Background: R/M HPVC (cervical, anal, oropharyngeal, etc.) are incurable by current therapies. For newly diagnosed LA HPV-OPSCC standard-of-care (SOC) is radiotherapy ± chemotherapy (C/RT) or surgery ± adjuvant C/RT, with considerable risk of relapse. Newly diagnosed LA SNSCC treatment follows the OPSCC paradigm, and detection of HPV appears to confer improved prognosis. Neoadjuvant PD-1 immune checkpoint blockade (ICB) before surgery may improve RFS and is being evaluated in a multicenter phase III clinical trial (Keynote-689). PRGN-2009 (P) is a novel gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of HPV 16 and 18 shown to induce HPV specific responses (preclinical models). Bintrafusp alfa (BA) is a bifunctional fusion protein targeting TGF-β and PD-L1 with promising activity in HPVC. This trial will evaluate the safety and activity of P/ P + BA in patients with previously treated R/M HPVC and as neoadjuvant/induction therapy before SOC surgery or C/RT in newly diagnosed LA HPV-OPSCC and HPV-SNSCC. Methods: This is a first-in-human, investigator-initiated, single-center phase I/II trial. Pts with previously treated (incl. ICB) R/M HPVC are eligible for Phase I: P dose escalation arm (3+3 design, 6-12 patients) testing 2 dose levels (1x10¹¹, 5x10¹¹ viral particle units, SC Q2W three times, then Q4W), and combination arm (10 patients) testing P (recommended phase 2 dose (RP2D), same schedule) + BA (1200 mg IV Q2W). Treatment (both arms) will continue until disease progression, unacceptable toxicity, decision to withdraw. Primary endpoint is safety. Secondary endpoints include ORR (RECIST 1.1), PFS, and OS. For Phase II, patients with newly diagnosed stage II/III (AJCC Cancer Staging Manual, 8th ed.) HPV-OPSCC and stage II/III/IVA/IVB HPV-SNSCC planned for SOC C/RT or surgery will be eligible for two treatment arms of 20+2 patients each (sequential): P arm and P + BA, to evaluate the treatment activity. All patients will have pre-treatment biopsy, receive two cycles of the study treatment at the NCI Clinical Center two weeks apart, followed by post-treatment biopsy and SOC treatment (at the referring institution) 4 weeks after the first study treatment. Primary endpoint is post-treatment ≥2-fold increase in tumor-infiltrating CD3+ cells. Secondary endpoints include RFS, OS. Exploratory endpoints for both arms include analyses of immune subsets, soluble factors, and HPV-specific immune responses in peripheral blood and tissue where available, and in Phase II sequencing (exome, scRNA), immune spatial profiling with multiplex immunofluorescence, and salivary HPV DNA. Clinical trial registry: NCT04432597. Clinical trial information: NCT04432597