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HPV-Associated Head and Neck Cancer: History
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Subjects: Oncology
Contributor: Malvi Savani

Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this entry is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.

  • head and neck squamous cell carcinoma
  • novel therapies
  • human papillomavirus
  • immunotherapy

1. Introduction

HPV-positive HNSCC represents a distinct disease entity with molecular, pathological, and clinical features that lead to an improved response to standard therapy and a favorable prognosis compared to HPV-negative HNSCC. Weinberger and colleagues initially identified an OPC molecular profile associated with favorable prognosis: specifically, the presence of HPV16 DNA and overexpression of p16. The latter implies functionally relevant HPV; conventional thinking is that p16 is upregulated as a consequence of retinoblastoma (Rb) degradation by the oncoprotein E7 [1]. Alternately, McLaughlin-Drubin et al. have shown that p16 upregulation is Rb-independent but indeed E7-dependent, as E7 drives the upregulation of KDM6B histone demethylase [2]. Ultimately, HPV status and tobacco history were identified as the two most important prognostic factors in OPC [3], and in 2017 the American Joint Commission on Cancer codified a new staging system for p16-positive OPC to improve hazard discrimination.

These poor outcomes have driven increased research into novel immunotherapeutic and targeted approaches in HNSCC. Immunotherapy has emerged as a promising therapeutic avenue in HPV-positive HNSCC as HPV-driven carcinogenesis is propelled by loss of immunologic control with chronic viral infection resulting in a unique, non-self, antigenic target [4]. In this review, we highlight the role of immunotherapy as an established standard of care, as well as explore emerging immunotherapies including novel checkpoint inhibitors, antibodies and fusion protein constructs, vaccines, and chimeric antigen receptor (CAR) T-cell therapy in HPV-positive HNSCC ( Figure 1 ).

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Figure 1. Mechanisms of Standard and Novel Immunotherapies in HPV-Positive HNSCC. The schema is a simplified illustration of the sites of action of novel immunotherapies within the tumor microenvironment of HPV-positive HNSCC. Monalizumab (A) is an anti-NKG2A mAb that augments the cytotoxic activity of NK cells. The Fc tail of cetuximab (B) and other IgG1 mAb can bind CD16 (the Fc receptor) on NK cells, triggering antibody-dependent, cell-mediated cytotoxicity. Tiragolumab (C) is a human anti-TIGIT mAb that prevents TIGIT from binding with its ligand, CD155, on dendritic and tumor cells. Nivolumab and pembrolizumab are mAb directed against the PD-1 receptor, while durvalumab and atezolizumab are mAb directed against its ligand, PD-L1 (D). Ipilimumab and tremelimumab (E) are mAb directed against CTLA-4. Urelumab and utomilumab (F) are mAb agonists of CD137. CP-870,8893 (G) is an agonist anti-CD40 mAb that activates CD40. MEDI6469 (H) is a murine-human OX40 agonist mAb. MBG453 (I) is a high-affinity, humanized IgG4 antibody targeting TIM-3. Eftilagimod alpha (J) is a is a soluble LAG-3 fusion protein that mediates antigen presenting cell activation and CD8 T-cell activation by binding to a subset of MHC class II molecules. Immunotherapeutic vaccines including MEDI0457, ISA-101, ADXS11-001 and TG4001 (K) incorporate HPV16 E6 and E7 antigens.

2. Primary Prevention of HPV-Positive HNSCC

HPV is a double-stranded DNA virus that infects the epidermal and mucosal surfaces of the oropharynx, genital, and anal regions and is an established causative agent in oropharynx, cervical, vulvar, anal, and penile cancers. HPV infection is common and occurs through mucosal surface contact with an infected sexual partner [5]. Three prophylactic HPV vaccinations are currently approved by the FDA including the quadrivalent HPV vaccine, Gardasil, a bivalent HPV vaccine, Cervarix, and a nine-valent vaccine, Gardasil 9, with the latter providing protection against HPV-6, 11, 16, 18, 31, 33, 45, 53, and 58 [5]. Each vaccine is recommended for a specific sex and age group. HPV vaccination for all individuals aged 9–26 years is recommended by the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices. Additionally, the FDA has approved HPV vaccination for all individuals aged 27–45 years who have not been adequately vaccinated previously [6]. The indications for these prophylactic HPV vaccinations were established based on impact on anogenital HPV infections. However, the effectiveness against oral HPV infection specifically has only been analyzed retrospectively but was shown to have 88–93% efficacy [7]. HPV vaccinations are only effective for primary prevention with the primary mechanism of action involving the induction of anti-L1 capsid antibodies, effectively blocking the initial step of viral entry. Although numerous epidemiological studies have shown an association between oral HPV DNA detection or anti-HPV16 E6 seropositivity and consequent risk of developing OPC, no validated screening test analogous to the Papanicolaou smear exists for HPV-positive HNSCC [8].

3. Meta-Analysis of PD-1 Inhibition in HNSCC

In an effort to further understand the impact of HPV status on response to anti-PD1 immunotherapy, recent meta-analyses have been conducted. In a meta-analysis assessing results from 11 clinical trials including 1860 patients evaluating immunotherapy in R/M HNSCC, patients with HPV-positive HNSCC demonstrated an improved risk ratio (1.29, p = 0.24) and OS (11.5 vs. 6.3 months) in comparison to patients with HPV-negative disease [9]. The most common immunotherapy agents across the trials were anti-PD1 agents (pembrolizumab, nivolumab) and anti-PD-L1 inhibitors (durvalumab and atezolizumab). Of note, motolimod, a Toll-Like Receptor (TLR)-8 agonist, was assessed in two trials and monalizumab, a natural killer group 2 member A (NKG2A) inhibitor, was used in one. The data also found PD-L1 to be predictive in evaluating response to immunotherapy. The best outcomes to immunotherapy were observed in patients who had tumors expressing both HPV and PD-L1.

In another recent meta-analysis, data from 7 studies including 814 patients with R/M HNSCC were analyzed. This meta-analysis was restricted to patients treated with PD-1 or PD-L1 inhibitors as single agents. The objective response rate (ORR) of patients with HPV-positive HNSCC was significantly greater than that of their HPV-negative counterparts (OR = 1.77 ; 95% CI = 1.14–2.74; p = 0.01). The odds ratio (OR) was more impressive for the pooled anti-PD-L1 trials (OR = 2.66; 95% CI = 1.16–6.11; p = 0.02) in comparison to the pooled anti-PD-1 trials (OR = 1.51; 95% CI = 0.90–2.54; p = 0.12). Patients with HPV-positive HNSCC also were noted to have a lower risk of death in comparison to patients with HPV-negative HNSCC (HR = 0.77; 95% CI = 0.60–0.99; p = 0.04) [10].

Possible mechanisms underlying clinical benefit, including ORR and OS, in HPV-positive HNSCC treated with immunotherapy relates to the unique tumor microenvironment of HPV-positive tumors. Chiefly, the HPV-specific T-cells, type I-oriented CD4+ and CD8+ T-cells, dendritic cells, and dendritic-like macrophages, as well as the synthesis of E6 and E7 oncoproteins, induce the immune system to detect tumor cells [9]. Chakravarthy and colleagues have shown a difference in the tumor infiltrating lymphocyte levels between HPV-positive and HPV-negative OPC, reinforcing the hypothesis that a difference in immune response between the two groups may contribute to the observed survival benefit [11].

4. Novel Immune Therapies

Emerging immunotherapies in HPV-positive HNSCC include novel immune checkpoint inhibitor combinations, therapeutic vaccines, adoptive cell therapy, and gene editing approaches. Current clinical trials are summarized in Table 1.
Table 1. Clinical trials evaluating novel immunotherapies in HPV-positive HNSCC.
Treatment Indication Clinical Trial ID
Anti-PD-1/L1 Checkpoint Inhibitor Plus Standard of Care Combinations
Durvalumab (anti-PD-L1), cetuximab (anti-EGFR), and radiation therapy Locally advanced HNSCC NCT03051906
Ipilimumab (anti-CTLA4), nivolumab (anti-PD1), and radiation therapy HPV-positive advanced OPCs NCT03799445
Maintenance cemiplimab (anti-PD1) Locally advanced HNSCC NCT04831450
Nivolumab plus ipilimumab compared to the standard of care (EXTREME Regimen) First-line R/M HNSCC NCT02741570
Nivolumab/carboplatin/paclitaxel HPV-positive OPC NCT03342911
Nivolumab plus paclitaxel R/M HNSCC NCT04282109
Novel Immune Checkpoint Inhibitors
Atezolizumab (anti-PD-L1) plus tiragolumab (anti-TIGIT) R/M PD-L1 positive HNSCC NCT04665843
Nivolumab plus relatlimab (anti-LAG-3) R/M HNSCC progressed on prior immunotherapy NCT04326257
TSR-022 (anti-TIM-3) Advanced solid tumors NCT02817633
MBG453 (anti-TIM-3) ± PDR001 (anti-PD1) Advanced solid tumors NCT02608268
T Cell Receptor Costimulatory Agonists
Anti-OX40 Antibody (OX40 agonist) Head and neck cancers NCT02274155
PF-04518600 (OX40 agonist) alone/or in combination with PF-05082566 (4-1BB agonist) Advanced or metastatic carcinoma NCT02315066
PF-05082566 plus pembrolizumab (anti-PD1) Advanced solid tumors NCT02179918
Avelumab (anti-PD-L1)in combination with utomilumab (4-1BB agonist) locally advanced or metastatic solid tumors NCT02554812
Urelumab (4-1BB agonist) and cetuximab Advanced/metastatic head and neck cancers NCT02110082
CP-870,893 (CD40 agonist) Advanced solid tumors NCT02225002
Novel Antibodies and Fusion Proteins
Monalizumab (NK cell NKG2A inhibitor) plus cetuximab R/M HNSCC NCT04590963
CUE-101 (HPV-16 E7 T cell activator) HPV-positive R/M HNSCC NCT03978689
Eftilagimod alpha (soluble LAG3 protein) and pembrolizumab R/M HNSCC NCT03625323
PDS0101 (liposomal multipeptide vaccine targeting HPV-16 E6 and E7) + NHS-IL12 (Interleukin-12) + M7824 (bifunctional fusion protein targeting TGF-β and PD-L1) HPV-positive cancers NCT04287868
Vaccines
Utomilumab and ISA101b vaccine (synthetic long HPV16 E6/E7 peptides vaccine) HPV-positive OPCs NCT03258008
ISA101b and pembrolizumab plus cisplatin HPV-positive HNSCC NCT04369937
ADX 11-001 Vaccine (live attenuated Listeria monocytogenes bacterium) HPV-positive OPC NCT02002182
PRGN-2009 Vaccine (novel gorilla adenovirus vaccine) alone or in combination with M7824 (anti-PDL1/TGF-beta trap) HPV-positive cancers NCT04432597
DPX-E7 Vaccine (synthetic peptide-based vaccine of HPV16 E711-19) HPV-positive OPC, cervical and anal cancers NCT02865135
BNT113 Vaccine (RNA-lipoplex (RNA-LIP)-based mRNA vaccine encoding HPV-16 E6 and E7) plus pembrolizumab HPV-positive and PD-L1 expressing HNSCC NCT04534205
PDS0101 plus pembrolizumab HPV-positive HNSCC NCT04260126
Adoptive T-cell Transfer
RPTR-168 (Autologous IL-12/multi-targeted primed T cells) HPV-positive HNSCC, cervical and melanoma NCT04762225
E7 TCR T cells HPV-positive cancers NCT02858310
T Cell Receptor Immunotherapy Targeting HPV-16 E6 HPV-positive cancers NCT02280811
Abbreviations: CAR, chimeric antigen receptor; EXTREME indicates cetuximab/platinum/5-fluorouracil; HPV, human papillomavirus; HNSCC, head and neck squamous cell carcinoma; IL, interleukin; OPC, 1oropharyngeal cancer; PD-1, programmed cell death protein 1; R/M, recurrent/metastatic.

4.1. Checkpoint Inhibitor Combinations with Standard Therapies

The further elucidation of tumor immunology in the context of HPV-positive and HPV-negative HNSCC led to the hypothesis that anti-PD1 mAb may synergize with standard cytotoxic therapies, including chemotherapy and radiation, leveraging the immune response to immunogenic cell death. As observed in KEYNOTE-048, the efficacy of combining an anti-PD1 checkpoint inhibitor with cytotoxic chemotherapy displaced the then-standard of care, the EXTREME regimen. Platinum-5-fluorouracil is hypothesized increase tumor antigen presentation, immunogenic cell death, infiltration of CD8+ T-cells, and ultimately an antitumor immune response [12]. Moreover, tumor upregulation of PD-L1 expression is a consequence of chemotherapy, and is associated with worse clinical outcomes, making PD-1/PD-L1 blockade in addition to cytotoxic chemotherapy a rational therapeutic approach [13].
The combination of pembrolizumab plus the chimeric mouse IgG1 anti-epidermal growth factor receptor (EGFR) mAb, cetuximab, was investigated in a phase II trial in patients with platinum-resistant or -ineligible R/M HNSCC; at 6 months, the ORR was 45% (95% CI 28–62) with serious treatment-related adverse events noted in 5 of 33 (15%) participants [14]. Approximately 33% of patients enrolled in this study had HPV-positive OPC with no statistically significant disparity noted in relation to HPV status and OS or progression-free survival (PFS), although the study was not powered to detect this association.

4.2. Novel Immune Checkpoint Inhibitors

Beyond PD-1, T-cell exhaustion markers including CTLA-4, T-cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) have been identified as candidate targets for immune checkpoint blockade [15]. Like PD-1, these targets are upregulated in HPV-positive HNSCC compared to HPV-negative samples, likely due to the stimulus of chronic infection. Gameiro and colleagues showed a survival benefit in patients with HPV-positive HNSCC with higher expression of these exhaustion markers while no survival advantage was noted in HPV-negative HNSCC with similar elevated expression of these markers [15].
Early immune checkpoint inhibitor combinations have included anti-PD-1/L1 inhibitors with mAb targeting CTLA-4. The anti-PD-L1 mAb durvalumab was compared to investigator’s choice standard chemotherapy in the randomized phase III EAGLE trial including 736 patients with R/M HNSCC and did not improve survival as a single agent or in combination with the CTLA-4 inhibitor, tremelimumab. Although the study was not intended to evaluate OS among immunotherapies, the addition of tremelimumab did not enhance the activity of durvalumab. Moreover, HPV status did not appear to impact OS with either regimen on subgroup analysis [16].
CheckMate 651 is a phase III, randomized, multicenter trial studying nivolumab in combination with ipilimumab, a CTLA-4 inhibitor, versus EXTREME as first-line therapy in R/M HNSCC (NCT02741570). The trial has completed accrual; a recent press release from Bristol Myers Squibb expressed that the study did not reach its primary endpoints including OS and PFS although a positive trend was noted in OS in a subgroup of patients whose tumors expressed PD-L1 with a CPS ≥ 20 [17].
Novel mAb are currently being investigated in combination with PD-1/L1 inhibitors. Tiragolumab, a human anti-TIGIT mAb, is being compared to placebo in combination with atezolizumab as first-line treatment for R/M, PD-L1 positive HNSCC (SKYSCRAPER-09) (NCT04665843). Relatlimab, an anti-LAG-3 mAb, is being studied in combination with nivolumab for the treatment of R/M HNSCC (NCT04326257).

4.3. Costimulatory T Cell Receptor Agonists

Costimulatory receptors constitute a repertoire of second signaling molecules that propagate T cell receptor signaling, and include CD137 (4-1BB), OX40, and CD40. Sparse data exist with regards to the emerging role of costimulatory T cell receptor agonists in the context of HPV status in the treatment of HNSCC. However, in mouse models, CD137 agonists are synergistic with cisplatin and radiation therapy in inhibiting tumor growth in HPV-positive HNSCC [18]. As such, several costimulatory agonists are currently under investigation to establish their safety and therapeutic utility in HNSCC.
Utomilumab (PF-05082566), also a human mAb agonist of CD137, was also studied in combination with a humanized mAb targeting CCR4, mogamulizumab, in a phase Ib study of patients with advanced solid tumors. The study demonstrated a favorable safety profile and included 11 patients with HNSCC of which 7 had disease refractory to anti-PD-1/PD-L1 therapy [19]. Utomilumab was also evaluated in combination with pembrolizumab in patients with solid tumors including HNSCC in KEYNOTE-036, a phase 1b trial that has been completed (NCT02179918). Another phase Ib/II multicenter trial, JAVELIN Medley, is evaluating the safety of avelumab in combination with utomilumab (NCT02554812).

4.4. Novel Antibodies and Fusion Protein Constructs

Reinforcing the innate immune system to mediate anti-tumor activity by augmenting NK cell antibody-dependent cell-mediated cytotoxicity is a strategy that is increasingly under consideration [20]. Monalizumab, a mAb targeting NKG2A, is currently under investigation in HNSCC [20][21]. The NKG2A heterodimeric receptor is a prominent NK inhibitory receptor. Monalizumab prevents binding of the HLA E ligand, often overexpressed in HNSCC, to NKG2A resulting in increased cytotoxic activity [20]. The relevance of HPV status for the activity of monalizumab is currently unknown. In a Phase 1b/2 trial presented at the European Society for Medical Oncology (ESMO) 2019 congress, the combination of monalizumab 10 mg/kg every 2 weeks and cetuximab showed an acceptable safety profile and a response rate of 27.5% (36% and 17% in anti-PD1 immunotherapy-naïve, n = 22, and immunotherapy-pretreated patients, n = 18, respectively) in 40 patients who had progressed after platinum-based chemotherapy and had received ≤2 prior lines of therapy [22]. The Phase II expansion cohort evaluating monalizumab and cetuximab in immunotherapy-pretreated patients affirmed an ORR of 20% across 40 patients enrolled [23]. A phase III clinical trial of monalizumab plus cetuximab compared to placebo plus cetuximab is currently underway in R/M HPV-positive and negative HNSCC following progression on standard platinum and anti-PD1 immunotherapy (NCT04590963).

4.5. Vaccines

HPV-positive HNSCC contains promising non-self antigens, including E6 and E7, which are specific to HPV-infected cells and not healthy cells. The E6 and E7 oncoproteins are requisite for maintenance of the aberrant phenotype, and as foreign antigens will be recognized by the human immune system [24]. Enhancing anti-HPV T cell activity is the goal of several HPV-targeted therapeutic vaccines currently under investigation in HPV-positive HNSCC.
MEDI0457 is a DNA immunotherapeutic vaccine of HPV-16 and HPV-18 E6/E7 expressing plasmids coupled with IL-12 expressing plasmids [25]. In a phase Ib/II pilot study consisting of 21 patients with locally advanced, p16-positive HNSCC, MEDI0457 was dosed perioperatively or following completion of concurrent chemoradiotherapy. An increase in the tumor-infiltrating CD8+ T-cell: regulatory T-cell ratio was noted following MEDI0457 administration as was the presence of HPV-16-specific T-cells [25]. MEDI0457 was studied in combination with anti-PDL1 durvalumab in a phase Ib/IIa trial in patients with HPV-positive R/M HNSCC who had progressed on at least one prior regimen [26]. At interim analysis, ORR was 22.2% with 3 complete responses (CR) and 3 partial responses (PR). Treatment-related adverse events (AE) were noted in 77.1% of patients, predominantly grade 1–2. Fatigue (37.1%) and injection site pain (34.3%) were the most common AEs. No patients had a grade 4/5 treatment-related AE. An increase in both tumoral CD8+ T cells as well as peripheral HPV-specific T cells was shown.

4.6. Adoptive T Cell Transfer

In adoptive cell-based therapies, dendritic cells, B cells and/or T cells are isolated from a patient, transduced ex vivo in order to express or target a specific antigen, then infused back to the same patient [27][28]. CAR-T cells are engineered T cells that express a single-chain fragment variable, which can in turn recognize a tumor-specific antigen. CD3-related components and costimulatory domains are also often included. MHC class I molecules process and present epitopes from E6 and E7 and may be optimal targets for T cell receptor (TCR) gene engineered T cells [28]. An E6-specific anti-PD1 engineered TCR T cell is under evaluation in a phase I study for patients with HPV-positive HNSCC or cervical cancer (NCT03578406). An E7 TCR-engineered T cell is being investigated in a phase I/II clinical trial in HPV16-associated cancers including OPCs (NCT02858310).

This entry is adapted from the peer-reviewed paper 10.3390/cancers13235889

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