New treatment strategies for HPV-positive head and neck cancer

Eur Arch Otorhinolaryngol (2014) 271:1861–1867 DOI 10.1007/s00405-013-2603-0

REVIEW ARTICLE

New treatment strategies for HPV-positive head and neck cancer B. Kofler • S. Laban • C. J. Busch B. Lo¨rincz • R. Knecht

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Received: 7 April 2013 / Accepted: 12 June 2013 / Published online: 10 August 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Epidemiological studies show an increasing incidence of human papilloma virus-associated oropharyngeal cancer. HPV-positive head and neck squamous cell carcinoma (HNSCC) is recognized as a special subgroup of HNSCC. Because HPV-positive patients are often younger and have an outstanding prognosis, long-term toxicities of therapy have become an important issue. Current clinical trials focus on a reduction of treatment-related toxicity and the development of HPV-specific therapies. New treatment strategies include a dose reduction of radiotherapy, the use of cetuximab instead of cisplatin for chemoradiation and transoral robotic surgery (TORS). Increasing comprehension of the molecular background of HPV-associated HNSCC has also lead to more specific treatment attempts including immunotherapeutic strategies. Whereas recently published data shed light on immune mechanisms resulting in a tolerogenic niche for HPV and HPV-associated HNSCC, other studies focus on specific vaccination of HPV-positive HNSCC. This study will summarize current therapy approaches and illustrate ongoing clinical trials in the field of HPV-positive HNSCC. Keywords HPV-positive HNSCC Reduction of toxicity Immunological therapy TORS Vaccination PD-1:PD-L1 pathway

B. Kofler and S. Laban have shared first authorship. B. Kofler (&) S. Laban C. J. Busch B. Lo¨rincz R. Knecht Department of Otorhinolaryngology and Head and Neck Surgery, Head and Neck Cancer Center of the University Cancer Center Hamburg, University Medical Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany e-mail: [email protected]

Introduction Head and neck cancer is one of the most common cancers worldwide and was ranked as the eighth leading cause of cancer death [1]. Epidemiological studies show an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) especially of the tonsils and the base of the tongue. Data from the USA suggest that 18 % of all head and neck cancers in 1973 were oropharyngeal cancer, compared to 31 % in 2004 [2]. Studies in Sweden showed similar results [3]. In the last few years, studies all over the world have shown that a significant percentage of oropharyngeal cancers were associated with human papilloma virus (HPV) [4]. These studies suggest HPV as the primary cause for the increasing incidence of oropharyngeal cancer in the USA and Europe. More than 100 different types of HPV have been identified and 15 types are thought to have a high-risk oncogenic potential. Of these 15 types, HPV-16 causes [90 % of the HPV-positive head and neck squamous cell carcinoma [5]. Studies show that an infection with high-risk HPV is an independent risk factor for the development of HNSCC and needs to be considered along with the traditional risk factors such as tobacco abuse or alcohol [6, 7]. HPV-positive cancer patients tend to be younger than HPV-negative HNSCC patients. Because the transmission of HPV is thought to require mucosal skin-to-skin contact, a sexual transmission is supposed, for oropharyngeal sites especially oro-genital contact [8]. HPV-positive patients are known to have a better prognosis than HPV-negative ones. Multiple studies show that HPV-positive patients are more responsive to treatment and have better rates of disease-specific survival than patients with traditional risk factors such as tobacco and alcohol [9, 10]. This was demonstrated in retrospective and

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prospective clinical trials. These trials showed higher response rates after induction chemotherapy and after chemoradiation treatment as well as superior survival results for overall and progression-free survival for HPVpositive HNSCC patients [11–13]. Furthermore, younger age and improved survival of HPV-positive HNSCC patients imply that a reduction of treatment-related toxicity may be necessary. This reduction needs to be achieved without risking the good survival results of HPV-positive head and neck cancer patients. Currently, different strategies to achieve this reduction of treatment-related morbidity are pursued. The most important ones and new, more specific therapy approaches will be presented in this review.

Eur Arch Otorhinolaryngol (2014) 271:1861–1867

Fig. 1 Phase II trial of Mehrotra et al. with reduction of radiation dose for HPV-associated oropharyngeal SCC. Non-smoking HPVpositive patients with T1-3/N1-2 oropharyngeal cancer receive a dose-reduced radiotherapy if complete or partial response after induction chemotherapy was shown. HPV human papillomavirus, OPSCC oropharyngeal squamous cell carcinoma, TPF induction chemotherapy with docetaxel (T), cisplatin (P), 5-floururacil (F), CR complete response, PR partial response, SD stable disease, PD progressive disease, RT radiotherapy, CT chemotherapy, RCT radiochemotherapy

Review New therapeutic strategies Reducing toxicity by a modification of radiation dose As mentioned above, the combination of good prognosis and younger age of HPV-positive HNSCC has led to claims of reduction in treatment-related morbidity. There are different possibilities to decrease toxicity, one of which is the reduction of the standard dose of definitive radiotherapy (70 Gy). At the American Society of Oncology (ASCO) meeting 2012, two studies with this strategy have been presented. In both of these trials, HPV-positive patients received an induction chemotherapy (ICT) followed by a dose-reduced chemoradiation for patients who responded well to ICT. The results of these studies are not available yet. One of these studies is a trial of HPV-positive patients with T1-3/N1-2 oropharyngeal cancer presented by Mehrota et al. This trial is currently recruiting patients. Patients are required to be nonsmokers or to have a history of less than 10-pack years of smoking. The protocol starts with three cycles of docetaxel (T), cisplatin (P) and 5-flurouracil (F) (TPF) as induction chemotherapy. As shown in Fig. 1, after induction chemotherapy a restaging is followed. Patients with complete or partial response (CR/PR) receive a dosereduced radiotherapy with 66 Gy with or without chemotherapy, under the assumption that the good response to chemotherapy predicts the overall response to radiotherapy or chemoradiation. In contrast to this, patients with stable or progressive disease (SD/PD) will receive standard chemoradiotherapy with the full dose of definitive radiotherapy. The main goal is to improve functional quality of life. In Fig. 1, the treatment protocol and the main inclusion criteria are depicted [14].

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Fig. 2 Eastern Cooperative Oncology Group trial ECOG 1308. HPVpositive patients with stage III or IV resectable oropharyngeal cancer receive cetuximab and dose-reduced radiotherapy, if complete response after induction chemotherapy was shown. HPV human papillomavirus, OPSCC oropharyngeal squamous cell carcinoma, TPC induction chemotherapy with paclitaxel (T), cisplatin (P), cetuximab (C), CR complete response, SD stable disease, PR partial response, RT radiotherapy

A similar study design can be found in the Eastern Cooperative Oncology Group trial ECOG 1308, shown in Fig. 2. The study recruited 90 HPV-positive patients with stage III or IV resectable oropharyngeal cancer. Patients received three cycles of induction chemotherapy with paclitaxel (90 mg/m2 on days 1, 8, and 15), cisplatin (75 mg/m2 on day 1) and cetuximab (loading dose of 400 mg/m2 on day 1, followed by 250 mg/m2 weekly). After induction chemotherapy all patients had a clinical and radiological restaging. Patients who achieved a complete response (CR) received radiation up to 54 Gy and cetuximab. All patients with partial response (PR) or stable disease (SD) received the standard dose of radiotherapy and cetuximab [15]. The trial has completed the recruitment phase and first results can be expected in the next few years. Figure 2 provides a schematic diagram of the protocol. Reducing toxicity by replacement of cisplatin with cetuximab Another strategy to reduce toxicity is the replacement of cisplatin with cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR) for chemoradiation. Cisplatin is still considered the gold standard for chemoradiation, but cetuximab may be less toxic with


comparable treatment results in retrospective analyses [16, 17]. A direct comparison of cisplatin- and cetuximab-based chemoradiation has not been performed prospectively. A trial from Warwick Medical School, termed DeESCALaTE HPV [determination of epidermal growth factor receptor inhibitor (cetuximab) versus standard chemotherapy (cisplatin) early and late toxicity events in human papillomavirus-positive oropharyngeal squamous cell carcinoma] compares a regimen of cisplatin (100 mg/ m2; on days 1, 22, 43) and normofractionated radiotherapy with cetuximab and normofractionated radiotherapy. The primary end point of this trial is the rate of severe toxicity (grade 3–5) under the assumption that a cetuximab-based radiotherapy will lead to less morbidity and better quality of life without a significant difference in overall survival or locoregional control. Treatment-naive patients with p16positive stage III–IVb oropharyngeal cancer can be included into this trial. In this phase III study, 304 patients are planned for accrual [18]. A schematic trial protocol is provided in Fig. 3. The Radiation Therapy Oncology Group (RTOG) trial RTOG 1016 is based on the same assumption. In this study, patients with p16-positive oropharyngeal cancer (T1-2, N2a-3 or T3-4, any N-status) can be included. The control arm consists of accelerated intensity-modulated radiation therapy (IMRT) with 70 Gy for 6 weeks and high-dose cisplatin (100 mg/m2) at day 1 and 22 (as used in RTOG 0129). The experimental arm consists of accelerated IMRT with 70 Gy for 6 weeks and eight doses of cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly). The primary end point of RTOG 1016 is overall survival and non-inferiority is expected for the experimental arm [19]. The trial is currently recruiting well and first results can be expected in the next few years (Fig. 4). Reducing toxicity: revisiting the need for chemotherapy added to adjuvant radiotherapy In one study, the indication for adjuvant chemoradiation for surgically treated HPV-positive oropharyngeal cancer was reevaluated [20]. Lymphonodular extracapsular spread

Fig. 3 Clinical trial De-ESCALaTE HPV. HPV-positive patients with oropharyngeal cancer receive in this randomized trial standard radiochemotherapy or cetuximab and radiotherapy with 70 Gy. HPV human papillomavirus, OPSCC oropharyngeal squamous cell carcinoma, RT radiotherapy, RCT radiochemotherapy, R randomization

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Fig. 4 Radiation Therapy Oncology Group (RTOG) trial RTOG 1016. HPV-positive patients with oropharyngeal cancer receive in this randomized trial accelerated IMRT and high-dose cisplatin or accelerated IMRT and eight doses of cetuximab. HPV human papillomavirus, OPSCC oropharyngeal squamous cell carcinoma, IMRT intensity-modulated radiation therapy, P cisplatin, R randomization

(ECS) and positive microscopic margins after tumor resection are established as the major risk factors to determine whether adjuvant chemoradiation is indicated [21]. Sinha et al. evaluated whether in the cohort of p16positive oropharyngeal cancer patients ECS also determines the need for adjuvant chemoradiation. In this study, 152 patients with p16-positive OPSCC and pathologically positive neck disease who underwent transoral laser microsurgery were included. The authors used two different measures to assess extracapsular spread: ECSReport, taken from the patholohistological report which was evaluated by several pathologists and ECSGraded a more stringent categorization. ECSGraded included a distinguished grading system from 0 to 4, which was determined by only one study pathologist who was blinded to treatment and outcome. In contrast to 124/152 patients who were rated positive for ECS by ECSReport, only 73/152 patients had ECS in the more distinguished grading ECSGraded. Of 152 patients, 133 (87 %) received adjuvant therapy of which 66 patients (43 %) received radiotherapy alone and 67 (44 %) received chemoradiotherapy. The patients were matched for important parameters like comorbidities, smoking status, T-stage, N-stage, surgical margins, number of lymph nodes, angioinvasion, perineural invasion, lymphatic invasion and the influence of ECS on treatment outcome and the influence of the kind of adjuvant treatment was determined. The primary end point was disease-free survival (DFS), whereas secondary end points included overall survival (OS), disease-specific survival and the pattern of recurrence. The results showed that after a median follow-up of 43 months, ECS was neither associated with a poor disease-free survival (ECSReport p = 0.23/ ECSGraded p = 0.09) nor with any of the other end points. Only extensive ECS (ECSGraded 4 = irregular mass of tumor with no histologic evidence of residual lymph node tissue architecture = soft tissue metastasis) was associated with reduced disease-free survival (DFS) (80 % vs. 93 %; p = 0.02). However, further analysis demonstrated that in patients with extracapsular spread or soft tissue metastasis, adjuvant chemoradiotherapy was not associated with better disease-free survival compared to radiotherapy alone in a

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multivariate analysis (p = 0.46). In conclusion, the impact of ECS on patient outcome and the choice of adjuvant treatment for p16-positive oropharyngeal cancer need to be revisited. It seems not to have the same influence on prognosis and the need for treatment intensification as in a non-selected cohort of patients with different primary sites and p16-negative tumors. Since in the original work by Cooper and Bernier the determination of p16-status was not performed, this question should be addressed in a new prospective trial design for HPV-positive patients. Less invasive surgery: the conceptual role of TORS in treating HPV-driven OPSCC Another strategy to reduce morbidity for HPV-positive patients is the primary treatment by surgery employing new, less invasive procedures like transoral robotic surgery (TORS), laser surgery or a combination of both, i.e., transoral robotic laser surgery. As the socioeconomic differences between the classic, and tobacco- and alcoholinduced OPSCC patient population and the HPV-driven OPSCC population are obvious—the latter being generally younger, otherwise healthier, professionally and sexually active, wealthier and socially better networked—it is paramount that their treatment plan takes all those circumstances into account [22]. Having been successfully treated with primary chemoradiation as a one-off treatment option, a younger patient may suffer longer from the long-term side effects of conservative treatment and, ironically enough, may have more time to potentially develop a second primary as a consequence of their first treatment. Yet, classic open surgery often involving lip split, mandible split, lateral pharyngotomy or tongue-dropout via floor of mouth release has its significant access-related collateral damages, leaving cosmetic and functional impairments behind, and has not been a very attractive option either. For this specific, HPV-driven OPSCC patient population, TORS may provide lower morbidity, but equally effective and oncologically safe primary treatment opportunity [23, 24]. From a pure oncological point of view, TORS is not supposed to be better or worse than any other surgical treatment modality. It is rather the surgical access and the lack of related collateral damage that makes the difference. As with every decision-making process on deciding whether to operate on a specific tumor of a specific patient or not, three basic questions are to be answered: (a) Can clear margins be achieved? (b) Can function be preserved? (c) Will the planned surgery reduce the need for adjuvant therapy? Primary, curative surgery can only be justified in cases where the answer is a firm yes to all these three questions. If so, the surgical modality must be chosen according to the anatomy and tumor characteristics. If oncological

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safety can equally be achieved using several approaches, the least morbid option is to be preferred. Among the advantages of TORS, the only real feature that makes it the cutting edge approach in today’s spectrum of multimodal HNSCC therapy is the fact that it makes it far easier and less morbid to achieve 5 mm clear surgical margins around a multi-planar en bloc resection in the area of interest, especially in the oropharynx, without requiring mandible split or floor of mouth release. The possible reduction in adjuvant treatment [25] is a consequence of the reliable margin status and the inherent better prognosis of HPV-driven SCC, irrespective of the treatment modality. When this, i.e., the 5 mm clear margin status of the primary tumor is coupled with a reliable surgical and histopathological staging of the neck with a sufficient nodal yield [26], a custom tailored adjuvant therapy can be discussed with the purpose of further reducing additional morbidity to the extent of omitting adjuvant therapy in selected cases, where even surgical monomodality might be an option [27, 28]. An American study group assessed HPV-positive patients who were treated by TORS followed by adjuvant therapy if indicated. The study included 150 patients, who received surgery by TORS and radiotherapy (IMRT, 54 Gy in 30 daily fractions) or concurrent chemoradiotherapy (cisplatin 100 mg/m2 on days 1, 22 and 43) if indicated. Of this population, only 50 patients underwent HPV assessment and 37 were HPV positive. The results showed that the disease-specific survival after a 2-year follow-up was 89.5 % for HPV-positive patients and 100 % for HPVnegative patients. The authors could not show any significant difference in disease-free survival between HPV positive and HPV-negative lesions which may be confounded by the small cohort of patients and the relatively short follow-up [29]. Immunotherapeutic approaches Immunological background for treatment of HPV-positive HNSCC Because HPV-positive tumors are induced by a viral infection of HPV, these tumors have a different pathological background compared to cancer induced by traditional risk factors such as tobacco and alcohol. The viral infection can serve as a foreign antigen that might enhance the immune system’s response to the tumor. Humoral immune responses against the viral antigens E6 and E7 have been found frequently in HPV-positive cancer patients and can be correlated with increased survival, implying an important role in the immunological recognition of HPV [30]. That is why HPV-associated HNSCC is considered an optimal entity for immunotherapy.


At the ASCO 2012, the immunological role of the human papillomavirus was one of the highly discussed subjects. Park et al. [31] presented their findings about forkhead box p3 (FOXP3)-positive T cell status as a prognostic factor in tonsillar carcinoma. FOXP3 is known to play an important role in the development and function of regulatory T cells (Treg). In this study, paraffinembedded cancer tissue of 79 patients with locally advanced tonsillar carcinomas was analyzed for the HPV surrogate marker p16 and the presence of tumor-infiltrating FOXP3-positive T cells before treatment. 63 patients (80 %) were considered HPV positive with p16 overexpression and in 38 patients (48 %) FOXP3-positive Treg were detected. The authors reported that Treg involvement was significantly associated with HPV-positive status (p = 0.011). The 5-year overall survival in HPV-positive patients was significantly higher than in HPV-negative patients (p = 0.025). Furthermore, the 5-year overall survival in Treg-positive patients was higher than in the Tregnegative group (p = 0.001). In multivariate analysis the detection of FOXP3-positive T cells and p16 overexpression were identified as independent prognostic factors (p = 0.001 and p = 0.016). In contrast to this finding, several previously reported studies in other tumor entities—including lung cancer, gastric cancer, endometrial cancer and also tongue cancer—the presence of FOXP3positive Treg has been associated with poor survival [32– 36]. On the other hand for nasopharyngeal cancer, Treg have been identified as a prognostic marker for favorable prognosis [37]. In summary, there are conflicting data concerning the prognostic value of FOXP3-positive Treg in different cancer studies. One explanation may be that in HPV-positive tonsillar cancer, there is a tolerogenic environment for the HPV-positive cancer cells at baseline. The favorable prognosis of HPV-positive tumor patients may act as a confounder leading to the identification of Treg as a positive prognostic marker. Another explanation could be that during therapy the ratio between tolerogenic Treg and cytotoxic T cells may shift in favor of effector T cells and induce an immune reaction directed against HPV-positive cancer cells. The same mechanism might be the reason for the results with nasopharyngeal cancer, which is often associated with Epstein–Barr virus infection. Recently, the group of Heusinkveld et al. discussed the important immunological role of HPV 16-specific systemic and local T cells. HPV-positive HNSCC expresses the two viral oncoproteins E6 and E7. These two oncoproteins are foreign to the body, so they are thought to have an immunogenic potential. Heusinkveld et al. evaluated the presence of systemic and local T cells reactive against these oncoproteins. The study included 50 patients with HNSCC, 12 of which were positive for DNA of HPV16. Almost all HPV-positive tumors were oropharyngeal

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cancers. The authors found circulating HPV16- and p53specific T cells in 17/47 and 7/45 tested patients. In 20 of these patients, T cells were isolated from tumor cultures and/or lymph nodes. Tumor-infiltrating HPV16-specific T cells were found in six of eight HPV-positive tumors. In the 12 HPV-negative tumors, no HPV16-specific T cells were found. In-depth analysis of the HPV16-specific T cell response revealed that this response comprised a broad repertoire of CD4? T-helper type 1 and 2 cells, CD4? regulatory T cells and CD8? T cells reactive to HPV16. The local presence of HPV16-specific T cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and supports the approaches for immunotherapy of HPV-positive HNSCC [38]. A possible mechanism for tumor immune escape in HPV-positive HNSCC has been examined by Lyford-Pike et al. The authors provided evidence for an adaptive immune resistance mechanism, which is mediated trough the PD-1:PD-L1 pathway. PD-1 is the programmed death 1 protein, a T cell coinhibitory receptor, which delivers inhibitory signals to the effector T cells. There are two known ligands of this receptor, PD-L1 and PD-L2. PD-L1 is the primary ligand and is up-regulated in several solid tumors [39]. In vitro studies showed that blockage of the interaction between PD-1 and PD-L1 potentiates the immune response and mediates preclinical antitumor activity [40, 41]. Lyford-Pike et al. analyzed tumor infiltrating lymphocytes (TIL) for PD-1 expression and the PDL1 expression in HPV-positive HNSCC. The authors showed that the majority of CD8? TILs in HPV-positive HNSCC express the PD-1 co-inhibitory receptor and there was a higher PD-1 expression by CD4? and CD8? T cells in tonsil tissue as compared to the peripheral blood. In 20 patients with HPV-positive HNSCC, 14 (70 %) expressed PD-L1. A very interesting point is that the ligands PD-L1 on the tumor cells were predominantly located at the periphery of tumor nests, whereas only 1 of the 14 patients demonstrated diffuse PD-L1 expression. Furthermore the authors found an association between expression of ligand PD-L1 on tumor cells and tumor-associated macrophages and the presence of TIL. In the microenvironment of HPVHNSCC, a significant increase of CD8-positive TIL and interferon-c (INF-c) mRNA in PD-L1? compared to PDL1- cancers was seen. This study showed that the PD1:PD-L1 interaction creates an immune-privileged site for initial virus infection, leading to adaptive immune resistance once tumors are established. These findings suggest that the blockade of this pathway could be a new approach to treat HPV-positive tumors [42]. These new findings are of special significance since recently two phase I trials about safety and activity of a PD-L1 and a PD-1 antibody in patients with advanced cancer have been published in a highly rated journal [39, 43]. In these studies, patients with

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selected advanced cancers were treated with either a PD-1 antibody [43] or a PD-L1 antibody [39]. Both these antibodies block the interaction between PD-1 and PD-L1. The patient cohorts included non-small cell lung cancer (NSCLC), melanoma, colorectal cancer, renal cell cancer, ovarian cancer, pancreatic cancer, gastric cancer and breast cancer patients. All these patients have had tumor progression after at least one previous course of tumorappropriate therapy for advanced or metastatic disease. Further, authors reported high rates of objective response, a complete or partial response, especially in NSCLC, melanoma and renal-cell cancer. A significant proportion of such responses lasted for 1 year or longer. In the trial with the PD-1 antibody, these extraordinarily long-lasting responses were noted only in patients expressing PD-L1 in the tumor. That is why this treatment approach may be of great interest for HPV-positive head and neck cancer in the future. Due to these impressive results, Bristol-Myers Squibb plans to move directly into phase III trials. Vaccination Another immunotherapeutic approach for head and neck cancer patients are vaccines intended to stimulate an antitumor immune response. Voskens et al. [44] published a study with Trojan vaccines in patients with advanced HNSCC. The vaccines were composed of HLA-I and HLAII restricted melanoma antigen E (MAGE)-A3 or human papillomavirus (HPV)-16 derived peptides. The study was composed of 31 patients with recurrent or metastatic HNSCC who could not be treated with standard therapy or refused standard therapy. All patients were tested for MAGE-A3 or HPV-16 expression and the presence of the HLA-A*02 genotype. Of the 31 screened patients, only 5 could be enrolled in the study. The dose of vaccine was 300 lg of Trojan peptide supplemented with Montanide and granulocyte macrophage colony-stimulating factor (GM-CSF). The patients received up to four injections of the vaccine in intervals of 4 weeks. Unfortunately, none of these patients showed a complete response. However, four patients recognized the full Trojan constructs and constituent HLA-II peptides. A currently ongoing study by Sara Pai at the Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins University) uses a different approach. In this trial, a HPV16 DNA vaccine administered by an electroporation device is tested in different doses with a single dose of low-dose cyclophosphamide (i.v.). The study is currently recruiting patients and no data are available yet. Good results have been shown in women with HPV-16positive, grade 3 vulvar intraepithelial neoplasia, who were vaccinated three to four times with a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7. After

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1 year, 15 of 19 patients showed clinical response and 9 of 19 patients had a complete response. Every patient had a T cell response induced by the vaccine [45]. This study showed that vaccinations with long peptides of HPV-specific E6 and E7 may be a new approach for therapy of HPV-positive HNSCC as well. For better treatment efficiency, such vaccination approaches may in the future be combined with traditional therapy modalities like surgery or chemoradiation.

Conclusion This article shows that the subgroup of HPV-positive HNSCC is being recognized as a separate entity in an increasing manner and clinical trials exclusively for HPVpositive HNSCC are available. The focus of these trials is on the one hand on reduction of treatment related morbidity. On the other hand, the increasing immunological understanding of HPV-positive HNSCC has been leading to new and HPV-specific treatment approaches. In the struggle to reduce toxicity and discover new therapies, caution needs to be applied so as not to pose a risk to the good prognosis of HPV-positive patients. Results from HPV-specific trials can be expected in the coming years.

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