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High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies.

Background VCN-01 is an oncolytic adenovirus with replication restricted to cells with a nonfunctional retinoblastoma pathway. Upon selective replication VCN-01 expresses the matrix remodeling-enzyme hyaluronidase to enhance virus spreading and tumor uptake of different therapeutics, including immune check-point inhibitors. In a phase I performed in pancreatic carcinoma VCN-01 reached tumors after systemic administration and induced CD8-infiltration, tumor inflammation and PD-1/PD-L1 up-regulation. We hypothesize these intratumor effects may help to overcome the observed resistance to Durvalumab and other PD-(L)-1 checkpoint inhibitors Trial Design NCT03799744 is a multi-center, open-label dose-escalation phase I study evaluating the safety, tolerability and efficacy of the combination of VCN-01 plus durvalumab in R/M HNSCC patients who have progressed on prior PD-(L)-1 checkpoint inhibitors. Patients need to have neutralizing antibodies levels against adenovirus ≤1/350 dilution to be included. The study follows a 3 + 3 design with two dose levels for VCN-01 (3,3.1012 & 1.1013 vp) combined with Durvalumab at a fixed dose of 1500mg intravenous (i.v.). Two treatment arms are explored: I) Concomitant single i.v. dose of VCN-01 with durvalumab on cycle 1 day 1 followed by durvalumab Q4W; II) Sequential single i.v. VCN-01 on cycle 1 day -14 plus durvalumab on cycle 1 day 1 followed by durvalumab Q4W. Patients continue durvalumab Q4W until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to evaluate the safety and tolerability of VCN-01 with durvalumab in the two regimens of administration and to establish the recommended phase II dose. Secondary objectives are progression free survival, overall response rate by irRECIST /RECIST, VCN-01 pharmacokinetics and shedding in blood. Other exploratory biomarkers will be analyzed in tumor biopsies (immune markers), serum (hyaluronidase levels), stool (microbiome) and imaging (dynamic contrast-enhanced MRI, diffusion weighted imaging and T2 mapping). The study opened recruitment in April 2019 with 7 out of 18 planned patients enrolled at time of submission. Clinical trial identification NCT03799744. Legal entity responsible for the study Catalan Institute of Oncology (ICO). Funding VCN Biosciences, AstraZeneca. Disclosure M. Jove: Advisory / Consultancy: Boehringer Ingelheim. I. Brana: Advisory / Consultancy, Research grant / Funding (self): Orion Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Janssen; Research grant / Funding (self): KURA; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Shattuck; Research grant / Funding (self): Northern Biologics; Research grant / Funding (self): Rakutan Aspirian; Research grant / Funding (self): Naobiotics. M. Taberna: Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Merck; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Nanobiotics. E. Garralda: Leadership role, Research grant / Funding (institution): Novartis; Leadership role: Principia Biopharma Inc; Leadership role: Lilly, S.A; Advisory / Consultancy, Leadership role: Roche / Genentech Inc; Leadership role: Loxo Oncology Inc; Advisory / Consultancy, Leadership role: F.Hoffmann La Roche Ltd; Leadership role: Symphogen A/S; Speaker Bureau / Expert testimony, Leadership role, Travel / Accommodation / Expenses: MSD; Leadership role: Incyte; Leadership role: Pharma Mar; Leadership role: Kura Oncology; Leadership role: Macrogenics; Leadership role, Travel / Accommodation / Expenses: Glycotope; Leadership role: Pierre Fabre; Leadership role: Cellestia Biotech; Leadership role, Travel / Accommodation / Expenses: Menarini Ricerche; Leadership role: Blueprint Medicines; Leadership role: Beigene; Leadership role: Sierra Oncology; Leadership role: Genmab; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services ; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: NeoMed Therapeutics; Advisory / Consultancy: SeaGen; Speaker Bureau / Expert testimony: ThermoFisher. G. Capella: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo Piqueras: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. All other authors have declared no conflicts of interest.

Background The etiologic role of human papillomavirus (HPV) in oropharyngeal cancer (OPC) is well established and it explains the increase of young patients (pts) affected with OPC. This is an observational study representing a real-world experience evaluating clinicopathologic features and prognosis in young ( Methods We conducted a retrospective cohort study of pts diagnosed with OPC in four Catalonian hospitals from 1991 to 2017. Data was collected from medical records. Unconditional logistic regression was used to compare age groups and Proportional hazards model (Cox regression) and Cumulative Incident Function (CIF) to analyze OPC-specific survival (OPC-sS) in locally advanced cases. Results A total of 865 pts were included, 49 in the young group (median age 42; range 28.5-45.0) and 816 in the old group (median age 61; range 45.1-93.9). There were no differences between age groups in terms of sex, anatomic subsite, toxic habits, HPV status (positivity defined as double p16/DNA positivity) or stage at diagnosis. There were more non-smokers HPV-related (HPV+) OPC pts than HPV-negative (HPV-) ones (p-value Conclusions HPV is the most important prognostic factor in OPC independent of age. Legal entity responsible for the study ICO (Catalan Institute of Oncology). Funding The Instituto de Salud Carlos III-ISCIII (Spanish Government) co funded by EDER funds/ European Regional Development Fund (ERDF) - a way to build Europe (References: PI1102096, PI1401918, PI1500500, PI1501205, RD12/0036/0056, CIBERESP, CIBERONC). Disclosure M. Nieva: Travel / Accommodation / Expenses: Takeda; Travel / Accommodation / Expenses: Merck. S. Tous: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Merck. M. Mena: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: AZ; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix. L. Alemany: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck. M. Taberna: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AZ; Advisory / Consultancy: Nanobiotics; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol Myers. All other authors have declared no conflicts of interest.