Neoadjuvant Immunotherapy Strategies in HPV-Related Head-and-Neck Cancer

Abstract

Purpose of review:

Herein, we review current evidence and future directions of neoadjuvant immunotherapy in HPV-related head and neck squamous cell carcinoma (HNSCC) by describing published data and ongoing clinical trials.

Recent findings:

Although HNSCCs have shown response to immune checkpoint inhibitors in recurrent/metastatic disease, a limited number of patients benefit from this treatment. There is an expanding interest in clarifying the clinical benefit of immunotherapy in earlier stage disease setting including at initial presentation. Neoadjuvant immunotherapy for HPV-related HNSCCs represents a rational approach, as these cancers bear strong viral antigens.

Summary:

The majority of patients with HPV-related HNSCC have good prognosis and treatment de-intensification strategies are under evaluation to decrease toxicity and maintain efficacy. On the other hand, a subset of patients with HPV-related HNSCC have a poorer prognosis and additional treatment options are need to improve outcome. Multiple clinical trials are ongoing to evaluate whether neoadjuvant immunotherapy will achieve these goals.

Introduction

Head and neck squamous cell carcinoma (HNSCC) accounts for 4% of all cancers, with 66,000 newly diagnosed patients every year in the United States (1). HNSCC occurs in various subsites including the oral cavity, pharynx and larynx, but overall, HNSCC can be divided into two subsets based on etiology. Conventional HNSCC develops from environmental exposures such as smoking and alcohol consumption, whereas infection by the human papillomavirus (HPV-related HNSCC) results in the second form. These two subsets have distinct genetic alterations, treatment response and survival. HPV-related HNSCC are highly sensitive to chemotherapy and radiotherapy, with a three-year survival of over 80% compared to below 60% in advanced HPV-negative HNSCC (2). Even though HPV-related HNSCC has a good prognosis, standard of care treatment has remained the same as for HPV-unrelated HNSCC. However, radical tumor resection can cause functional decline in mastication, speech or swallowing, and patients treated with (chemo)radiation therapy also face severe late toxicities such as dysphagia, odynophagia and dry mouth. Thus, the major focus in HPV-related HNSCC has been on how to de-escalate treatment without altering the survival while decreasing toxicity. Although there are several ongoing and completed trials focused on de-escalation strategies in HPV-related HNSCC, consensus recommendations have not been reached. (3).

As in other cancer types, immune checkpoint inhibitors (CPIs) have been approved and show improved survival in recurrent or metastatic HNSCC compared to standard of care (4) (5). These approvals are based on the effectiveness of CPIs in HNSCC and have encouraged investigation of CPIs in earlier stage disease. Whereas the rationale for treatment intensification by adding CPIs to standard of care treatments in poor prognosis HPV-unrelated HNSCC is clear, such an approach does not clearly align with current de-intensification strategies in HPV-related HNSCC. By contrast, if CPIs could safely lead to de-intensification of definitive therapy (such as decreasing the radiation dose, excluding chemotherapy or reducing the surgical morbidity), immune therapy would be an attractive treatment of choice. From this point of view, clinical trials using immunotherapy in an earlier stage setting are being carried out, including in the neoadjuvant setting.

Although HPV-related HNSCC have a generally favorable prognosis, an additional consideration is that a subset of these patients have less favorable disease because of a history of smoking or advanced primary site and/or nodal disease burden (2) (6). Thus, for these patients with “high risk” HPV-related HNSCC, adding immunotherapy to conventional treatment has the potential to improve survival, similar to treatment intensification approaches in HPV-unrelated HNSCC.

In this review, we discuss the potential advantages of using immune CPIs in the neoadjuvant setting, and review completed trials including those with HPV-related HNSCC, and the ongoing clinical trials and future direction of this field.

Current understanding of neoadjuvant immunotherapies in HNSCC

Several groups including ours have explored the impact of delivering CPIs in the neoadjuvant setting (7) (8) (9) (10) (11) (12) (13). Most of these studies have focused on the HPV-unrelated HNSCC setting as this group of patients has the poorest outcomes and could benefit from treatment intensification. Neoadjuvant therapy has several hypothetical advantages (14) including (1) the treatment-naïve patient setting where the immune system has not been adversely impacted by radiation or chemotherapy, (2) ability to prime the immune system with tumor still in place, and (3) the potential for limited surgery or adjuvant treatment (15). Studies to date have focused on pathologic tumor responses (pTR) in the neoadjuvant setting as a surrogate marker for response. This finding in the surgical resection specimens including histiocytic reaction and tumor cell necrosis is consistent with priming or activation of the immune system. Complete pathologic responses (CRs) to neoadjuvant chemotherapy in oral cancers have been shown to be associated with better clinical outcomes (16, 17). However, neoadjuvant CPI HNSCC studies to date show that CRs are much less common in HNSCC compared to lung or melanoma neoadjuvant studies (18-20). Partial pathologic responses (10-90% pathologic treatment effect) are observed in up to 75% of HNSCC patients undergoing neoadjuvant therapy but it is unclear whether this finding will translate to be a surrogate for better patient outcomes. Importantly, preliminary data presented recently at ASCO 2021, showed that patients with partial/major pathologic responses have improved clinical outcomes compared to those without a pathologic response (21).

Neoadjuvant immunotherapy clinical trials in HPV-related HNSCC

To date, there have been five clinical trials published that included HPV-related HNSCC patients treated with neoadjuvant immunotherapy—four included CPIs, and one was with a HPV-DNA vaccine. The Checkpoint Inhibitors Assessment in Oropharynx Cancer (CIAO) trial enrolled 29 resectable oropharyngeal carcinoma patients including 24 (83%) who were p16 positive (HPV-related) (10). Patients were randomly assigned to durvalumab (D) or durvalumab and tremelimumab (D/T) followed by surgery. The primary endpoint was based on an assessment of intra-tumoral CD8+ T cell infiltration between baseline and post-treatment samples with the goal of showing an increase (0.5-fold) between D and D/T groups. There were three secondary endpoints including safety with treatment-related adverse events (TRAE), efficacy (by RECIST1.1) and major pathological response (mPR, <10% viable tumor in surgical specimen). The primary endpoint was not met, as the D/T group did not have an increased CD8+ T cell infiltration compared to D alone. Some patients in both groups had dramatic increases in CD8+ infiltrates. Overall, 12 (43%) patients had partial tumor response (≥30% tumor reduction by RECIST1.1), 11 of which were HPV-related, showing that 46% of the HPV-related HNSCC patients showed significant response to neoadjuvant immunotherapy. Of the twelve patients with partial tumor response, six received D, and six received D/T. Pathologically, primary site and lymph node mPR was confirmed in 2 of 25 and 8 of 19 patients, respectively. There was no data of HPV status with pathological response. 3/15(20%) in D, and 1/14(7%) in the D/T had grade 3 TRAEs (transaminitis, lipase increase, or diarrhea). Although two patients received only one dose of CPI due to adverse events, all patients underwent planned surgery. This trial was the first to show safety and efficacy of anti-PD1 blockade alone or with anti-CTLA4 in the neoadjuvant setting with HPV-related HNSCC.

CheckMate 358 was a multi-center Phase I/II trial that tested the impact of nivolumab in the neoadjuvant setting for virus-associated malignancies including HPV-related HNSCC (11). Importantly, this trial tested two cohorts of HNSCC patients: 26 HPV-related and 26 HPV-unrelated stage III/IV (AJCC 7th edition) HNSCC patients allowing for a comparison of pathologic responses between these groups. Patients received two doses of neoadjuvant nivolumab (240 mg) 4 and 2 weeks prior to surgery. The primary endpoint was safety of this regimen, which included TRAEs and surgical delays that were defined as delays of greater than 4 weeks from scheduled surgery date as a result of TRAE(s). Exploratory endpoints were pathologic response based on residual viable tumor (RVT); (complete response (pCR)= no RVT, major pathologic response (MPR) = ≤10% RVT, pathologic partial response (pPR) = >10% to 50% RVT), radiographic response based on RECIST v1.1, recurrence-free survival (RFS) and overall survival (OS). This study reported that 5 (19.2%) and 3 (11.5%) of the patients experienced grade 3/4 TRAEs in HPV-related and -unrelated patients, respectively. There were no TRAE-related surgical delays in either group, showing the feasibility of this protocol. In the HPV-related group, 14 (56%) patients had any decrease in tumor size, and 3 (12%) scaled down over 30%. Pathologically, none had pCR, one (5.9%) had MPR and 3 (17.6%) had pPR, giving an MPR/pPR rate of 23.5%. RFS was 88.0% and OS was 100% with a median follow-up of 33.1 and 34.3 months, respectively. In the HPV-unrelated group, 10 (41.7%) patients showed any radiographic tumor shrinkage, and 2 (8.3%) had reductions over 30%. Pathologically, none had pCR nor MPR and only 1 (5.9%) had pPR. RFS was 54.2% and OS was 49.8% with a median follow-up of 36.3 and 37.1 months respectively. Comparing the pathological response, HPV-related patients responded better than HPV-unrelated patients, with an MPR/pPR rate of 23.5% vs 5.9%. Taking into consideration that 86.4% of the patients in the HPV-related group were stage IV (AJCC 7th edition) and that majority of the patients were former or current smokers, this trial highlights the potential of neoadjuvant immunotherapy in relatively high-risk HPV-related HNSCC.

A trial to de-escalate radiation therapy intensity by using neoadjuvant immunoradiotherapy has also been conducted. Leidner reported a phase Ib clinical trial (NCT03247712) including 16 HPV-unrelated HNSCC patients to study the effect of immunotherapy + SBRT (stereotactic body radiation therapy) before surgery (12). Operable HPV-related OPC patients were enrolled into three groups: Group 1 received neoadjuvant nivolumab and SBRT (40Gy/ 5 fractions) 1 week later with additional nivolumab (weeks 2, 4) followed by surgery in week 6; Group 2 was the same as Group 1 except the SBRT dosing was reduced to 24Gy/ 3 fractions and Group 3 received SBRT alone at 24Gy/ 3 fractions followed by surgery. A fourth group of HPV-unrelated patients was also included where patients received the same treatment as Group 2. All groups received adjuvant nivolumab for 3 months post-surgery. Safety was assessed by surgical delay due to neoadjuvant treatment, and efficacy was assessed by pathological response based on viable tumor cells (no viable tumor cells; complete pathologic response (cPR), fewer than 10% viable tumor cells; mPR) and clinical to pathological downstaging (using RECIST1.1) based on AJCC 8th edition after neoadjuvant treatment. There was one Grade 3 immune related adverse event (mucositis) in the three HPV-related cohorts, but there was no dose-limiting toxicities and no delay of surgery, indicating the safety of this protocol. For groups 1 and 2 the pCR rate was 100% (5/5 patients) and 80% (4/5 patients), respectively. Clinical to pathological downstaging was confirmed in all of these patients. In the neoadjuvant SBRT alone group, pCR rate was 50% (3/6 patients) and downstaging was confirmed in 5(83%) patients. Due to small numbers and the absence of an immunotherapy alone group, we cannot conclude the independent effect of neoadjuvant immunotherapy in this trial. The 50% to 80% difference with addition of nivolumab will need to be examined in larger cohorts. However, considering that most of the patients were non-smokers or <10 packs years, and that T stage was ≤T3, this trial indicates the potential of neoadjuvant radioimmunotherapy to de-intensify treatment in operable low-risk HPV-related patients. On the other hand, whether this approach constitutes treatment intensification with radiation, immunotherapy and surgery in this relatively low-risk group is also a concern. Long-term follow-up data are awaited to show survival and tolerability benefit. Finally, Group 4 data showed that pCR was 20% (n=1) and mPR was 60% (n=3). Similar to the HPV-related setting, these data are limited due to sample size.

A fourth clinical trial (NCT03238365) tested nivolumab with or without tadalafil before surgery for previously untreated resectable HNSCC (13). In this trial, 44 patients were enrolled and 22 were p16-positive and 24 had oropharyngeal primary tumors. We discuss details of this trial here but further data on responses in HPV-related patients were not available in the publication. Patients were randomized into two groups with a nivolumab monotherapy group and a nivolumab + tadalafil group. Nivolumab was administered twice at biweekly intervals and tadalafil was given orally every day for 4 weeks. After treatment, a CT was obtained and surgery was carried out on day 31. Co-primary endpoints were radiographic volumetric response (RVR) and pathologic treatment effect (PTE). PTE was calculated as the percentage of the tumor showing response based on criteria reported by Uppaluri et al. (7). Interestingly, based on the pathologic findings, this trial also compared the impact of neoadjuvant treatment between tumor and metastatic lymph nodes. Discordance was defined as a difference of more than 20% in PTE. As a result, response did differ between tumor and lymph nodes in 50% of the patients with lymph nodes showing higher PTE. Overall, 17(40%) were radiographic responders (over 10% reduction in volume). Interestingly, for pathologic response, 3(12%) showed complete PTE and 17(40%) showed moderate PTE (over 20%), indicating that half the patients showed pathologic response. Again, specific data on HPV status and PTE was not provided so conclusions related to this cannot be made. This trial did provide intriguing data on discordant primary versus metastatic lymph node responses and the efficacy of neoadjuvant immunotherapy.

Finally, Aggarwal et al. reported on a phase Ib/II trial using MEDI0457, a combination of DNA plasmids which encode E6/E7 genes of HPV16/18 and human IL-12 as neoadjuvant/adjuvant therapy (22). Patients were assigned to receive either MEDI0457 1-2 doses before surgery (group 1), followed by adjuvant administration of up to 4 doses or MEDI0457 as an adjuvant after chemoradiotherapy (group 2). Baseline biopsy and surgical samples were assessed for group 1, and peripheral blood samples were obtained at baseline and at multiple time-points during and after treatment for all the patients. The primary endpoint was safety, and secondary endpoints were immunologic responses using tissue and peripheral blood samples. Twenty-two patients were enrolled with 6 in group 1 and 16 in group 2. MEDI0457 was safe with no grade 3/4 adverse events. Of the 6 patients in group 1, 5 were eligible for comparing matched baseline and surgery specimens. Two of five patients had increased CD8+ T cell infiltration and 3/5 patients had decreased FoxP3+ T cell infiltration. Together, 4/5 patients showed an increase in CD8/FoxP3 ratio, indicating that neoadjuvant MEDI0457 can alter the tumor microenvironment into a favorable state. MEDI0457 induced peripheral immunological response with increased E6/7 antibody response and interferon-gamma production. All patients showed response to at least 1 antigen after MEDI0457 injection, and surprisingly, the reactivity was detected 3 months after the last injection, indicating the establishment of long-lasting antibody response by vaccination.

These clinical trials collectively underscore the potential of neoadjuvant immunotherapy in HPV-related HNSCC. As there are only a limited number of publications with heterogeneous populations including HPV status, a more focused trial is needed to evaluate the early signal that efficacy is better compared to HPV-unrelated patients. Furthermore, trials with standard of care versus neoadjuvant treated patients are needed to show actual prolonged survival for high-risk HPV-related HNSCC or deintensification possibilities with less toxicities for low-risk HPV-related patients.

Ongoing neoadjuvant immunotherapy trials

Multiple immunotherapy trials for HPV-related HNSCC are ongoing. Excluding the clinical trials enrolling both HPV-related and unrelated patients, there are 16 trials focusing on neoadjuvant immunotherapy in HPV-related HNSCC (Table 1). Note, here we use the term neoadjuvant to also include primary radiation-based approaches where immunotherapies are given prior to definitive radiation treatment. These clinical trials can be classified as 1) pre-surgical, 2) immunoradiotherapy, 3) de-escalation, 4) high-risk HPV, or 5) vaccine-related trials.

Table 1.

Ongoing neoadjuvant immunotherapy trials

NCT number	Phase	Protocol	Drugs	Primary endpoint	Principal Institute
NCT02827838	II	Neoadjuvant	Duravalumab	Systemic immune response	Wake Forest University Health Science, USA
NCT03618134	Ib/II	Neoadjuvant	Durvalumab, Tremelimumab	incidence of adverse events (CTCAE), 2-year PFS	UCLA, USA
NCT03799445	II	Neoadjuvant/concurrent	Nivolumab, Ipilimumab	Dose limiting toxicity (DLT), Complete response rate, 2-year PFS	MD Anderson Cancer Center, USA
NCT03410615	II	Neoadjuvant/concurrent/adjuvant	Durvalumab	3-year event free survival	Princess Margaret Cancer Centre, Canada
NCT03952585 *	II/III	Neoadjuvant/concurrent	Nivolumab	PFS (up to 6 years), QOL	NCI, USA
NCT04988074 *	II	Neoadjuvant	Cemiplimab	2-year PFS, QOL and swallowing function (MDADI, SSQ)	Johns Hopkins University, USA
NCT04867330 *	II	Neoadjuvant	Toripalimab, Docetaxel, Cisplatin	2-year PFS	Fudan University, China
NCT03107182 *	II	Neoadjuvant	Nivolumab, Carboplatin, Nab-paclitaxel	deep response rate (DRR) defined as ≥50% tumor shrinkage by RECIST	University of Chicago, USA
NCT03838263	II	Neoadjuvant	Nivolumab	feasibility	Hopital Europeen Georges Pompidou, France
NCT04116047	III	Neoadjuvant/adjuvant	Duravalumab,	overall survival and event-free survival (f/u to 8 years)	University of Birmingham, UK
NCT03829722	II	Neoadjuvant/concurrent/adjuvant	Nivolumab, Carboplatin, Paclitaxel	2-year PFS	University of Michigan, USA
NCT04852328 **	II	Neoadjuvant	CUE-101	treatment-related adverse events, Change of HPV specific CD8+ T cells in peripheral blood and tumor	Washington University, USA
NCT04630353 **	I	Neoadjuvant	HB201	Measurement of antigen specific CD8+ T cells	Medical College of Wisconsin, USA
NCT02002182 **	II	Neoadjuvant	ADXS11-001 (ADXS-HPV)	HPV-Specific T cell response rate, Grade 3/4 toxicity	Icahn School of Medicine at Mount Sinai and Baylor College of Medicine, USA
NCT04432597 **	I/II	Neoadjuvant	HPV Vaccine PRGN-2009 M7824(Anti-PDL1/TGF-Beta Trap)	Safety and recommended phase II dose of PRGN-2009, change in CD3+ tumor infiltrating T cells	NCI, USA
NCT04369937 **	II	Neoadjuvant, concurrent	ISA101b, Pembrolizumab	2-year PFS	UPMC Hillman Cancer Center, USA

^*de-escalation trials using immunotherapy.

^**vaccine related trials

1). Pre-surgical immunotherapy trials

Similar to the previously described CHECKMATE 358 (11) and NCT03247712 (12), there are two ongoing pre-surgical immunotherapy trials (NCT02827838 and NCT03618134). NCT02827838 is a phase II trial where operable HNSCC patients including HPV-positive ones will receive durvalumab for up to 2 courses before undergoing surgery. Primary endpoints are evaluation of immune response in blood and tissue. NCT03618134 is a phase Ib/II trial studying the effect of stereotactic body radiation therapy (SBRT) + immunotherapy prior to surgical resection. Patients will receive SBRT and durvalumab (Cohort 1) or SBRT, durvalumab and tremelimumab as neoadjuvant therapy prior to TORS/neck dissection. Primary endpoints are safety and PFS. Considering the results from NCT03247712(12), positive results are expected including insights on inclusion of CTLA4 blockade.

2). Neoadjuvant/concurrent Immuno-radiotherapy trials

NCT03799445, NCT03410615, and NCT03952585 (HN-005) are the three trials that examine the efficacy of neoadjuvant immunotherapy + immunoradiotherapy. NCT03799445 is a phase II trial treating patients with neoadjuvant/concurrent nivolumab + ipilimumab for one cycle (3 doses nivolumab and 1 dose ipilimumab). A second cycle of nivolumab/ipilimumab is given starting at 6 weeks after first dose of nivolumab combined with initiation of IMRT. This trial is unique in that it combines anti-PD1 and anti-CTLA4 antibodies with radiation therapy in a sequential fashion and may circumvent some of the concerns of combining CPIs with radiotherapy. Primary endpoints are dose-limiting toxicities, complete response rate and PFS. Although the anti-PD1 and anti-CTLA4 antibody combination has failed so far in recurrent/metastatic HNSCC (23), the potential sequential use of CPI + radiation therapy makes this protocol interesting. NCT03410615 is a phase II trial comparing standard cisplatin and radiation (70 Gy) with neoadjuvant/concurrent immunoradiotherapy. In the experimental arm, durvalumab will be administered 1 week prior to radiation and continued 4 weeks after initial dose, concurrent with radiotherapy, and will be maintained every 4 weeks after radiotherapy. Primary endpoint is 3-year event free survival. This trial was initially planned to also test the durvalumab and tremelimumab combination but this arm has been closed. In the Phase III part of NCT03952585 (HN-005) standard of care cisplatin + IMRT/IGRT (70 Gy) treatment is compared with cisplatin + reduced dose IMRT/IGRT (60 Gy) or neoadjuvant/concurrent nivolumab with reduced dose IMRT/IGRT. Over 700 patients are planned to be enrolled and PFS and QOL will be assessed as primary endpoints. This trial has the potential to directly alter first-line treatment strategies in HPV-related HNSCC and may shift standard treatment from chemoradiotherapy (CRT) to de-intensified CRT or neoadjuvant/adjuvant immunoradiotherapy.

3). Neoadjuvant immunotherapy for de-escalation strategies

In line with the goal to de-escalate treatment intensity in HPV-related HNSCC, clinical trials to assess whether neoadjuvant immunotherapy can de-intensify treatment are being carried out (NCT04988074, NCT04867330, NCT03107182). NCT04988074, also known as the MINIMA trial, assigns patients to de-escalated treatment or standard treatment based on the progress after neoadjuvant immunotherapy of cemiplimab with or without carboplatin/paclitaxel. Patients assigned to de-escalated treatment will receive surgery (TORS) or low-dose radiation therapy (42Gy), and those assigned to non-de-escalated therapy will receive surgery + post-operative radiation therapy or CRT (60Gy). This trial will assess the QOL and swallowing function as primary endpoints to show the efficacy of de-escalation treatment. Similarly, NCT04867330 gives two cycles of toripalimab + docetaxel + cisplatin prior to cisplatin CRT. If the response to induction therapy is over 50%, patients receive de-intensified treatment, which is radiotherapy (60Gy) without cisplatin, and if the response is not significant (under 50%), patients receive standard treatment of cisplatin + radiation therapy (70Gy). NCT03107182, also known as the OPTIMA-II trial, administered three cycles of neoadjuvant immune-chemotherapy consisted of nivolumab + nab-paclitaxel + carboplatin. Following induction treatment, patients were assessed based on response and risk status and assigned to 3 different treatment intensity groups; Group A: 50Gy radiation therapy or TORS + selective neck dissection with or without adjuvant radiation therapy, Group B: 50Gy radiation therapy + cisplatin or 45Gy radiation therapy + TFHX (paclitaxel, 5-FU, hydroxyurea, dexamethasone), Group C: 70Gy radiation therapy + cisplatin or 75Gy radiation therapy + TFHX. Early results of this trial have been presented by Rosenburg et al. at the ASCO 2021 meeting (24). Seventy-three HPV-related OPC patients with N2/3 metastatic cervical lymph nodes or locally advanced T3/4 primary tumors were enrolled. Surprisingly, 70.8% of the patients showed deep response which was defined as over 50% decrease in tumor size (RECIST 1.1). De-escalated treatment (Group A and B) was assigned to 84.9% of the patients. The 2-year OS for Group A, B, and C were 96.0%, 91.9%, and 100.0%, respectively. Grade 4 toxicity due to treatment was similar between the three groups, but the number of patients requiring gastrostomy tubes differed significantly, with Group A 7.1%, Group B 44.1%, and Group C 75.0%. These results show the short-term efficacy of adding induction immuno-chemotherapy to de-escalate treatment intensity without decreasing survival but decreasing treatment-related acute toxicities.

4). Neoadjuvant immunotherapy for high-risk, HPV-related patients

Trials to assess whether addition of neoadjuvant immunotherapy to CRT can improve survival in high-risk, HPV-related HNSCC patients are also being conducted (NCT03838263, NCT04116047, NCT03829722). NCT03838263 compares standard cisplatin CRT with neoadjuvant nivolumab prior to standard cisplatin CRT in high-risk, HPV-positive OPC patients (T4 (any N), N2/N3 (any T) or T1-3N1/T3N0 with smoking of over 10 pack- year). The primary endpoint in this trial is to assess the feasibility of adding neoadjuvant immunotherapy to standard dose chemotherapy. NCT04116047, also called the CompARE trial, is a phase III trial comparing standard CRT (triweekly cisplatin + 70Gy) with de-escalated CRT (cisplatinon week 1 and 5 + 64Gy) or neoadjuvant durvalumab once prior to standard CRT followed by adjuvant durvalumab. Patients with T4 or N3 or T1-T4 with N2b-N3 nodes and smoking history of over 10 pack years will be enrolled. Primary endpoints are overall survival and event-free survival. The results from this trial have the potential to change the first-line treatment of high-risk, HPV-related HNSCC. NCT03829722 is a phase II trial planned to give 4 doses of nivolumab before and concurrent with RT followed by 4 doses of adjuvant nivolumab. Weekly carboplatin/paclitaxel will also be administered during RT. High risk, HPV-positive OPC was defined as stage III (cT4 or cN3) or those with "matted lymph nodes". Although there are some differences in types of enrolled patients, results of these trials are awaited to impact the prognosis of high-risk patients by using immunotherapy strategies.

5). Neoadjuvant vaccine related trials

HPV-related malignancies provide a unique opportunity to target defined viral antigens in the tumor. Clinical trials to assess whether neoadjuvant stimulation of the immune system by HPV-related peptides is effective are being studied (NCT04852328, NCT04630353, NCT02002182, NCT04432597, NCT04369937). NCT04852328 uses CUE-101, which is a single chain HLA with modified IL-2 loaded with an E7 derived peptide that has been reported to show selective binding to and activation of HPV16 E7 specific CD8 T cells (25). Patients receive CUE-101 before standard of care, and the safety of the drug and change in HPV-specific T cells will be analyzed. NCT04630353 is a phase I study and will use HB201 an HPV16 E6/E7 fusion protein. HB201 will be delivered intravenously or intratumorally before surgery, and antigen-specific CD8+ T cells in blood and tissues will be assessed. NCT02002182 is the only neoadjuvant vaccine-related trial completed to date. ADXS11-001 is a modified lysteriolysin O molecule combined with E7 oncoprotein and has been reported to be able to stimulate both innate immunity and trigger E7-specific immune response (26). Patients were vaccinated twice with ADXS11-001 and then received trans-oral surgery. Primary outcomes were HPV-specific T cell response and the number of participants with any Grade 3/4 toxicities. There is no published data yet, but according to the data posted on ClinicalTrials.gov, serious adverse events were found in 55.6% of the patients. The results concerning T cell response are awaited in order to know the immunologic efficacy of this drug. NCT04432597 and NCT04369937 study the combination of vaccine and CPI, which is mechanistically an attractive strategy. NCT04369937 assesses the efficacy of vaccine (ISA101b) + pembrolizumab in intermediate-risk, HPV-related HNSCC patients. ISA101b is a mixture of 9 synthetic long peptides derived from oncoprotein E6 and 3 from E7. Enrolled patients will receive ISA101b followed by pembrolizumab + cisplatin CRT (pembrolizumab 200mg triweekly, cisplatin 100mg triweekly, IMRT 70Gy). The primary outcome will be 2-year progression free survival, to see whether addition of this combination therapy can improve prognosis. NCT04432597 uses an HPV vaccine (PRGN-2009) alone or in combination with M7824, which is an anti-PDL1/TGF-β Trap, in patients with HPV-associated cancers including HPV-related HNSCC. PRGN-2009 is a gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of E6 and E7 of HPV 16/18(27). This is a phase I/II trial, and after determining the RP2D, PRGN-2009 will be given with or without M7824 for neoadjuvant therapy to assess for a change in CD3+ tumor infiltrating T cells.

Conclusion

Data from recurrent/metastatic setting show the potential of immunotherapy in early stage HPV-related HNSCC. Although there are a limited number of published trials, HPV-related HNSCC patients do show responses to neoadjuvant immunotherapy. Given the fact that HPV-related HNSCCs already have a good prognosis using standard therapy, results from the ongoing trials to reveal whether addition of neoadjuvant immunotherapy can safely de-intensify definite treatment strategies are awaited. For the subset of high-risk, HPV-related HNSCC patients, addition of neoadjuvant immunotherapy may improve outcomes, and results from phase III trials may change first-line treatment. Vaccine-related therapies also represent an exciting approach taking advantage of the known viral specific antigens in this disease. In conclusion, HPV-related HNSCC represents an ideal target for neoadjuvant immunotherapy, and results from the multiple ongoing trials are anticipated.