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.