HPV-associated Oropharyngeal Cancer Research Articles

Reducing HPV-Associated Oropharyngeal Cancer Risk and Exploring the Role of Safe Sexual Activity and Behavioral Modifications

Reducing HPV-Associated Oropharyngeal Cancer Risk and Exploring the Role of Safe Sexual Activity and Behavioral Modifications

Development of a prediction model for tube feeding dependence in HPV-associated oropharyngeal cancer patients undergoing chemoradiotherapy.

This study aimed to develop a prediction model for feeding tube dependence in a large homogenous cohort of HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) patients receiving chemoradiotherapy (CRT). We further aimed to externally validate three previously published feeding tube prediction models on this cohort. p16-confirmed HPV+OPSCC patients treated with definitive CRT at a tertiary cancer centre between April 2017 and February 2022 were identified. The primary endpoint was G-tube dependence, defined as enteral feeding for≥4 weeks following CRT. Clinical and dosimetric data were extracted from electronic patient records. Multivariable analyses (MVA) assessed the associations of potential predictors with G-tube dependence. The discriminatory performance of three previously published models was assessed on this cohort using the area under the receiver operating curve (AUC), and calibration was evaluated with calibration plots. A total of 291 patients were included (TNM8 stage I: 129; II:67; III: 95). MVA identified Dmean to the superior pharyngeal constrictor muscle, D70% to the middle pharyngeal constrictor muscle, and modified diet texture at baseline as predictive for G-tube dependence, with the AUC of 0.68. External validation of three existing models yielded an AUC of 0.60, 0.63, and 0.67, with no evidence of good calibration. Despite a sizable cohort and comprehensive capture of dosimetric information, our prediction model, and external validation of previously published models, showed moderate performance. This suggests that additional factors beyond disease and treatment may need to be considered in future models to refine nutrition support decisions.

Improved efficacy of therapeutic HPV DNA vaccine using intramuscular injection with electroporation compared to conventional needle and needle-free jet injector methods.

We have previously developed a candidate therapeutic HPV DNA vaccine (pBI-11) encoding mycobacteria heat shock protein 70 linked to HPV16/18 E6/E7 proteins for the control of advanced HPV-associated oropharyngeal cancer (NCT05799144). While naked DNA vaccines are readily produced, stable, and well tolerated, their potency is limited by the delivery efficiency. Here we compared three different IM delivery strategies, including intramuscular (IM) injection, either with a needle alone or with electroporation at the injection site, and a needle-free injection system (NFIS), for their ability to elicit gene expression and to improve the potency of pBI-11 DNA vaccine. We found that electroporation after IM injection significantly increases gene expression from a luciferase-encoding DNA construct compared to IM injection alone or NFIS. We also showed that single administration of pBI-11 DNA via electroporation-mediated delivery generates the greatest increase in HPV antigen-specific CD8 + T cell-mediated immune responses, resulting in the most potent antitumor effect compared to the other two methods. We further compared the response to three repeat immunizations via each of these different methods. We found that electroporation-mediated delivery of pBI-11 DNA generates the greatest HPV antigen-specific CD8 + T cell immune responses and therapeutic antitumor effects compared to the other two methods. Monitoring of mouse behaviors and body weight, and necropsy indicated that electroporation-mediated delivery of clinical grade pBI-11 DNA vaccine was well-tolerated and presented no evident local or systemic toxicity. These findings provide rationale for clinical testing of pBI-11 DNA vaccine delivered by electroporation for the control of HPV16/18-associated infections and/or cancers.

Impact of circulating tumor human papillomavirus DNA kinetics on disease outcomes in HPV-associated oropharyngeal cancer.

Circulating tumor tissue modified (TTMV)-HPV DNA has emerged as a promising biomarker in human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). The objective of this study was to assess ctHPVDNA TTMV clearance kinetics during RT and its relationship with progression in HPV-OPSCC. We identified 80 non-metastatic HPV-OPSCC patients with 366 TTMV samples who underwent prospective plasma TTMV testing before, during and after curative intent RT or CRT between June 2021 and February 2023. Patients with rapid favorable clearance (>95% decline from pre-treatment value) of TTMV were compared to those with suboptimal clearance (<95%). The primary objective was to evaluate the relationship between TTMV clearance during CRT and its impact on progression free survival (PFS). The median follow-up was 14.7 months. Clinical nodal stage was associated with higher TTMV-HPV DNA scores at baseline, with a median score of 128, 778, and 1219 for N0/N1, N2a/b, and N2c/3 patients, respectively. Patients who had persistent TTMV at the end of RT had an inferior PFS compared to those who cleared their TTMV at 2 years (91.7% vs. 71.7%) (log rank, p = .042). Among patients who had complete clearance of their TTMV at 3 months, those who had a negative, equivocal, and incomplete PET response had a 2-year PFS of 94.3%, 77.8%, and 59.3%, respectively (log-rank, p = .029). Our study indicates that persistent TTMV-HPV DNA is associated with worse PFS and may portend unfavorable outcomes. Thus, monitoring TTMV clearance kinetics could be a valuable biomarker for guiding treatment decisions in patients with HPV-OPSCC.

Abstract PR007: Screening early detection of HPV-associated oropharynx cancers with multi-feature HPV whole genome sequencing liquid biopsy

Abstract Early detection of HPV-associated oropharyngeal cancer (HPV+OPSCC), the most common HPV cancer in the United States, could reduce disease-related morbidity, yet currently there are no screening tests. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC at diagnosis. It was previously unknown if ctHPVDNA is detectable prior to HPV+OPSCC diagnosis, and thus it’s potential as a screening test. We recently reported (2023 AACR-AHNS Head and Neck Cancer Conference) detection of ctHPVDNA with 79% overall sensitivity at 100% specificity in a case-control cohort of HPV+OPSCC patients with plasma samples collected 1-11 years prior to diagnosis (n=28) and age- and sex-matched controls (n=28) from the MassGeneralBrigham Biobank (MGBB) using a custom multi-feature HPV whole genome sequencing liquid biopsy, termed HPV-DeepSeek, demonstrating for the first time, the feasibility of blood-based screening for HPV+OPSCC. Here, we extend and validate these finding in a second independent cohort and generate combined metrics for estimating HPV+OPSCC screening accuracy by HPV-DeepSeek. We conducted a blinded case-control study nested within the NCI PLCO Screening Trial. PLCO enrolled 155,000 healthy participants from November 1993-July 2001 with plasma sample collected at multiple time points. All patients were followed for cancer outcomes. PLCO participants who were diagnosed with OPSCC &amp;gt;6 months after blood sample contribution were identified and matched 1:2 with controls based on smoking status, sex, race, year of blood collection, and year of birth. 400ul of plasma was retrieved, blinded, and transferred for testing. After quality control, the cohort included 72 OPSCC cases and 144 controls. Samples had previously underdone HPV E6 antibody testing which was used as a marker of HPV status. All samples were run on HPV- DeepSeek using pre-defined cut points and results were returned to NCI CDAS where case- control status was unblinded. 32 OPSCC cases were HPV E6 antibody positive and thus regarded as HPV16+OPSCC. 20/32 were ctHPVDNA positive and 12/32 were ctHPVDNA negative (overall sensitivity 63%). Specificity was 99%. The mean lead time of positive cases was 6.3 years, and the maximum lead time was 11.3 years. Sensitivity was highest closest to diagnosis and declined further from diagnosis (100% within 3 years of cancer diagnosis, 58% from 3-9 years, 20% from 9-12 years; p&amp;lt;0.001). Four additional samples were positive for non- HPV16 genotypes (31, 33, 33, 39) in the overall cohort. When combined with the MGBB cohort, overall screening sensitivity was 70% and specificity was 99%. Sensitivity within 3 years of cancer diagnosis was 100%. ctHPVDNA can be detected in the blood up to 11 years prior to diagnosis with HPV+OPSCC, with ≥99% specificity, and an overall screening sensitivity of 70% in a cohort of 100 OPSCC cases and 172 controls using a multi-feature HPV WGS liquid biopsy. ctHPVDNA detection alone, or in combination with previously identified serological biomarkers, may be a feasible approach to screening for HPV+OPSCC. Citation Format: Krystle Kuhs, Hilary Robbins, Dipon Das, Michael Bryan, Ling Aye, Yana Al-Inaya, Shun Hirayama, Viktor Adalsteinsson, Michael Lawrence, Tim Waterboer, Daniel L Faden. Screening early detection of HPV-associated oropharynx cancers with multi-feature HPV whole genome sequencing liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR007.

MHealth interventions to improve public knowledge of HPV-associated oropharyngeal cancer in the UK

In the United Kingdom (UK), the current prevalence rates of oropharyngeal cancer linked to human papillomavirus (HPV) are 6.29% and 2.04% in men and women, respectively. Over the years, the burden of this disease has increased in the UK, and this is mainly due to the rising prevalence of HPV infection in the UK. Research evidence has shown that over 70% of oropharyngeal cancers in the UK are linked to HPV. Oral sex is the major route of transmission of HPV, and over 63% of UK young adults are found to have a positive history of oral sex practice. However, only a minority of the UK population are aware of HPV-associated oropharyngeal cancer; this therefore calls for more public health efforts to increase awareness and knowledge on HPV-associated oropharyngeal cancer in the UK. While the use of technology-based, clinic-based, and community-based interventions have been employed to improve public awareness and knowledge on the role of HPV-associated oropharyngeal cancer, mobile health (mhealth) interventions have not been seriously explored despite existing robust evidence on the effective roles of mhealth in improving awareness and knowledge in diverse diseases. This article therefore calls for the adoption and use of mhealth interventions in educating the UK’s population on HPV-associated oropharyngeal cancer. The use of mhealth interventions in this regard is highly viable as its implementation closely aligns with the country’s National Health Service (NHS) commitment towards the digital transformation of the UK’s healthcare system.

Oxygen-Enhanced MRI Detects Incidence, Onset, and Heterogeneity of Radiation-Induced Hypoxia Modification in HPV-Associated Oropharyngeal Cancer.

Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in human papillomavirus-associated oropharyngeal head and neck squamous cell cancer. A total of 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy and then at weeks 2 and 4 (W2 and W4) into therapy. Two pretreatment scans assessed biomarker within-subject coefficient of variation and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modeling. Responding lesions were identified by comparing HVMRI change with RC limits of agreement. Oxygen-enhanced MRI identified hypoxia in all lesions. The HVMRI within-subject coefficient of variation was 24.6%, and RC limits of agreement were -45.7% to 84.1%. A cohort median pretreatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both P < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients. Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in human papillomavirus-associated oropharyngeal carcinoma. See related commentary by Mason, p. 5503.

Update on Pathologic Conditions, Imaging Findings, Prevention, and Management of Human Papillomavirus-related Neoplasms.

Human papillomavirus (HPV) is the most common sexually transmitted infection that proliferates in the squamous epithelium and is the most common source of viral-related neoplasms. Low-risk subtypes (HPV-6 and -11) cause respiratory papillomas (laryngeal, tracheal, and bronchial) and condyloma acuminata of the penis, anus, and perineal region (anogenital warts). High-risk subtypes (HPV-16, -18, -31, and -33) are responsible for oropharyngeal squamous cell carcinoma (SCC) that involves the tongue base, tonsils, posterior pharyngeal wall, and larynx and malignancies of the anogenital region (cancers of the cervix, vagina, vulva, penis, and anal canal). Recent studies have increasingly shown a favorable treatment response and substantial differences in the overall prognosis associated with HPV-associated oropharyngeal cancers. Given this fact, oropharyngeal, cervical, and penile SCCs are classified as HPV-associated and HPV-independent cancers in the current World Health Organization classification. Imaging is essential in the early detection, diagnosis, and staging of HPV-associated cancers. Imaging also helps assess treatment response and postoperative complications and is used for long-term surveillance. HPV-associated oropharyngeal SCCs have well-defined borders and solid and cystic nodal metastases at imaging. Updated screening and vaccination guidelines are currently available that have great potential to decrease the overall disease burden and help control this worldwide public health concern. Novel therapeutic strategies, such as immunotherapies, are being explored, and imaging biomarkers that can predict treatment response and prognosis are being investigated; radiologists play a pivotal role in these efforts. ©RSNA, 2024 Supplemental material is available for this article.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Trends in HPV-associated cancer incidence in Texas medically underserved regions.

While cervical cancer incidence rates (IR) in the United States have dropped in the last 20 years, non-cervical human papillomavirus (HPV) associated cancers increased. Many people in Texas (TX) live in medically underserved areas and have higher risk of developing HPV-associated cancers. Since previous studies of these regions focused on cervical cancer, we included other HPV-associated cancers in our analysis of IR in East TX and the TX-Mexico Border compared to other TX regions. Cancer data from 2006 to 2019 were obtained from the TX Cancer Registry. Cases of HPV-associated cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers and corresponding patient-level demographic data were included. We calculated IR per 100,000 and drew heat maps to visualize cancer IR by county. To control potential confounders, we added county-level risk factors: rates for smoking, excessive drinking, obesity, STIs, primary care provider availability and dentist availability, from the County Health Rankings and Roadmaps program. We reported IRs by region and time and estimated unadjusted and adjusted risk ratio (RR) for association of each type of cancer and region. Lastly, we created adjusted models for each cancer by period to see time trends of regional differences. Risk of anal, cervical, and oropharyngeal cancer was lower at parts of the Border than in the rest of TX in the adjusted model. We also observed increasing anal and oropharyngeal cancer risk and decreasing cervical and vaginal cancer risk over time. Patient sociodemographics, behavioral risk factors, and access to care may contribute to some observed differences in cancer IR across regions. This indicates that targeted prevention efforts towards these regions, especially in low socioeconomic status communities, may benefit future generations.

Detection of HPV DNA in Saliva of Patients with HPV-Associated Oropharyngeal Cancer Treated with Radiotherapy.

To investigate the technical feasibility of RT-PCR and direct sequencing to quantify HPV DNA in the saliva of patients with Human-Papilloma-Virus related oropharyngeal cancer (HPV-OPC), the level of which is known to predict prognosis after treatment. Nine patients with locally advanced HPV-OPC treated with definitive radiotherapy with chemotherapy or cetuximab, or radiotherapy alone between April 2016 and September 2017, were enrolled, two of whom also received induction chemotherapy. Saliva was collected before (baseline), during (mid-RT) and after (post-RT) radiotherapy. HPV-16 DNAs (E6 and E7) in saliva were quantified by RT-PCR and sequencing, the latter using a custom cancer panel. Correlations between HPV DNA levels and clinical outcomes were assessed. Compared to the baseline, the relative cycle threshold (Ct) value of E6 and E7 reduced at the point of mid-RT in the majority of the patients (100% and 75% for E6 and E7, respectively). Similarly, the relative Ct value from the baseline to post-RT reduced in 86% and 100% of the patients for E6 and E7, respectively. During the follow-up period, three patients (33%) experienced disease progression. The relative baseline Ct values of these three patients were in the top 4 of all the patients. The sequences of HPV DNA were detected in five (83%) of six samples of the baseline saliva that underwent DNA sequencing, along with several gene mutations, such as TP53,CDKN2A and PIK3CA. This study demonstrates that, in addition to detection and quantification of HPV DNA by RT-PCR, detection by sequencing of HPV-DNA using a customized cancer panel is technically possible.

Using Low-cost Videoscopes to Obtain Accurate Video "Oral Selfies" as Screening for HPV-associated Oropharyngeal Cancer: A New Screening Technology?

Human papillomavirus (HPV)-related oropharyngeal cancers associated with sexual contact are increasing, with high rates in men who have sex with men. HPV-related cancers have the advantage of being frequently detectable through oropharyngeal visual examination and having much higher survival rates than classic oropharyngeal cancers. It has been demonstrated that gay and bisexual men can take smartphone oropharyngeal "selfies" of sufficient quality for screening. However, there is an issue with the inability to move the tongue to allow a clear view of the palatine tonsils, where a majority of oropharyngeal cancer cases occur. We attempted to investigate the feasibility of using commercially available videoscopes to visualize the oropharynx. Fourteen healthy volunteers used a provided low-cost commercial endoscope to video their oropharynx. Participants used the videoscope connected to a laptop and could visualize the oropharynx on the screen. Attempts were observed, and the process was noted. A focus group of participants was carried out immediately afterwards to ascertain barriers and facilitators to using the videoscopes. All participants were able to use the videoscope and obtain videos of sufficient clarity to note major oropharyngeal landmarks. The palatine tonsils were initially difficult to visualize because the tongue could not be sufficiently controlled. Participants were given time to practice using visual cues to control the position of the tongue, which helped in obtaining good videos. Videoscopes can be used effectively with minimal instruction and provide a better view than still images, as they illuminate and magnify the site. Low-cost commercially available videoscopes may be an improvement over smartphone "selfies".

Neoadjuvant sintilimab and platinum-doublet chemotherapy followed by transoral robotic surgery for HPV-associated resectable oropharyngeal cancer: Single-arm, phase II trial.

6011 Background: De-escalation treatments for HPV-associated (HPV+) oropharyngeal cancer (OPC) have been well discussed. Meanwhile, the combination of anti-PD-1 therapy and chemotherapy (immunochemotherapy, ICT) and transoral robotic surgery (TORS) shows promising results in OPC, especially in HPV+ ones. This study aims to investigate the efficacy and safety of neoadjuvant ICT and sequential TORS to reduce functional impairments and omit adjuvant radiotherapy for resectable HPV+ OPC. Methods: In the single-arm, phase II trial, patients with resectable HPV+OPC (cT2-4N0-3M0, AJCC 8.0) were recruited and received neoadjuvant sintilimab (200mg), platinum (cisplatin 60mg/m2, or carboplatin AUC=5), and paclitaxel (nab-paclitaxel 260mg/m2, or docetaxel 75mg/m2) every 3 weeks for 2 cycles, followed by radical surgery (with TORS as an option). The primary endpoint was major pathological response (MPR; defined as residual viable tumor of less than or equal to 10%) in the primary lesion. The secondary endpoints include pathologically complete response (pCR) of all resected lesions, objective response rate (ORR) according to RECIST 1.1, disease-free survival (DFS) rate and overall survival (OS) rate at 1 and 3 years, quality of life (QoL) by EORTC QLQ-H&amp;N35 questionnaire. Results: From February 1, 2022 to November 30, 2023, 27 patients were enrolled and received 2 cycles of neoadjuvant ICT. After neoadjuvant therapy, all 27 cases achieved partial response (PR), the ORR was 100%. Among them, 25 patients received radical surgery (per-protocol population), including 21 with TORSs. The pathological evaluation showed 24 patients (96.0%) achieved MPR, and 13 (52.0%) achieved pCR of all samples including primary lesions and resected lymph nodes. Grade 1-2 treatment-related adverse events (TRAE) occurred in 24/27 patients (88.9%). The most common TRAEs included rash (12, 44.4%), alopecia (10, 37.0%), nausea (8, 29.6%) and weakness (8, 29.6%), while only one patient (3.7%) experienced grade 3 TRAEs, including febrile leukopenia, pneumonia and diarrhea. These adverse reactions were manageable and no surgical delay occurred. After the surgery, the majority of patients had active follow-up without any adjuvant treatment (19/25, 76%), while 4 patients received adjuvant anti-PD-1 therapy and only 2 had adjuvant radiotherapy. At an average follow-up time of 8.2 months, the 6-month DFS and OS were both 100%. Furthermore, compared to the baseline, 22 patients (88%) reported similar or improved QoL scores at 3 months after surgeries. Conclusions: Neoadjuvant sintilimab plus platinum-doublet chemotherapy and sequential TORS achieved satisfactory pathological response, favorable functional preservation and tolerable toxicity in patients with resectable HPV+OPC. Further follow-up is warrant to confirm long-term survival benefits. Clinical trial information: ChiCTR2200058650.

Phase II trial of immunotherapeutic HPV vaccine PRGN-2009 with pembrolizumab before standard treatment in subjects with newly diagnosed HPV-associated oropharyngeal cancer.

TPS6124 Background: A majority of oropharyngeal cancer (OPC) is caused by human papillomavirus (HPV). While highly responsive to standard of care (chemoradiotherapy or surgery) and with an overall good prognosis, both disease and treatment are highly morbid, frequently resulting in profound toxicity. Furthermore, relapsed disease is usually incurable and associated with profound morbidity. Additionally, concurrent chemoradiotherapy requires significant time and travel commitments, often resulting in major financial and caregiver burdens. Thus, treatment regimens which allow the de-escalation of therapy, radiotherapy in particular, are needed, both for improving cure rates and reducing toxicity; ideally while also improving therapeutic equity. Immunotherapy has proven, clinically significant activity in recurrent/advanced OPC (Burtness et al, Lancet 2019); recent data (Forde et al, NEJM, 2022; Patel et al, NEJM, 2023) suggest greater activity of immunotherapy in the neoadjuvant vs adjuvant setting. PRGN-2009 is a replication-deficient gorilla adenovirus vaccine targeting HPV16/18 T-cell epitopes (E6/E7) with demonstrable ability to generate T-cell responses to HPV16/18 E6/7. Pembrolizumab is an anti-PD-1 monoclonal antibody with proven activity in OPC. We hypothesize that neoadjuvant administration of immune checkpoint blockade with a therapeutic HPV vaccine will induce a significant antitumor immune response and improve outcome. Methods: This is a single-site, single-arm, Phase II clinical trial investigating the biological activity of neoadjuvant PRGN-2009 and Pembrolizumab in early-stage HPV-associated oropharyngeal cancer. Patients must have: newly diagnosed, biopsy-proven, HPV-associated, stage I-III OPC, RECIST 1.1 measurable disease, satisfactory organ function and functional status (ECOG ≤2) and be candidates for definitive therapy (either surgery or chemoradiotherapy). Exclusion criteria include: active autoimmune disease, steroid use of ≥10mg prednisolone-equivalent daily, pregnancy or uncontrolled medical illness which could compromise trial participation. Chronic viral infection (HIV, HBV, HCV) is permissible, if patients have a CD4+ count ≥200 and are on antiviral therapy with undetectable viral load. The primary objective is evaluating the antitumor immune response of PRGN-2009 in combination with Pembrolizumab (determined as a ≥2-fold increase in tumor infiltrating CD3+ cells); secondary endpoints include: response rate (by RECIST 1.1), relapse-free survival, safety and tolerability and if PRGN-2009/Pembrolizumab impacts time to initiation of definitive therapy. Biopsies are mandatory at baseline and at completion. This study is presently open in the NCI with 4 patients enrolled as of February 2024. Clinical trial information: NCT05996523 .

Characterization of novel compounds that directly bind to and inactivate the HPV E6 protein for treatment of HPV-associated cervical and oropharyngeal cancers.

e15122 Background: The human papillomavirus (HPV) E6 protein is necessary for viral genome replication and is always expressed in HPV-induced malignancies. We performed in silico screening of chemical libraries for molecules that bind to a pocket on the cancer associated HPV-16 E6 protein. We focused on the protein-protein interaction of E6 with one of its cellular binding partners, the ubiquitin ligase E6AP. In a trimolecular complex with E6, E6AP ubiquitinates p53, leading to its destruction by the proteasome. We designed, synthesized, and characterized &gt;300 compounds that 1) bind to the E6AP interaction surface of the HPV-16 E6 protein; 2) are armed with a ‘warhead’ to make an irreversible bond with a specific cysteine in this HPV-16 E6 binding pocket; 3) and restore levels of p53 and selectively decrease viability of HPV-16 expressing tumor derived cells. Methods: E6 inhibitor optimization was guided by in silico docking strategies, co-crystallization, and medicinal chemistry, followed by biochemical and cellular assays to iteratively design and synthesize molecules with increased E6 inhibitory activities. Results: We used whole protein mass spectrometry to interrogate covalent bonding to E6, showing irreversible binding to the cysteine in the targeted E6 binding pocket without the other 13 cysteines in E6, with Ki in the range of seconds. Biolayer interferometry and fluorescence polarimetry measured blockade of E6 with E6AP, with IC50 in the range of 400-600 nM. To establish in cell inactivation of E6, human cervical cancer derived SiHa cells that express HPV-16 E6 were incubated with compounds, showing dose dependent increase of p53 levels up to 8-fold after 24 hrs, an effect that was not observed in the HPV-16- cell line RPE-1 expressing wild-type p53. Viability of two cervical (SiHa, CaSki) and two oropharyngeal HPV-16+ cancer cell lines (UM-SC-47, UM-SCC-104) was reduced with an IC50 of ~2-3 µM, with an IC50&gt;30µM in RPE-1 cells and telomerase immortalized human keratinocytes. These in vitro and cell-based experiments revealed dependence on the cysteine residue in the E6AP binding pocket of E6. For in vivo proof-of-concept studies, we developed mouse xenograft models, performed by engrafting SiHa, UM-SC-47 and UM-SCC-104 cancer derived cells subcutaneously into the flank of immunodeficient mice. Lead compounds were administered by intraperitoneal injection and demonstrated nearly complete inhibition (&gt; 70% tumor reduction) in HPV-16 tumor growth compared to vehicle. Anti-tumor activity was not observed with the HPV-negative tumor cell line C33A. Conclusions: HPV-16 is identified in about 50% of all cervical cancers and the majority of head and neck malignancies. Inactivation of the HPV E6 protein represents the opportunity for a novel molecular targeted approach for medical treatment of HPV-16 expressing cancers of the cervix and oropharynx.

A cross-sectional study of the association of dental health factors with progression and all-cause mortality in men diagnosed with HPV-associated oropharyngeal cancer

BackgroundHuman Papillomavirus-associated oropharyngeal cancer (HPV-OPC) incidence is increasing among men in the United States. Poor dental health has previously been associated with risk of head and neck cancers, oral HPV infection, and persistence but it is not understood whether dental health is associated with outcomes. We sought to determine the association of dental health with progression free survival and overall mortality among men with an HPV-OPC.MethodsA cross sectional study of men diagnosed with HPV-OPC between 2014–2020 at Moffitt Cancer Center in Tampa, FL was conducted. Dental records were abstracted for assessment of dental fitness prior to cancer treatment. Five dental factors including number of teeth lost, pocket depth, gingival score, loss of attachment, and bone loss were individually examined. Risk factor and outcome data were collected from a patient risk questionnaire and medical record. Using item response theory, an overall dental fitness score from five dental factors was developed in which missing data were multiply imputed. Cox proportional hazards model was used to assess whether dental factors were associated with progression-free survival or overall mortality.ResultsAmong 206 HPV-OPC cases, median follow-up was 3.4 years (IQR: 2.4–4.4) during which 40 cases involved progression or mortality and 25 deaths occurred. Overall dentition was significantly associated with progression free survival (p = 0.04) and with overall survival (p = 0.03) though findings were not significant after adjustment for age at diagnosis, stage, and smoking history (p = 0.146 and p = 0.120, respectively). A pocket depth of 7 mm or more was associated with overall survival (HR: 5.21; 95% CI: 1.43—19.11) and this remained significant after adjustment for confounding (aHR: 4.14; 95% CI: 1.72—16.26).ConclusionsAmong men diagnosed with an HPV-associated OPC in the US, worse dental health was associated with reduced progression free survival and overall survival, but not after adjustment for confounders. Further studies are needed to examine whether dental health is associated with other prognostic factors and subsequent treatment-related outcomes.

Therapeutic Advances and Challenges for the Management of HPV-Associated Oropharyngeal Cancer.

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A.

The Human Papillomavirus Enigma: A Narrative Review of Global Variations in Oropharyngeal Cancer Epidemiology and Prognosis.

Oropharyngeal cancers (OPCs) in Asia account for 42% of the global burden and over 50% of related deaths. Human papillomavirus (HPV) is involved in over 70% of OPC cases in the Western hemisphere, but its role in the Eastern hemisphere is unclear. This study reviews OPC epidemiology, including prevalence, etiological factors (such as smokeless tobacco and HPV), and their interaction. Among the SEAR countries, India had the highest incidence of HPV-related OPCs at 38.4%, while data were unavailable for most African countries, with only a 14% incidence reported. Conversely, the American region exhibited one of the highest HPV positivity rates, reaching up to 65% in different states of the USA, while Brazil reported an incidence of up to 38%. In the European Union, the UK had the highest incidence of HPV-associated OPC, reaching up to 52%. In the Western Pacific region, New Zealand demonstrated the highest incidence at up to 78%. Smokeless tobacco consumption was higher in SEAR countries, which had a relatively lower incidence of HPV infection, suggesting a negative correlation between the two. Based on our literature search, the most common detection methods used globally are immunohistochemistry for p16 and polymerized chain reaction. OPCs are a global health concern, and proper identification and classification are vital. HPV-driven cancers have better survival rates, emphasizing the need for focused research on specific problem areas based on the burden of HPV-positive or HPV-negative cancers.

Comparison of TTMV-HPV DNA to Gold Standard PET for Evaluation of Treatment Response in HPV-Associated Oropharyngeal Cancer after Definitive Treatment

Comparison of TTMV-HPV DNA to Gold Standard PET for Evaluation of Treatment Response in HPV-Associated Oropharyngeal Cancer after Definitive Treatment

Moving from conventional to adaptive risk stratification for oropharyngeal cancer.

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.