saliva) by HPV status
NCT03618134	I/II	Neoadjuvant IRT (SBRT + [durvalumab ± tremelimumab]), then resection (TORS/neck dissection) and adjuvant durvalumab	Exploring safety, tolerability, and efficacy of neoadjuvant IRT with anti-PD-L1 with and without anti-CTLA-4
MINIMA (NCT04988074)	II	Neoadjuvant cemiplimab ± carboplatin/paclitaxel, then 2-armed biomarker-guided deintensification treatment strategy, followed by adjuvant cemiplimab	Novel neoadjuvant ICI strategy with added chemotherapy (based on IF study of immune microenvironment) and deintensified definitive regimen (based on rate of HPV-specific immune response [HPV FEST assay] and ctDNA clearance)
Optima II (NCT03107182)	II	Neoadjuvant nivolumab/nab-paclitaxel/carboplatin, then 3-armed deintensification treatment (strategy based on response), followed by adjuvant nivolumab	Novel deintensification strategy with preliminary results showing short-term efficacy and reduced toxicity (Rosenberg et al. 2021)
HPV-positive OPC (therapeutic vaccines)
NCT04852328	II	Neoadjuvant Cue-101 (E7-HLA-IL2-Fc fusion protein) followed by surgery/adjuvant CRT or definitive CRT	Novel therapeutic vaccine strategy for HLA-A*0201 positive patients)
NCT04630353	I	Neoadjuvant HB201 (HPV16 E6/E7 fusion protein) delivered intravenously prior to definitive surgery or CRT	Novel therapeutic vaccine strategy with response measured by E7/E6 antigen specific assay
NCT02002182	II	Neoadjuvant therapeutic vaccine ADXS 11-001 (ADXS-HPV) (live attenuated Listeria monocytogenes with a listeriolysin O to HPV-antigen fusion protein) followed by CRT versus CRT alone	Novel strategy using therapeutic vaccine designed to treat HPV-related dysplasia and malignancy
NCT04432597	I/II	Neoadjuvant PRGN-2009 (gorilla adenovirus–based vaccine specific to E6/E7 of HPV) combined with M7824 (anti-PD-L1/TGF-β) followed by definitive SoC treatment	Novel combined vaccine/dual-programmed ICI strategy for LA and/or metastatic HPV-associated OPC
NCT04369937	I/II	ISA101b (gorilla adenovirus–based vaccine specific to E6/E7 of HPV) then induction pembrolizumab followed by definitive cisplatin/IMRT (70 Gy)	Novel combined therapeutic vaccine/ICI strategy as induction before CRT for high-risk HPV-related LA OPC
High-risk OPL
IMPEDE trial (NCT04504552)	II	IV avelumab for patients with OLP and loss of tumor suppressor genes (9p21.3 and/or 3p14)	Novel immunopreventive strategy
NCT05327270	I	Intralesional nivolumab for patients with OPL	Novel immunopreventive strategy
NCT03603223	II	IV pembrolizumab for patients with leukoplakia	Novel immunopreventive strategy
NCT02882282	II	IV pembrolizumab for patients with oral intraepithelial neoplasms	Novel immunopreventive strategy

Abbreviations: CRT, chemoradiation therapy; ctDNA, circulating tumor DNA; CTLA-4, cytotoxic T lymphocyte-associated protein 4; ENE, extranodal extension; FEST, functional expansion of specific T cells; HLA, human leukocyte antigen; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; ICI, immune checkpoint inhibitor; IF, immunofluorescence; IGRT, image-guided radiation therapy; IL-2, interleukin-2; IMRT, intensity-modulated radiation therapy; IRT, immune-radiation therapy; IV, intravenous; LA, locally advanced; miR, micro-ribonucleic acid; OPC, oropharyngeal cancer; OPL, oral premalignant lesion; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1; PFS, progression-free survival; R/M, recurrent and metastatic; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SoC, standard of care; TGF-β, transforming growth factor–beta; TORS, transoral robotic surgery.

Overview of Investigational Approaches to LA HNSCC

The use of immunotherapy for LA HNSCC in the neoadjuvant, concurrent, and adjuvant settings also remains investigational.

Immunotherapy-Combined CRT for LA HNSCC

A phase Ib trial (NCT02586207) showed that pembrolizumab can be safely combined with CRT (Powell et al. 2020), but the subsequent phase III KEYNOTE-412 (NCT03040999) failed to show improved event-free survival with the combination in comparison to CRT alone (Schnellhardt et al. 2023). Likewise, the phase III JAVELIN HN 100 (NCT0295286), adding avelumab (anti-PD-L1) to CRT failed to improve progression-free survival (PFS) over CRT plus placebo (Lee et al. 2021). The phase II Debio 1143-201 (NCT02022098), evaluating xevinapant (an inhibitor of apoptosis protein), however, showed benefit over placebo when added to CRT (locoregional control at 18 mo of 54% versus 33%, P = 0.026) (Sun et al. 2020). Multiple phase III trials adding xevinapant to RT or CRT remain ongoing (Table 2) (Rao et al. 2023).

Induction Immunotherapy before Definitive (Nonsurgical) Treatment for LA HNSCC

The phase II CheckRad-CD8 (NCT03426657), on patients with nonresectable LA HNSCC, studied the feasibility of ICT induction (durvalumab [anti-PD-L1]/tremelimumab [anti-CTLA-4] plus cisplatin/docetaxel) followed by definitive IRT (durvalumab/tremelimumab plus radiotherapy). Successful induction, determined as pathological complete response, that is, no viable tumor or 20% increased intratumoral CD8+ T cells, was found in 72 of 80 patients (90%). These patients, after continuing with definitive IRT, then showed 1-y/2-y PFS of 78%/72% and OS of 90%/84% (Hecht et al. 2022), highlighting the feasibility of this regimen for nonresectable LA HNSCC.

Neoadjuvant Immunotherapy before Definitive (Surgical) Treatment for LA HNSCC

The addition of immunotherapy before surgery (neoadjuvant) aims to augment T-cell–mediated removal of micro-metastasis before and after surgery (Topalian et al. 2020).

A phase II trial (NCT02641093) (92 patients enrolled) examined the use of neoadjuvant/adjuvant pembrolizumab in high-risk HPV-negative LA HNSCC. After neoadjuvant pembrolizumab/surgery, patients with clear surgical margins and no extranodal extension (ENE) (intermediate-risk group) received adjuvant pembrolizumab/RT while patients with positive surgical margins and positive ENE (high-risk group) received adjuvant pembrolizumab/RT with the addition of cisplatin. The 1-y disease-free survival (DFS) in the intermediate-risk group was 97% (95% confidence interval [CI] 71%–90%), significantly better than the historical DFS of 65%, but the high-risk group was 66% (95% CI 55%–84%) (Wise-Draper et al. 2022). As such, neoadjuvant/adjuvant immunotherapy combinations remain experimental.

The phase III KEYNOTE-689 (NCT03765918) and phase II NCT02296684 are evaluating the addition of neoadjuvant/adjuvant pembrolizumab to standard of care (resection/adjuvant CRT) for high-risk resectable LA HNSCC (Shibata et al. 2021) (Table 2). Results of these studies are eagerly awaited.

Immunotherapy for High-Risk HPV-Related Oropharyngeal Cancer (OPC)

Despite the better prognosis of patients with HPV-related OPC in comparison to those with HPV-unrelated disease, there is still a 10% to 25% risk of disease progression (Fakhry et al. 2014).

The multicenter phase I/II CheckMate 358 (NCT02488759) on high-risk (stage T3/T4, majority former or current smoker), HPV-positive and -negative, resectable HNSCC examined the safety and efficacy of neoadjuvant nivolumab. Results showed the regimen to be generally safe, and biopsy of resected HPV-positive and HPV-negative tumors showed pathologic regressions in 3 of 17 patients (23.5%) and 1 of 17 patients (5.9%), respectively (Ferris et al. 2021).

Another study on HPV-related high-risk OPC (stage T4, N2/N3, or a smoking history >10 pack-years), the phase II IMMUNEBOOST (NCT03838263) evaluated nivolumab as induction prior to cisplatin-based CRT. Although initial results showed acceptable safety profiles, 4 of 41 patients in the experimental group eventually experienced toxicity (2 kidney failures, 2 ototoxicity) requiring deintensification of cisplatin (Mirghani et al. 2022). The PFS and OS results of this study are still pending.

Other ongoing studies (Table 2) on high-risk HPV-related OPC include a phase II trial (NCT03829722) comparing CRT to CRT with induction/concurrent/adjuvant nivolumab and the phase III CompARE (NCT04116047), comparing standard CRT to CRT with induction/adjuvant durvalumab.

Deintensification Trials for HPV-Related OPC

Given that OPC prognosis is overall favorable, there is interest in using immunotherapy to deescalate standard regimens (Rosenberg et al. 2021).

One ongoing phase II/III trial (NCT03952585), examining reduced-dose radiation (70 Gy to 60 Gy) CRT or IRT compared with standard CRT, has the potential to deintensify current first-line treatments in HPV-related OPC. Multiple other deintensification strategies, particularly for lower-risk HPV-related OPC, including induction ICI (NCT03799445, NCT03410615, NCT4867330) and neoadjuvant ICI (NCT02827838, NCT03618134, NCT04988074, NCT03107182), are underway. These, and other trials on therapeutic vaccines (e.g., NCT04852328, NCT04630353, NCT02002182, NCT04432597, NCT04369937) are eagerly awaited for their potential to bring a more personalized and less toxic approach to management of HPV-related OPC (Saito et al. 2022) (Table 2).

Selecting and Monitoring Immunotherapy by Biological Profile

In the dynamic field of HN cancer treatment, precision immuno-oncology stands at the forefront. This approach integrates immunologic and tumor bioprofiling, radiographic analysis, and clinical examination to fine-tune multimodal treatment regimens. These evolving strategies are crucial for determining the most effective combination, dosing, and scheduling of immunotherapies (Anagnostou et al. 2022; Rao et al. 2023; Yilmaz et al. 2023).

Biological Profiling in Initial Regimen Guidance

Key to formulating initial treatment strategies, biological profiling involves a comprehensive clinical examination, radiologic assessment, and tissue analysis. The focus is on identifying predictive and prognostic biomarkers, such as tumor stromal PD-L1 or immune cell content, tumor mutational burden (TMB), microsatellite instability (MSI), HPV status, and EBV status, among others (Sivapalan et al. 2023).

PD-L1 Measurement

PD-L1 expression in the TME, modulating the activity of CD8+ T cells, has emerged as a significant biomarker for immunotherapy. PD-L1 is measured through immunohistochemistry (IHC) on tumor stroma biopsies. Two scoring methods, tumor proportion score (TPS) and CPS, have been used. TPS calculates the ratio of PD-L1+ viable tumor cells to total viable tumor cells, while CPS calculates the ratio of combined PD-L1+ tumor cells, lymphocytes, and macrophages to total viable tumor cells (Parmar et al. 2022).

Although CPS and TPS can be used interchangeably for HNSCC, it has been found that CPS may be more sensitive at lower cutoffs (Emancipator et al. 2021). CPS categorization (<1%, 1% to 19%, ≥20%) has become pivotal in setting FDA approval benchmarks, with studies such as KEYNOTE-040 and KEYNOTE-048 demonstrating pembrolizumab as more effective in HNSCC patients with higher PD-L1 levels (Cohen, Soulières, et al. 2019; Harrington, Burtness, et al. 2023).

Tumor Mutational Burden (TMB)

TMB, indicating the number of mutations in tumor DNA, predicts response to immunotherapy. The phase II HAWK (NCT02207530) and CONDOR (NCT02319044) studies and the phase III EAGLE (NCT02369874) study illustrate the predictive value of TMB for survival, elucidating its role as a biomarker in treatment decisions (Wildsmith et al. 2023). The use of TMB, however, is currently advised only when CPS scores are unavailable, in which case TMB ≥10 would indicate potential benefit to PD-1 inhibitor (Orland et al. 2024).

Microsatellite Instability (MSI)

MSI, indicating defective tumor DNA mismatch repair, has been found for some cancers to predict increased response to anti-PD-1 ICIs (Yilmaz et al. 2023). Given a low rate of MSI incidence in HNSCC, however, the measure has not become standard of care and, at this time, is considered only when genome profiling is already performed elsewhere for care of the patient (Cohen, Bell, et al. 2019).

HPV Status

Viral antigens in HPV-infected tumors have been found to increase CD8+ T-cell infiltration (Matlung et al. 2016), suggesting increased likelihood of immunotherapy response in HPV+ tumors.

Meta-analyses of CheckMate 141, KEYNOTE-012 (NCT01848834), and KEYNOTE-055 (NCT02255097) demonstrate that HPV+ status can predict anti-PD-1/PD-L1 efficacy (Wang et al. 2019; Xu, Zhu, et al. 2021). The ongoing phase II MINIMA (NCT04988074), utilizing induction immunotherapy on patients with HPV-related OPC, is using multiple HPV-specific monitoring strategies (Table 2) to guide treatment deescalation. As this and other OPC trials (Table 3) continue, standardization of HPV detection and monitoring methods is advised (Xu, Zhu, et al. 2021) (Table 4).

Table 3.

Review of Clinical Trials Showing Evidence of Predictive Biomarkers in Head and Neck Cancer Immunotherapy.

Clinical Trial	Phase	Protocol/Immunotherapy	Predictive Biomarker Finding
PD-L1
KEYNOTE-040 (NCT02252042	III	Pembrolizumab versus methotrexate, docetaxel, or cetuximab	• Demonstrated pembrolizumab as more effective for R/M HNSCC with higher PD-L1 (Cohen, Soulières, et al. 2019)
KEYNOTE-048 (NCT02358031)	III	Pembrolizumab alone or combined with a platinum/5FU versus EXTREME	• Supported 2019 FDA approval of pembrolizumab as first line alone (when CPS <1%) or combined with platinum/5FU when CPS ≥1% (Harrington, Burtness, et al. 2023)
TMB
HAWK (NCT02207530)	II	Durvalumab (single-arm) in PD-L1–high patients	• Helped illustrate the predictive value of TMB for survival in patients with R/M HNSCC (Wildsmith et al. 2023) • If CPS scores are unavailable, TMB ≥10 indicates potential benefit to PD-1 inhibitor (Orland et al. 2024)
CONDOR (NCT02319044)	II	Durvalumab/tremelimumab versus durvalumab or tremelimumab monotherapy in PD-L1–low patients
EAGLE (NCT02369874	III	Durvalumab/tremelimumab versus durvalumab or tremelimumab monotherapy without regard to PD-L1 status
HPV+ status
Checkmate 141 (NCT02105636)	III	Nivolumab versus methotrexate, docetaxel, or cetuximab	• Used in meta-analyses to provide evidence that HPV+ status may predict response of HNSCC to PD-1/PD-L1 axis blockade in (Wang et al. 2019; Xu, Zhu, et al. 2021)
KEYNOTE-012 (NCT01848834)	I	Pembrolizumab monotherapy
KEYNOTE-055 (NCT02255097)	II	Pembrolizumab monotherapy
HAWK (NCT02207530)	II	Durvalumab (single arm)
EBV+ status
JUPITER-O2 trial (NCT03581786)	III	Toripalimab or placebo + gemcitabine-cisplatin	• Provided evidence that EBV+ status may predict response of R/M NPC to PD-1/PD-L1 axis blockade (Mai et al. 2023)

Abbreviations: 5FU, 5-fluorouracil; CPS, combined positive score; EBV, Epstein-Barr virus; EXTREME, combined platinum/5FU/cetuximab HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; NPC, nasopharyngeal carcinoma; PD-L1, programmed cell death protein ligand 1; R/M, recurrent and metastatic; TMB, tumor mutational burden.

Table 4.

Gaps and Their Potential Paths for Closure in Head and Neck Cancer Immunotherapy Research.

Research Area	Gap	Potential Path to Closure
Immunoradiotherapy	Uncertainty in the timing and sequencing of immunotherapy and radiotherapy for oligometastatic and LA HNSCC	• Clinical trials are advised to explore biomarker-driven protocols and immune-radiotherapy timing and sequencing that maximize efficacy while minimizing toxicity (De Felice et al. 2023)
Trials with immunotherapy as neoadjuvant before definitive (surgical) treatment for LA HNSCC	Lack of standardized pathological scoring methods, for example, PR, to evaluate immunotherapy response (Shibata et al. 2021)	• Convene expert panel that includes oral and head and neck pathologists to standardize best pathological methods
HPV as a biomarker of OPC response to immunotherapy	Unknown effect of anatomical subsite and PD-L1 expression combined with HPV status	• Collection and analysis of data on anatomic subsite, combined PD-L1/HPV subgroups (Xu, Zhu, et al. 2021)
	Lack of standardized methodology across clinical trials for determining and monitoring HPV+ tumors (Xu, Zhu, et al. 2021)	• Research comparing predictive accuracy of available HPV test and monitoring methods, for example, p16 IHC, PCR, ISH, HPV FEST
EBV as a biomarker of NPC response to immunotherapy	Unknown values at which plasma EBV DNA copy number become clinically significant	• Clinical trial use of standardized evaluation methods and cutoffs for plasma EBV DNA assays (Bossi et al. 2023)
Immunotherapy for high-risk OPLs	Inconsistent terminology and methods for OPL diagnosis	• Oral maxillofacial and/or head and neck pathology standardization of terminology and methods for diagnosis
	Biomarkers, for example, PD-L1, HPV status, or TMB, with unknown utility to predict response of OPL to immunotherapy	• Continued trials on OPL measuring biomarkers before and after immunotherapy with study endpoints should prioritize cancer-free survival
Oral-irAEs	Oral manifestations often underrecognized and inadequately managed (Klein et al. 2022)	• Addition of oral-irAE diagnostic terminology to CTCAE • Development of globally accepted grading system for oral-irAEs in clinical trials (Srivastava et al. 2024)
	Low knowledge on the relationship between oral-irAEs and overall HNSCC prognosis (Jacob et al. 2021)	• Standardized diagnostic and management strategies to optimize the clinical benefit of ICI therapy (Klein et al. 2022) • Long-term studies evaluating the relationship between oral-irAEs, their management, and risk for HNSCC recurrence (Elad et al. 2023)

Abbreviations: CPS, combined positive score; CTCAE, Common Terminology Criteria for Adverse Events; EBV, Epstein-Barr virus; FEST, functional expansion of specific T cells; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; irAEs, immune-related adverse event; ISH, in situ hybridization; LA, locally advanced; NPC, nasopharyngeal carcinoma; OPL, oral premalignant lesion; PCR, polymerase chain reaction; pTR, pathological tumor response; PR, pathological response.

EBV Status

EBV infection is critical to the development of nasopharyngeal carcinoma (NPC). EBV viral counts, although not used to select immunotherapy, have been shown to correlate with prognosis (Bossi et al. 2023).

In the phase III JUPITER-O2 (NCT03581786) on patients with R/M NPC, patients were randomized to receive anti-PD-1 toripalimab or placebo in combination with gemcitabine-cisplatin. Patients receiving the toripalimab regimen showed a longer PFS (median, 21.4 vs 8.2 mo; hazard ratio, 0.52 [95% confidence interval, 0.37 to 0.73]) and a more likely reduction of plasma EBV DNA to undetectable levels. The toripalimab group also showed fewer patients with plasma EBV rebound after treatment, suggesting EBV DNA copy number might be useful for predicting disease progression (Mai et al. 2023). However, standardized evaluation methods and cutoffs for EBV DNA assays are needed (Bossi et al. 2023) (Table 4).

Radiomics-Based Biomarkers

Radiomics is the quantitative analysis of diagnostic images (e.g., magnetic resonance imaging, computed tomography, or positron emission tomography scans) using several mathematical algorithms (Smussi et al. 2023). These imaging features seen before and/or during treatment can predict treatment response. Radiomics in conjunction with blood immune panels (e.g., lymphocyte-to-monocyte ratio) has been studied as a means to optimize prediction of response to immunotherapy (Volpe et al. 2023), although currently no radiomic features are used to guide treatment (Smussi et al. 2023).

In summary, although the use of biomarkers in HN cancer immunotherapy is making ground (Table 3), there are still gaps to close (Table 4). Yet, the integration of biological, radiographic, and clinical data toward precision immuno-oncology holds promise for HN cancer treatment and paves the way for more effective personalized care for this population.

Prevention of HNSCC by Immunotherapy for Oral Premalignant Lesions

Oral premalignant lesions (OPL; also known as oral potentially malignant disorders), such as leukoplakia, erythroplakia, and proliferative verrucous leukoplakia, often represent a difficult to manage disease entity requiring close and long-term monitoring and treatment (Wetzel and Wollenberg 2020; Warnakulasuriya et al. 2021). Given the limitations in local excision or laser therapy to prevent recurrence, other therapies are now being studied.

Based off reports of PD-1 and PD-L1 expression as markers of malignant transformation in oral leukoplakia (Ries et al. 2021), anti-PD-1/PD-L1 antibodies have been tested to immunoactivate the oral microenvironment of OPL. A phase II nonrandomized controlled trial (NCT03692325) assessed the safety and efficacy of nivolumab in 33 patients with high-risk leukoplakias, defined by the authors as multifocal (≥2) lesions, contiguous lesions ≥3 cm, or a single lesion ≥4 cm showing any degree of epithelial dysplasia (Hanna et al. 2024). Results showed a 2-y cancer-free survival of 73%, consistent with only potential anti-PD-1 activity; however, follow-up was limited to a median 21.1 (5.4 to 43.6) mo. Although no correlation with CPS score was noted, lesions that progressed more frequently showed loss of the tumor suppressor gene, 9p21.3, a finding consistent with other studies (Han et al. 2021; William et al. 2021). Future trials are advised to use a larger sample size and follow-up time and to prioritize cancer-free survival with biomarker stratification.

Other ongoing immunopreventive studies include the phase II IMPEDE (NCT04504552) using avelumab on patients with high-risk OPL and loss of 9p21 and/or 3p14, a phase I trial (NCT05327270) evaluating the response of OPLs to intralesional nivolumab, a phase II trial (NCT03603223) studying the response of leukoplakia to intravenous pembrolizumab, and a phase II trial (NCT02882282) studying response of oral intraepithelial neoplasms to intravenous pembrolizumab. As with immunotherapy trials on HNSCC, these trials on OPL would benefit from oral maxillofacial and/or head and neck pathology collaboration, particularly to standardize pathological methods and terminology.

Furthermore, therapeutic vaccination, as a means to stimulate lymphocytes to recognize and destroy neoplastic cells (Koyande et al. 2022), may also be effective against oral dysplasia. Vaccines for HNSCC, being developed against E6/E7 oncogenes (in HPV-related OPCs; Table 2) and against EBV antigens (in most NPCs), along with other novel immunotherapies (Parmar et al. 2022; Ritter et al. 2023), should be considered as OPL reversal strategies continue to evolve.

Oral-irAEs

As immunotherapies are increasingly used for various cancers, including HN cancer, the understanding of their potential oral- and nonoral-irAEs (Fig. 1) has become critical (Schneider et al. 2021; Elad et al. 2023; Villa and Kuten-Shorrer 2023).

Monitoring and Management

Oral- and nonoral-irAEs can occur anywhere from days to months or years after starting ICIs and should be evaluated carefully to rule out an unrelated disease (Schneider et al. 2021; Klein et al. 2022; Elad et al. 2023). In 2021, ASCO convened an expert panel to publish guidelines on the management of irAEs (Schneider et al. 2021); however, oral-irAEs were not included.

A meta-analysis of 18 randomized clinical trials (N = 11,465 patients) for PD-1/PD-L1 inhibitors reported 11.8% of patients with skin rash, 2.7% of patients with any grade stomatitis, and 0.2% of patients with high-grade stomatitis (Yang et al. 2019). Furthermore, a retrospective study of 4,683 ICI-treated patients found 317 (6.8%) having developed oral-irAEs (Xu, Wen, et al. 2021). Of those, 217 (68.5%) patients had xerostomia, 106 (33.4%) had oral mucosal disorders, and 76 (24.5%) had dysgeusia. Management of oral-irAEs in the setting of HN cancer therefore benefits from multidisciplinary care including dentists to optimize oral function, nutrition, and speech.

Oral-irAEs can be temporary or chronic, and numerous strategies for their prevention, early detection, and management have been discussed (Xu, Wen, et al. 2021; Klein et al. 2022; Elad et al. 2023; Vigarios and Sibaud 2023; Villa and Kuten-Shorrer 2023). However, with unstandardized terminology for oral-irAEs in clinical trials and clinical practice globally, evidence-based data are limited (Srivastava et al. 2024).

Most oral toxicities are recorded using the Common Terminology Criteria for Adverse Events (CTCAE v5.0), which includes scales for oral mucositis, dry mouth, and oral dysesthesia, but specific terminology for oral-irAEs has been lacking. Recently, a grading system (G1 through G4) for salivary and mucosal oral-irAE, and accompanying management guidelines, has been proposed (Klein et al. 2022). Oral mucosal clinical features were classified as oral lichen planus-like, bullous pemphigoid/mucous membrane pemphigoid-like, erythema multiform-like, Stevens-Johnson syndrome-like, and toxic epidermal necrolysis-like. The term “-like” was added to reflect the uncertainty as to whether these changes are oral-irAEs or distinct disease processes that might have happened independently.

To prevent and alleviate the severity of oral-irAEs, patients before and after immunotherapy should receive timely treatment for any dental disease and preventive measures, including dental prophylaxis and counseling for dry mouth. If oral-irAEs do arise, patients should be referred to a dental specialist (e.g., oral medicine, oral pathology, or oral and maxillofacial surgeon) to guide management (Elad et al. 2023). For patients before and after RT, clinicians are also advised to follow the current guidelines for the prevention and management of RT-induced oral mucositis (Peterson et al. 2024).

Furthermore, given the rare report of patients on ICIs with oral lichen planus-like lesions that progressed to oral cancer, patients with oral-irAEs are advised to seek reevaluation of their oral mucosal lesions once or twice per year, or sooner if any abnormality is identified (Elad et al. 2023).

Finally, novel treatment strategies for oral-irAEs may be developed based on treatments for irAE of the gastrointestinal system. For example, patients with colitis as an irAE from ICIs were found to recover via fecal microbiota transplantation to restore the gut microbiome and associated regulatory T lymphocytes (Wang et al. 2018). These results suggest the possibility that oral microbiome restoration may provide a similar benefit to oral mucosal irAEs and may be explored further by oral health professionals as a novel therapeutic avenue (Jacob et al. 2021).

The Role for Dental Care before, during, and after Immunotherapy to Minimize Side Effects and Optimize Outcomes

As oral-irAEs may be secondary to lymphocytes in the oral mucosa overreacting to oral microbes, guidance on regular oral hygiene should be encouraged throughout dental and/or oncology follow-up. Counseling on therapies for salivary flow to optimize oral flora, pH, and debris clearance should also be taught and reinforced by a competent multidisciplinary health professional team (Villa and Kuten-Shorrer 2023).

Given oral-irAEs often overlap with irAEs of other organ systems (e.g., dermatologic, gastrointestinal, or endocrine) (Xu et al. 2024), oral health professionals, including both general and oral medicine/dental oncology experts, should complete a thorough intraoral and extraoral exam and review of systems (Fig. 1, right) and ensure all oral and systemic findings are documented and communicated effectively back to patients’ oncology teams.

Conclusion

Given the growing list of life-extending HN cancer immunotherapies, we have provided an overview of key concepts in HNSCC immunotherapy and oral-irAE management of relevance to the modern dentist. General and HN cancer–specialized dentists, including oral medicine specialists, oral pathologists, oral and maxillofacial surgeons, and prosthodontists are encouraged to utilize these updates to guide evidence-based practice. Where gaps in knowledge exist (Table 4), clinicians and researchers are encouraged to design and/or refer to the appropriate clinical trial. With growing awareness of the risks for oral-irAEs, early and ongoing involvement of dentists in their prevention, diagnosis, and treatment is crucial. The added value of the dental community to HN cancer outcomes, before, during and after immunotherapy, much as for treatment of any cancer, is apparent, highlighting this timely opportunity for improved oral health in cancer care programs.

Author Contributions

J.W. Goetz, contributed to conception and design, drafted and critically revised the manuscript; G. Rabinowits, N. Kalman, A. Villa, contributed to conception and design, critically revised manuscript. All authors gave their final approval and agree to be accountable for all aspects of the work.